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  • Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice
    Neurochem. Int. (IF 3.603) Pub Date : 2018-12-07
    Fukie Yaoita, Masahiro Tsuchiya, Yuichiro Arai, Takeshi Tadano, Koichi Tan-No

    Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety-related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The percentage (%) of open arm time and total number of arm entries were increased in powdered diet-fed mice in the EPM test. We also examined the effects of diazepam, benzodiazepine anti-anxiety drug, bicuculline, GABA-A receptor antagonist, methylphenidate, dopamine transporter (DAT) and noradrenaline transporter (NAT) inhibitor, atomoxetine, selective NAT inhibitor, GBR12909, selective DAT inhibitor, and PD168077, selective dopamine D4 receptor agonist, on the changes of the EPM in powdered diet-fed mice. Methylphenidate and atomoxetine are clinically used to treat attention deficit/hyperactivity disorder (ADHD) symptoms. The % of open arm time in powdered diet-fed mice was decreased by treatments of atomoxetine, methylphenidate and PD168077. Diazepam increased the % of open arm time in control diet-fed mice, but not in powdered diet-fed mice. The powdered diet feeding induced a decrease in GABA transaminase, GABA metabolic enzymes, in the frontal cortex. Moreover, the powdered diet feeding induced an increase in NAT expression, but not DAT expression, in the frontal cortex. These results suggest that the long-term powdered diet feeding may cause low anxiety or impulsivity, possibly via noradrenergic and/or dopaminergic, and GABAAergic mediations and increase the risk for onset of ADHD-like behaviors.

  • Neuronal SNARE complex: A protein folding system with intricate protein-protein interactions, and its common neuropathological hallmark, SNAP25
    Neurochem. Int. (IF 3.603) Pub Date : 2018-12-02
    Srijeeb Karmakar, Laipubam Gayatri Sharma, Abhishek Roy, Anjali Patel, Lalit Mohan Pandey

    SNARE (Soluble NSF(N-ethylmaleimide-sensitive factor) Attachment Receptor) complex is a trimeric supramolecular organization of SNAP25, syntaxin, and VAMP which mediates fusion of synaptic vesicles with the presynaptic plasma membrane. The functioning of this entire protein assembly is dependent on its tetrahelical coiled coil structure alongside its interaction with a large spectrum of regulatory proteins like synaptotagmin, complexin, intersectin, etc. Defects arising in SNARE complex assembly due to mutations or faulty post-translational modifications are associated to severe synaptopathies like Schizophrenia and also proteopathies like Alzheimer's disease. The review primarily focuses on SNAP25, which is the prime contributor in the complex assembly. It is conceptualized that the network of protein interactions of this helical protein assists as a chaperoning system for attaining functional structure. Additionally, the innate disordered nature of SNAP25 and its amyloidogenic propensities have been highlighted employing computational methods. The intrinsic nature of SNAP25 is anticipated to form higher-order aggregates due to its cysteine rich domain, which is also a target for several post-translational modifications. Furthermore, the aberrations in the structure and expression profile of the protein display common patterns in the pathogenesis of a diverse synaptopathies and proteopathies. This work of SNARE literature aims to provide a new comprehensive outlook and research directions towards SNARE complex and presents SNAP25 as a common neuropathological hallmark which can be a diagnostic or therapeutic target.

  • Ukgansan protects dopaminergic neurons from 6-hydroxydopamine neurotoxicity via activation of the nuclear factor (erythroid-derived 2)-like 2 factor signaling pathway
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-30
    Hyeyoon Eo, Eugene Huh, Yeomoon Sim, Myung Sook Oh

    The sustenance of redox homeostasis in brain is the crucial factor to treat Parkinson's disease (PD). Nuclear factor (erythroid-derived 2)-like 2 factor (Nrf2)-mediated antioxidant response is well known for the main cellular endogenous defense mechanisms against oxidative stress. This study investigated for the first time the effects and possible mechanisms of action of Ukgansan on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in both in vitro and in vivo models of PD. We investigated the protective effect of Ukgansan against 6-OHDA with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. In addition, we demonstrated that Ukgansan significantly increased the expression of antioxidant response elements (ARE) and pro-survival protein as Bcl2 and suppressed the expression of pro-apoptotic factors, such as Bax, cytochrome c, and caspase-3 using immunoblotting. For the in vivo study, we used a mouse model of PD involving stereotaxic injection of 6-OHDA into the striatum (ST). Ukgansan alleviated motor dysfunctions induced by 6-OHDA followed by pole, open-field, and rotation tests. Dopaminergic neuronal loss and Nrf2 activation were evaluated by immunohistochemistry in the mouse ST and substantia nigra pars compacta (SNpc) regions. Ukgansan significantly protected dopaminergic neurons from 6-OHDA toxicity in mouse ST and SNpc by activating Nrf2. These results indicate that Ukgansan inhibited 6-OHDA-induced dopaminergic neuronal cell damage via activation of Nrf2 and its related factors in 6-OHDA-induced dopaminergic loss in vitro and in vivo. Thus, Ukgansan might delay the progression of PD via maintenance of redox homeostasis.

  • Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins
    Neurochem. Int. (IF 3.603) Pub Date : 2018-12-01
    Nira de la Vega Gallardo, Marie Dittmer, Yvonne Dombrowski, Denise C. Fitzgerald

    Efficient myelin regeneration in the central nervous system (CNS) requires the migration, proliferation and differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes. In demyelinating diseases such as multiple sclerosis (MS), this regenerative process can fail, and therapies targeting myelin repair are currently completely lacking in the clinic. The immune system is emerging as a key regenerative player in many tissues, such as muscle and heart. We recently reported that regulatory T cells (Treg) are required for efficient CNS remyelination. Furthermore, Treg secrete CCN3, a matricellular protein from the CCN family, implicated in regeneration of other tissues. Treg-derived CCN3 promoted oligodendrocyte differentiation and myelination. In contrast, previous studies showed that CCN2 inhibited myelination. These studies highlight the need for further scrutiny of the roles that CCN proteins play in myelin development and regeneration. Collectively, these findings open up exciting avenues of research to uncover the regenerative potential of the adaptive immune system.

  • Individualized B cell-targeting therapy for neuromyelitis optica spectrum disorder
    Neurochem. Int. (IF 3.603) Pub Date : 2018-12-01
    Su-Hyun Kim, Jae-Won Hyun, Ho Jin Kim

    Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system characterized by severe attacks of optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), and area postrema syndrome. The majority of patients with NMOSD are seropositive for autoantibodies against the astrocyte water channel aquaporin-4 (AQP4). As convergent clinical and laboratory-based investigations have indicated that B cells play a fundamental role in NMO immunopathology, B cells have become an attractive therapeutic target. Rituximab is a therapeutic monoclonal antibody against CD20 expressed on B cells and increasingly used for the treatment of NMOSD. Although there is robust evidence for the efficacy and safety of rituximab in NMOSD, considerable variability has been noted in biological and clinical responses in patients. Therefore, the focus now is on understanding the mechanisms underlying the variability in response to rituximab and optimizing the use of rituximab for NMOSD. Identification of biomarkers for prediction of clinical response, and effective dosing and timing of treatment may provide useful tools for patient-tailored treatment in NMOSD. Herein, we review current evidence on factors that affect biological and clinical responses to rituximab and highlight the importance of individualized therapies for NMOSD.

  • Eomes-expressing T-helper cells as potential target of therapy in chronic neuroinflammation
    Neurochem. Int. (IF 3.603) Pub Date : 2018-12-01
    Shinji Oki

    Reserch progresses in understanding the pathogenicity of multiple sclerosis (MS) in the last couple of decade has enabled us to develop new drug entities available in the clinic. However, we still have not succeeded in preventing conversion from relapsing-remitting MS (RR-MS) to secondary progressive MS (SP-MS) and curing this intractable form of MS. Furthermore, diagnosis is usually retrospective and subjective, relying on gradual worsening of neurological signs/symptoms. This is obviously due to the lack of understanding for the pathogenicity driving disease progression in MS and of reliable biomarkers reflecting the progressive or stationary disease status. Two relevant components are involved in brain pathology of SP-MS, neurodegeneration and inflammation. Neurodegeneration may occur spontaneously in a neuron-intrinsic manner under chronic inflammation, such as glutamate excitotoxicity, mitochondrial/oxidative injury with iron deposit in the brain, and loss of trophic support. Meanwhile, inflammation is usually associated with recurrent relapse and the cumulative infiltration of immune cells, including T cells, B cells, and myeloid cells of peripheral or CNS origin, could ignite the processes of neurodegeneration. Especially, the higher frequency of leptomeningeal follicle-like structures observed in SP-MS patients suggests that immune cells sheltered behind a blood-brain barrier is still active under smoldering CNS inflammation. Recent successes in Ocrelizumab for primary progressive in MS (PP-MS) and Siponimod for SP-MS reappraised the importance of immune cells for pathogenesis progressive MS. Accordingly, our recent comparative analysis between MS and its animal model, experimental autoimmune encephalomyelitis (EAE), raises a new possibility that ectopic expression of eomesodermin (Eomes) in helper T (Th) cells constitutes a previously unappreciated subset of Th cells with cytotoxic potential against neuronal cells. In this review article, I will summarize the mechanisms proposed on pathogenesis of SP-MS and propose a new pathogenic mechanism for neurodegeneration mediated by unique cytotoxic Th cells.

  • A role for KCC3 in maintaining cell volume of peripheral nerve fibers
    Neurochem. Int. (IF 3.603) Pub Date : 2018-01-31
    Bianca Flores, Cara C. Schornak, Eric Delpire

    The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the peripheral and central nervous system. KCC3 is responsible for the efflux of K+ and Cl− in neurons to help maintain cell volume and intracellular chloride levels. A loss-of-function (LOF) of KCC3 causes Hereditary Motor Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) in a population of individuals in the Charlevoix/Lac-Saint-Jean region of Quebec, Canada. A variety of mouse models have been created to understand the physiological and deleterious effects of a KCC3 LOF. Though this KCC3 LOF in mouse models has recapitulated the peripheral neuropathy phenotype of HMSN/ACC, we still know little about the development of the disease pathophysiology. Interestingly, the most recent KCC3 mouse model that we created recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 gain-of-function (GOF). Despite the past two decades of research in attempting to understand the role of KCC3 in disease, we still do not understand how dysfunction of this cotransporter can lead to the pathophysiology of peripheral neuropathy. This review focuses on the function of KCC3 in neurons and its role in human and health and disease.

  • Axon-terminals expressing EAAT2 (GLT-1; Slc1a2) are common in the forebrain and not limited to the hippocampus
    Neurochem. Int. (IF 3.603) Pub Date : 2018-03-09
    Yun Zhou, Bjørnar Hassel, Tore Eid, Niels Christian Danbolt

    The excitatory amino acid transporter type 2 (EAAT2) represents the major mechanism for removal of extracellular glutamate. In the hippocampus, there is some EAAT2 in axon-terminals, whereas most of the protein is found in astroglia. The functional importance of the neuronal EAAT2 is unknown, and it is debated whether EAAT2-expressing nerve terminals are present in other parts of the brain. Here we selectively deleted the EAAT2 gene in neurons (by crossing EAAT2-flox mice with synapsin 1-Cre mice in the C57B6 background). To reduce interference from astroglial EAAT2, we measured glutamate accumulation in crude tissue homogenates. EAAT2 proteins levels were measured by immunoblotting. Although synapsin 1-Cre mediated gene deletion only reduced the forebrain tissue content of EAAT2 protein to 95.5 ± 3.4% of wild-type (littermate) controls, the glutamate accumulation in homogenates of neocortex, hippocampus, striatum and thalamus were nevertheless diminished to, respectively, 54 ± 4, 46 ± 3, 46 ± 2 and 65 ± 7% of controls (average ± SEM, n = 3 pairs of littermates). GABA uptake was unaffected. After injection of U-13C-glucose, lack of neuronal EAAT2 resulted in higher 13C-labeling of glutamine and GABA in the hippocampus suggesting that neuronal EAAT2 is partly short-circuiting the glutamate-glutamine cycle in wild-type mice. Crossing synapsin 1-Cre mice with Ai9 reporter mice revealed that Cre-mediated excision occurred efficiently in hippocampus CA3, but less efficiently in other regions and hardly at all in the cerebellum. Conclusions: (1) EAAT2 is expressed in nerve terminals in multiple brain regions. (2) The uptake catalyzed by neuronal EAAT2 plays a role in glutamate metabolism, at least in the hippocampus. (3) Synapsin 1-Cre does not delete floxed genes in all neurons, and the contribution of neuronal EAAT2 is therefore likely to be larger than revealed in the present study.

  • Activity dependent internalization of the glutamate transporter GLT-1 requires calcium entry through the NCX sodium/calcium exchanger
    Neurochem. Int. (IF 3.603) Pub Date : 2018-03-21
    Ignacio Ibáñez, David Bartolomé-Martín, Dolores Piniella, Cecilio Giménez, Francisco Zafra

    GLT-1 is the main glutamate transporter in the brain and its trafficking controls its availability at the cell surface, thereby shaping glutamatergic neurotransmission under physiological and pathological conditions. Extracellular glutamate is known to trigger ubiquitin-dependent GLT-1 internalization from the surface of the cell to the intracellular compartment, yet here we show that internalization also requires the participation of calcium ions. Consistent with previous studies, the addition of glutamate (1 mM) to mixed primary cultures (containing neurons and astrocytes) promotes GLT-1 internalization, an effect that was suppressed in the absence of extracellular Ca2+. The pathways of Ca2+ mobilization by astrocytes were analyzed in these mixed cultures using the genetically encoded calcium sensor GCaMP6f. A complex pattern of calcium entry was activated by glutamate, with a dramatic and rapid rise in the intracellular Ca2+ concentration partially driven by glutamate transporters, especially in the initial stages after exposure to glutamate. The Na+/Ca2+ exchanger (NCX) plays a dominant role in this Ca2+ mobilization and its blockade suppresses the glutamate induced internalization of GLT-1, both in astrocytes and in a more straightforward experimental system like HEK293 cells transiently transfected with GLT-1. This regulatory mechanism might be relevant to control the amount of GLT-1 transporter at the cell surface in conditions like ischemia or traumatic brain injury, where extracellular concentrations of glutamate are persistently elevated and they promote rapid Ca2+ mobilization.

  • Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1
    Neurochem. Int. (IF 3.603) Pub Date : 2018-04-27
    Robert B. Laprairie, Geraldine T. Petr, Yan Sun, Kathryn D. Fischer, Eileen M. Denovan-Wright, Paul A. Rosenberg

    GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5–10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD. If true, then some of the gene expression changes observed in HD might also be observed in the neuronal GLT-1 knockout. In situ hybridization using 33P labeled oligonucleotide probes was carried out to assess localization and expression of a panel of genes known to be altered in expression in HD. We found changes in the expression of cannabinoid receptors 1 and 2, preproenkaphalin, and PDE10A in the striatum of mice in which the GLT-1 gene was inactivated in neurons by expression of synapsin-Cre, compared to wild-type littermates. These changes in expression were observed at 12 weeks of age but not at 6 weeks of age. No changes in DARPP-32, PDE1B, NGFIA, or β-actin expression were observed. In addition, we found widespread alteration in expression of the dynamin 1 gene. The changes in expression in the neuronal GLT-1 knockout of genes thought to exemplify HD transcriptional dysregulation suggest an overlap in the synaptopathy caused by neuronal GLT-1 deletion and HD. These data further suggest that specific changes in expression of cannabinoid receptors, preproenkephalin, and PDE10A, considered to be the hallmark of HD transcriptional dysregulation, may be produced by an abnormality of glutamate homeostasis under the regulation of neuronal GLT-1, or a synaptic disturbance caused by that abnormality, independently of mutation in huntingtin.

  • Blockade and reversal of swimming-induced paralysis in C. elegans by the antipsychotic and D2-type dopamine receptor antagonist azaperone
    Neurochem. Int. (IF 3.603) Pub Date : 2018-05-22
    Osama Refai, Randy D. Blakely

    The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans are associated with multiple neurodegenerative and behavioral disorders, including Parkinson's disease, attention-deficit/hyperactivity disorder, addiction and schizophrenia. In the nematode C. elegans, DA signaling regulates mating behavior, learning, food seeking and locomotion. Previously, we demonstrated that loss of function mutations in the dat-1 gene that encodes the presynaptic DA transporter (DAT-1) results in a rapid cessation of movement when animals are placed in water, termed Swimming Induced Paralysis (Swip). Loss of function mutations in genes that support DA biosynthesis, DA vesicular packaging and DA action at the extrasynaptic D2-type DA receptor DOP-3 suppress Swip in dat-1 animals, consistent with paralysis as arising from excessive DA signaling. Although animals grown on the vesicular monoamine transporter antagonist reserpine diminish Swip, the drug must be applied chronically, can impact the signaling of multiple biogenic amines, and has been reported to have penetrant, off-target actions. Here, we demonstrate that the antipsychotic drug azaperone potently and rapidly suppresses Swip behavior in either dat-1 mutants, as well as in wildtype animals treated with the DAT-1 antagonist nisoxetine, with genetic experiments consistent with DOP-3 antagonism as the mechanism of Swip suppression. Reversal of Swip in previously paralyzed dat-1 animals by azaperone application demonstrates an otherwise functionally-intact swimming circuit in these mutants. Finally, whereas azaperone suppresses DA-dependent Swip, the drug fails to attenuate the DA-independent paralysis induced by βPEA, aldicarb or genetic disruption of γ-aminobutyric acid (GABA) signaling. We discuss our findings with respect to the use of azaperone as a potent and selective tool in the identification and analysis of presynaptic mechanisms that regulate DA signaling.

  • Hyperekplexia-associated mutations in the neuronal glycine transporter 2
    Neurochem. Int. (IF 3.603) Pub Date : 2018-05-30
    Beatriz López-Corcuera, Esther Arribas-González, Carmen Aragón

    Hyperekplexia or startle disease is a dysfunction of inhibitory glycinergic neurotransmission characterized by an exaggerated startle in response to trivial tactile or acoustic stimuli. Although rare, this disorder can have serious consequences, including sudden infant death. One of the most frequent causes of hyperekplexia are mutations in the SLC6A5 gene, encoding the neuronal glycine transporter 2 (GlyT2), a key component of inhibitory glycinergic presynapses involved in synaptic glycine recycling though sodium and chloride-dependent co-transport. Most GlyT2 mutations detected so far are recessive, but two dominant missense mutations have been described. The detailed analysis of these mutations has revealed structural cues on the quaternary structure of GlyT2, and opens the possibility that novel selective pharmacochaperones have potential therapeutic effects in hyperekplexia.

  • The neurotoxin diethyl dithiophosphate impairs glutamate transport in cultured Bergmann glia cells
    Neurochem. Int. (IF 3.603) Pub Date : 2018-06-13
    Tatiana N. Olivares-Bañuelos, Isabel Martínez-Hernández, Luisa C. Hernández-Kelly, Donají Chi-Castañeda, Libia Vega, Arturo Ortega

    Glutamate, the main excitatory neurotransmitter in the vertebrate Central Nervous System, is involved in almost every aspect of brain physiology, and its signaling properties are severely affected in most neurodegenerative diseases. This neurotransmitter has to be efficiently removed from the synaptic cleft in order to prevent an over-stimulation of glutamate receptors that leads to neuronal death. Specific sodium-dependent membrane transporters, highly enriched in glial cells, elicit the clearance of glutamate. Once internalized, it is metabolized to glutamine by the glia-enriched enzyme Glutamine synthetase. Accumulated glutamine is released into the extracellular space for its uptake into pre-synaptic neurons and its conversion to glutamate that is packed into synaptic vesicles completing the glutamate/glutamine cycle. Diverse chemical compounds, like organophosphates, directly affect brain chemistry by altering levels of neurotransmitters in the synaptic cleft. Organophosphate compounds are widely used as pesticides, and all living organisms are continuously exposed to these substances, either in a direct or indirect manner. Its metabolites, like the diethyl dithiophosphate, are capable of causing brain damage through diverse mechanisms including perturbation of neuronal-glial cell interactions and have been associated with attention-deficit disorders and other mental illness.In order to characterize the neurotoxic mechanisms of diethyl dithiophosphate, we took advantage of the well characterized model of chick cerebellar Bergmann glia cultures. A significant impairment of [3H] d-Aspartate transport was found upon exposure to the metabolite. These results indicate that glia cells are targets of neurotoxic substances such as pesticides and that these cells might be critically involved in the associated neuronal death.

  • Voltammetric evidence for discrete serotonin circuits, linked to specific reuptake domains, in the mouse medial prefrontal cortex
    Neurochem. Int. (IF 3.603) Pub Date : 2018-07-19
    A. West, J. Best, A. Abdalla, F. Nijhout, M. Reed, P. Hashemi

    The medial prefrontal cortex (mPFC) is an important brain region, that controls a variety of behavioral and functional outputs. As an important step in characterizing mPFC functionality, in this paper we focus on chemically defining serotonin transmission in this area. We apply cutting-edge analytical methods, fast-scan cyclic voltammetry (FSCV) and fast-scan controlled adsorption cyclic voltammetry (FSCAV), pioneered in our laboratory, for the first real-time in vivo analysis of serotonin in the mPFC. In prior in vivo work in the substantia nigra, pars reticulata, we found that our sub-second measurements of a single evoked serotonin release were subject to two clearance mechanisms. These mechanisms were readily modeled via Uptake 1, mediated by the serotonin transporters (SERTs), and Uptake 2, mediated by monoamine transporters (dopamine transporters (DATs), norepinephrine transporters (NETs), and organic cation transporters (OCTs)). Here in the mPFC, for the first time to our knowledge, we observe two release events in response to a single stimulation of the medial forebrain bundle (MFB). Of particular note is that each response is tied to a discrete reuptake profile comprising both Uptake 1 and 2. We hypothesize that two distinct populations of serotonin axons traverse the MFB and terminate in different domains with specific reuptake profiles. We test and confirm this hypothesis using a multifaceted pharmacological, histological and mathematical approach. We thus present evidence for a highly elaborate biochemical organization that regulates serotonin chemistry in the mPFC. This knowledge provides a solid foundation on which to base future studies of the involvement of the mPFC in brain function and behavior.

  • Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration
    Neurochem. Int. (IF 3.603) Pub Date : 2018-07-24
    Yun Zhou, Roni Dhaher, Maxime Parent, Qiu-Xiang Hu, Bjørnar Hassel, Siu-Pok Yee, Fahmeed Hyder, Shaun E. Gruenbaum, Tore Eid, Niels Christian Danbolt

    Glutamate-ammonia ligase (glutamine synthetase; Glul) is enriched in astrocytes and serves as the primary enzyme for ammonia detoxification and glutamate inactivation in the brain. Loss of astroglial Glul is reported in hippocampi of epileptic patients, but the mechanism by which Glul deficiency might cause disease remains elusive. Here we created a novel mouse model by selectively deleting Glul in the hippocampus and neocortex. The Glul deficient mice were born without any apparent malformations and behaved unremarkably until postnatal week three. There were reductions in tissue levels of aspartate, glutamate, glutamine and GABA and in mRNA encoding glutamate receptor subunits GRIA1 and GRIN2A as well as in the glutamate transporter proteins EAAT1 and EAAT2. Adult Glul-deficient mice developed progressive neurodegeneration and spontaneous seizures which increased in frequency with age. Importantly, progressive astrogliosis occurred before neurodegeneration and was first noted in astrocytes along cerebral blood vessels. The responses to CO2-provocation were attenuated at four weeks of age and dilated microvessels were observed histologically in sclerotic areas of cKO. Thus, the abnormal glutamate metabolism observed in this model appeared to cause epilepsy by first inducing gliopathy and disrupting the neurovascular coupling.

  • Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior
    Neurochem. Int. (IF 3.603) Pub Date : 2018-07-25
    Paul J. Gasser

    Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake1 transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake2 transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake1 and Uptake2 transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.

  • Identification of the benztropine analog [125I]GA II 34 binding site on the human dopamine transporter
    Neurochem. Int. (IF 3.603) Pub Date : 2018-08-17
    Michael J. Tomlinson, Danielle Krout, Akula Bala Pramod, John R. Lever, Amy Hauck Newman, L. Keith Henry, Roxanne A. Vaughan

    The dopamine transporter (DAT) is a neuronal membrane protein that is responsible for reuptake of dopamine (DA) from the synapse and functions as a major determinant in control of DA neurotransmission. Cocaine and many psychostimulant drugs bind to DAT and block reuptake, inducing DA overflow that forms the neurochemical basis for euphoria and addiction. Paradoxically, however, some ligands such as benztropine (BZT) bind to DAT and inhibit reuptake but do not produce these effects, and it has been hypothesized that differential mechanisms of binding may stabilize specific transporter conformations that affect downstream neurochemical or behavioral outcomes. To investigate the binding mechanisms of BZT on DAT we used the photoaffinity BZT analog [125I]N-[n-butyl-4-(4‴-azido-3‴-iodophenyl)]-4′,4″-difluoro-3α-(diphenylmethoxy)tropane ([125I]GA II 34) to identify the site of cross-linking and predict the binding pose relative to that of previously-examined cocaine photoaffinity analogs. Biochemical findings show that adduction of [125I]GA II 34 occurs at residues Asp79 or Leu80 in TM1, with molecular modeling supporting adduction to Leu80 and a pharmacophore pose in the central S1 site similar to that of cocaine and cocaine analogs. Substituted cysteine accessibility method protection analyses verified these findings, but identified some differences in structural stabilization relative to cocaine that may relate to BZT neurochemical outcomes.

  • Dopamine D1 receptor activation improves adult hippocampal neurogenesis and exerts anxiolytic and antidepressant-like effect via activation of Wnt/β-catenin pathways in rat model of Parkinson's disease
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-28
    Akanksha Mishra, Sonu Singh, Virendra Tiwari, Parul, Shubha Shukla

    Parkinson's disease (PD) is primarily characterized by midbrain dopamine depletion. Dopamine acts through dopamine receptors (D1 to D5) to regulate locomotion, motivation, pleasure, attention, cognitive functions and formation of newborn neurons, all of which are likely to be impaired in PD. Reduced hippocampal neurogenesis associated with dopamine depletion has been demonstrated in patients with PD. However, the precise mechanism to regulate multiple steps of adult hippocampal neurogenesis by dopamine receptor(s) is still unknown. In this study, we tested whether pharmacological agonism and antagonism of dopamine D1 and D2 receptor regulate nonmotor symptoms, neural stem cell (NSC) proliferation and fate specification and explored the cellular mechanism(s) underlying dopamine receptor (D1 and D2)- mediated adult hippocampal neurogenesis in rat model of PD-like phenotypes. We found that single unilateral intra-medial forebrain bundle administration of 6-hydroxydopamine (6-OHDA) reduced D1 receptor level in the hippocampus. Pharmacological agonism of D1 receptor exerts anxiolytic and antidepressant-like effects as well as enhanced NSC proliferation, long-term survival and neuronal differentiation by positively regulating Wnt/β-catenin signaling pathway in hippocampus in PD rats. shRNA lentivirus mediated knockdown of Axin-2, a negative regulator of Wnt/β-catenin signaling potentially attenuated D1 receptor antagonist induced anxiety and depression-like phenotypes and impairment in adult hippocampal neurogenesis in PD rats. Our results suggest that improved nonmotor symptoms and hippocampal neurogenesis in PD rats controlled by D1-like receptors that involve the activation of Wnt/β-catenin signaling.

  • Sexual dimorphism in inflammasome-containing extracellular vesicles and the regulation of innate immunity in the brain of reproductive senescent females
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-27
    Ami P. Raval, Camila C. Martinez, Nancy H. Mejias, Juan Pablo de Rivero Vaccari

    A woman's risk for stroke increases exponentially following the onset of menopause; however, the underlying mechanisms responsible for the increased risk remain unknown. The depletion of endogenous estrogen at menopause is known to activate the inflammatory response. Therefore, in this study we have used reproductively senescent (RS) rats to test the hypotheses that (1) inflammasome activation is significantly higher in the brain of RS females (RSF) as compared to their younger counterparts and age-matched senescent male rats, and that (2) RS triggers an innate immune response mediated in part by inflammasome-containing extracellular vesicles (EV) that originate in the female reproductive organs and then spreads to the brain. We tested these hypotheses using male and female Sprague–Dawley rats (Young: 6–7 months and RS: 9–13 months). Hippocampus, gonads and serum were collected. Additionally, cerebrospinal fluid (CSF) of pre- and post-menopausal women (ages 23 to 37 and 52 to 68) was purchased and extracellular vesicles (EV) were isolated from serum and CSF. The Inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and IL-1β were then resolved by immunoblotting. We found that inflammasome protein expression increased significantly in the analyzed tissues in RSF as compared to young females (YF), such difference was not present in age-matched male rat brains. Interestingly, we found that Nik-related kinase (NRK), which is present in female reproductive organs was present in the CSF and serum-derived EV, suggesting that the source of the EV seen in the brain during RS/menopause originate, in part, in the female reproductive organs. Thus, this study shows for the first time an involvement of the inflammasome originating in the female reproductive system as a contributor to inflammation in the brain that makes the peri-menopausal women's brain more susceptible to neurodegenerative diseases such as stroke.

  • Protective potentials of far-infrared ray against neuropsychotoxic conditions
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-28
    Naveen Sharma, Eun-Joo Shin, Nam Hun Kim, Eun-Hee Cho, Ji Hoon Jeong, Choon Gon Jang, Seung-Yeol Nah, Toshitaka Nabeshima, Yukio Yoneda, Jean Lud Cadet, Hyoung-Chun Kim

    Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the underlying mechanism conveyed by FIR remains unclear. Recently, we demonstrated that exposure to FIR induces antioxidant potentials via up-regulation of glutathione peroxidase (GPx)-1 gene. The antioxidant potentials might be important for the modulation on the neuropsychotoxic conditions. Exposure to FIR protects from methamphetamine (MA)-induced memory impairments via phosphorylation of ERK 1/2 signaling by positive modulation of protein kinase C δ (PKCδ), M1 muscarinic acetylcholine receptor (M1 mAChR), and nuclear factor E2-related factor 2 (Nrf2) transcription factor. In addition, exposure to FIR positively modulates MA-induced behavioral sensitization via attenuating mitochondrial dysfunction by down-regulation of dopamine D1 receptor. In this mini-review, we have discussed with the protective potentials mediated by FIR against MA-induced psychotoxic burdens.

  • Sex differences in risk factors for vascular contributions to cognitive impairment & dementia
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-22
    O.J. Gannon, L.S. Robison, A.J. Custozzo, K.L. Zuloaga

    Vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia. While males overall appear to be at a slightly higher risk for VCID throughout most of the lifespan (up to age 85), some risk factors for VCID more adversely affect women. These include female-specific risk factors associated with pregnancy related disorders (e.g. preeclampsia), menopause, and poorly timed hormone replacement. Further, presence of certain co-morbid risk factors, such as diabetes, obesity and hypertension, also may more adversely affect women than men. In contrast, some risk factors more greatly affect men, such as hyperlipidemia, myocardial infarction, and heart disease. Further, stroke, one of the leading risk factors for VCID, has a higher incidence in men than in women throughout much of the lifespan, though this trend is reversed at advanced ages. This review will highlight the need to take biological sex and common co-morbidities for VCID into account in both preclinical and clinical research. Given that there are currently no treatments available for VCID, it is critical that we understand how to mitigate risk factors for this devastating disease in both sexes.

  • Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-22
    Nandan K. Mondal, Jyotirmaya Behera, Kimberly E. Kelly, Akash K. George, Pranav K. Tyagi, Neetu Tyagi

    The objectives of this study are to identify the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion (I/R) injury and the therapeutic potential of tetrahydrocurcumin (THC) to mitigate mitochondrial dysfunction in experimental stroke model. In our study, 8–10 weeks old male C57BL/6 wild-type mice were subjected to middle cerebral artery occlusion (MCAO) for 40 min, followed by reperfusion for 72 h. THC (25mg/kg-BW/day) was injected intraperitoneally once daily for 3 days after 4 h of ischemia. The experimental groups were: (i) sham, (ii) I/R and (iii) I/R + THC. We noticed that THC treatment in ischemic mice significantly improved the functional capacity and motor co-ordination along with reduced neuroscore, infarct volume, brain edema and microvascular leakage in brain parenchyma. The study revealed that level of total homocysteine (tHcy), homocysteine metabolizing enzymes, mitochondrial oxidative stress were significantly altered in I/R mice compared to sham. We also observed alteration in mitochondrial transition pore, ATP production and O2 consumption in the ischemic brain as compared to sham. Further, elevated matrix metalloproteinases-9 (MMP-9) activity and reduced tight junction protein expressions intensified the brain vascular impairment in I/R mice compared to sham. Interestingly, we found that levels of mitophagy markers, fusion and fission proteins were significantly altered. However THC treatment in I/R mice almost normalized the above functional and molecular changes. Mechanistic study demonstrated that DNA Methyltransferase 1 (DNMT1) expression was higher and was associated with reduced mitochondrial tissue inhibitor of metalloproteinases 2 (TIMP-2) expression through hyper-methylation of CpG island of TIMP-2 promoter in I/R mice compared to sham. However, administration of epigenetic inhibitor, 5-Azacytidine (5-Aza) abrogated I/R induced hyper-methylation of TIMP-2 promoter and maintaining the extracellular matrix (ECM) integrity. In conclusion, this study suggests that THC epigenetically ameliorates mitochondrial dysfunction in brain vasculature during Ischemic Stroke.

  • Single dose of 17β-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-22
    N. Quillinan, A.L. Dingman, G. Deng, S. Tatum, J.E. Orfila, A.C. Clevenger, J. Klawitter, R.J. Traystman, P.S. Herson

    Each year there are approximately 7000 out of hospital cardiac arrests in the pediatric population, with 30% resuscitation rate and a 6–10% rate of survival to hospital discharge. Survivors of cardiac arrest exhibit learning and memory deficits that are devastating during the school years. Delayed neuronal cell death occurs in the hippocampus following cardiac arrest and likely contributes to memory impairments. Circulating endogenous estrogen in young adult females has been shown to provide protection against ischemic cell death, as does chronic exogenous administration of 17β-estradiol (E2). Chronic estrogen benefit can have undesirable feminizing effects, particularly in pre-adolescents. Here, we tested if a single-dose of E2 is neuroprotective in our pediatric cardiac arrest mouse model performed in juvenile mice. We subjected P21P25 C57Blk6 male and female mice to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). This developmental stage preceded the hormonal onset and serum estradiol and testosterone levels were not different. A single dose of E2 (100μg/kg) or vehicle was administered 30 min after resuscitation. Neuronal cell death measured 3 days after CA/CPR showed reduced hippocampal cell death in E2-treated females, but not males. Benefit of E2 in females was blocked by the P38 MAPK inhibitor, SB203580. Hippocampal-dependent memory function was equally impaired in E2-and vehicle-treated females measured in the contextual fear conditioning task at 7 days. Our findings demonstrate female-specific transient neuroprotection with E2 that does not provide sustained functional benefit.

  • Presynaptic regulation of dopamine release: Role of the DAT and VMAT2 transporters
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-19
    Kevin G. Mulvihill

    The signaling dynamics of the neurotransmitter dopamine has been established to have an important role in a variety of behavioural processes including motor control, cognition, and emotional processing. Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. This review provides an overview of how these transporter proteins are involved in molecular regulation and function together to govern the dynamics of vesicular release with opposing effects on the quantal size and extracellular concentration of dopamine. These transporter proteins are both focal points of convergence for a variety of regulatory molecular cascades as well as targets for many pharmacological agents. The ratio between these transporters is argued to be useful as a molecular marker for delineating dopamine functional subsystems that may differ in transmitter release patterns.

  • Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-15
    Yongli Chang, Chengxue Du, Lingna Han, Shuxuan Lv, Jin Zhang, Guanyun Bian, Guoyi Tang, Yiwei Liu, Tao Chen, Jian Liu

    The GABAergic rostromedial tegmental nucleus (RMTg) has reciprocal connections with the dopaminergic ventral tegmental area and substantia nigra pars compacta (SNc), and is involved in inhibitory control of monoaminergic nuclei. At present, it is not clear whether unilateral 6-hydroxydopamine lesions of the SNc in rats affect AMPA receptor-mediated excitatory transmission in the RMTg. Here we found that lesions of the SNc in rats increased the firing rate of GABAergic neurons and the level of glutamate in the RMTg compared to sham-operated rats. Intra-RMTg injection of AMPA receptor agonist (S)-AMPA increased the firing rate of the GABAergic neurons in both sham-operated and the lesioned rats, while AMPA receptor antagonist NBQX decreased the firing rate of the neurons. Further, intra-RMTg injection of (S)-AMPA decreased the levels of dopamine and serotonin in the medial prefrontal cortex (mPFC) in the two groups of rats; conversely, NBQX increased the levels of dopamine and serotonin. Compared to sham-operated rats, the duration of (S)-AMPA and NBQX action on the firing rate of GABAergic neurons in the RMTg and release of doapmine and serotonin in the mPFC was prolonged in the lesioned rats. In addition, lesions of the SNc in rats increased protein expression of t-GluR1 and p-GluR1-S831 subunits compared to sham-operated rats. Therefore, these changes in the lesioned rats are associated with increased release of glutamate and up-regulated expression of GluR1 subunit-containing AMPA receptors in the RMTg, which suggest that degeneration of the nigrostriatal pathway enhances AMPA receptor-mediated excitatory transmission in the RMTg.

  • Impact of C57BL/6 substrain on sex-dependent differences in mouse stroke models
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-15
    Thaddeus S. Nowak, Megan K. Mulligan

    We have recently found significant variation in stroke vulnerability among substrains of C57BL/6 mice, observing that commonly used N-lineage substrains exhibit larger infarcts than C57BL/6J and related substrains. Parallel variation was also seen with respect to sex differences in stroke vulnerability, in that C57BL/6 mice of the N-lineage exhibited comparable infarct sizes in males and females, whereas infarcts tended to be smaller in females than in males of J-lineage substrains. This adds to the growing list of recognized phenotypic and genetic differences among C57BL/6 substrains. Although no previous studies have explicitly compared substrains with respect to sex differences in stroke vulnerability, unrecognized background mismatch has occurred in some studies involving control and genetically modified mice. The aims of this review are to: present the evidence for associated substrain- and sex-dependent differences in a mouse permanent occlusion stroke model; examine the extent to which the published literature in other models compares with these recent results; and consider the potential impact of unrecognized heterogeneity in substrain background on the interpretation of studies investigating the impact of genetic modifications on sex differences in stroke outcome. Substrain emerges as a critical variable to be documented in any experimental stroke study in mice.

  • Intracellular emetic signaling cascades by which the selective neurokinin type 1 receptor (NK1R) agonist GR73632 evokes vomiting in the least shrew (Cryptotis parva)
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-16
    W. Zhong, S. Chebolu, N.A. Darmani

    To characterize mechanisms involved in neurokinin type 1 receptor (NK1R)-mediated emesis, we investigated the brainstem emetic signaling pathways following treating least shrews with the selective NK1R agonist GR73632. In addition to episodes of vomiting over a 30-min observation period, a significant increase in substance P-immunoreactivity in the emetic brainstem dorsal motor nucleus of the vagus (DMNX) occurred at 15 min post an intraperitoneal (i.p.) injection GR73632 (5 mg/kg). In addition, time-dependent upregulation of phosphorylation of several emesis -associated protein kinases occurred in the brainstem. In fact, Western blots demonstrated significant phosphorylations of Ca2+/calmodulin kinase IIα (CaMKIIα), extracellular signal-regulated protein kinase1/2 (ERK1/2), protein kinase B (Akt) as well as α and βII isoforms of protein kinase C (PKCα/βII). Moreover, enhanced phospho-ERK1/2 immunoreactivity was also observed in both brainstem slices containing the dorsal vagal complex emetic nuclei as well as in jejunal sections from the shrew small intestine. Furthermore, our behavioral findings demonstrated that the following agents suppressed vomiting evoked by GR73632 in a dose-dependent manner: i) the NK1R antagonist netupitant (i.p.); ii) the L-type Ca2+ channel (LTCC) antagonist nifedipine (subcutaneous, s.c.); iii) the inositol trisphosphate receptor (IP3R) antagonist 2-APB (i.p.); iv) store-operated Ca2+ entry inhibitors YM-58483 and MRS-1845, (i.p.); v) the ERK1/2 pathway inhibitor U0126 (i.p.); vi) the PKC inhibitor GF109203X (i.p.); and vii) the inhibitor of phosphatidylinositol 3-kinase (PI3K)-Akt pathway LY294002 (i.p.). Moreover, NK1R, LTCC, and IP3R are required for GR73632-evoked CaMKIIα, ERK1/2, Akt and PKCα/βII phosphorylation. In addition, evoked ERK1/2 phosphorylation was sensitive to inhibitors of PKC and PI3K. These findings indicate that the LTCC/IP3R-dependent PI3K/PKCα/βII-ERK1/2 signaling pathways are involved in NK1R-mediated vomiting.

  • Autophagy activation alleviates nonylphenol-induced apoptosis in cultured cortical neurons
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-14
    Siyao Li, Zhixin Jiang, Wenjie Chai, Yuanyuan Xu, Yi Wang

    Emerging evidence indicates that nonylphenol (NP), a widely diffused and stable environmental contaminant, causes damage to the central nervous system (CNS). Although NP could cross the blood-brain barrier (BBB) and accumulate in key brain regions, little is known about the direct effects of NP on neurons. In this study, we aimed to investigate the direct effects of NP exposure on induction of apoptosis and autophagy in primary cortical neurons. Results showed that exposure to NP decreased the cell viability in a concentration-dependent manner. The exposure led to both the increase of TUNEL-positive neurons and the activation of caspase-3. Increased levels of endoplasmic reticulum (ER) stress-related proteins, GRP78, CHOP, ATF4, and casepase-12, were observed in neurons exposed to NP. At the same time, the exposure decreased Bcl-2/Bax ratio and mitochondrial transmembrane potential, and increased the release of Cytochrome-C. In addition, NP exposure enhanced LC3-II conversion, decreased levels of SQSTM1/p62, and increased levels of Beclin-1 and LAMP2. NP exposure also reduced the protein levels of p-mTOR, and did not change the levels of total mTOR. Furthermore, to investigate the role of autophagy in NP-induced apoptosis, both the autophagy inhibitor chloroquine (CQ) and the autophagy inducer rapamycin (RAP) were applied to modulate autophagy activation in primary cortical neurons. The inhibition of autophagy caused by CQ enhanced NP-induced apoptosis; conversely, RAP-induced autophagy remarkably suppressed it. In conclusion, our findings demonstrate that NP exposure induced apoptosis with a concomitant increase of autophagic flux in primary cortical neurons, which supports the idea that this potential neurotoxin has direct effects of on neurons. Both ER stress and mitochondrial pathways may be involved in NP-induced apoptosis in neurons. Furthermore, our results also suggest that autophagy activation might be a protective strategy to ameliorate NP-induced apoptosis in neurons.

  • The prion protein in neuroimmune crosstalk
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-15
    Øyvind Salvesen, Jörg Tatzelt, Michael A. Tranulis

    The cellular prion protein (PrPC) is a medium-sized glycoprotein, attached to the cell surface by a glycosylphosphatidylinositol anchor. PrPC is encoded by a single-copy gene, PRNP, which is abundantly expressed in the central nervous system and at lower levels in non-neuronal cells, including those of the immune system. Evidence from experimental knockout of PRNP in rodents, goats, and cattle and the occurrence of a nonsense mutation in goat that prevents synthesis of PrPC, have shown that the molecule is non-essential for life. Indeed, no easily recognizable phenotypes are associate with a lack of PrPC, except the potentially advantageous trait that animals without PrPC cannot develop prion disease. This is because, in prion diseases, PrPC converts to a pathogenic “scrapie” conformer, PrPSc, which aggregates and eventually induces neurodegeneration. In addition, endogenous neuronal PrPC serves as a toxic receptor to mediate prion-induced neurotoxicity. Thus, PrPC is an interesting target for treatment of prion diseases. Although loss of PrPC has no discernable effect, alteration of its normal physiological function can have very harmful consequences. It is therefore important to understand cellular processes involving PrPC, and research of this topic has advanced considerably in the past decade. Here, we summarize data that indicate the role of PrPC in modulating immune signaling, with emphasis on neuroimmune crosstalk both under basal conditions and during inflammatory stress.

  • An overview of the neuroprotective potential of rosmarinic acid and its association with nanotechnology-based delivery systems: A novel approach to treating neurodegenerative disorders
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-12
    Flávia Nathiely Silveira Fachel, Roselena Silvestri Schuh, Kleyton Santos Veras, Valquíria Linck Bassani, Letícia Scherer Koester, Amelia Teresinha Henriques, Elizandra Braganhol, Helder Ferreira Teixeira

    Neurodegenerative disorders (ND) are characterized by slow and progressive neuronal dysfunction induced by the degeneration of neuronal cells in the central nervous system (CNS). Recently, the neuroprotective effects of natural compounds with anti-inflammatory and antioxidant activities has been clearly demonstrated. This appears to be an attractive therapeutic approach for ND, particularly regarding the use of polyphenols. In this review, we present an overview of the neuroprotective potential of rosmarinic acid (RA) and discuss the use of nanotechnology as a novel approach to treating ND. RA presents a variety of biological important activities, i.e. the modulation of pro-inflammatory cytokine expression, prevention of neurodegeneration and damage reduction. However, its poor bioavailability represents a limitation in terms of pharmacodynamics. In this sense, nanotechnology-based carriers could allow for the administration of higher but still safe amounts of RA, aiming for CNS delivery. Nasal administration could be a pleasant route for delivery to the CNS, as this represents a direct route to the CNS. With these advantages, RA-loaded nanotechnology-based therapy through the nasal route could be promising approach for the treatment of ND.

  • Behavioral tests predicting striatal dopamine level in a rat hemi-Parkinson's disease model
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-09
    Kazuya Miyanishi, Mohammed E. Choudhury, Minori Watanabe, Madoka Kubo, Masahiro Nomoto, Hajime Yano, Junya Tanaka
  • Pentobarbital and other anesthetic agents induce opposite regulations of MAP kinases p-MEK and p-ERK, and upregulate p-FADD/FADD neuroplastic index in brain during hypnotic states in mice
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-10
    Glòria Salort, María Álvaro-Bartolomé, Jesús A. García-Sevilla

    Midazolam and ketamine-induced anesthesia were recently shown to induce a disruption of MEK/ERK sequential phosphorylation with parallel upregulation of p-FADD in the mouse brain. The present study was designed to assess whether other structurally diverse anesthetic agents (pentobarbital, ethanol, chloral hydrate, isoflurane) also impair brain p-MEK to p-ERK signal and increase p-FADD during the particular time course of ‘sleep’ in mice. Pentobarbital (50 mg/kg)-, ethanol (4000 mg/kg)-, chloral hydrate (400 mg/kg)-, and isoflurane (2% in O2)-induced anesthesia (range: 24–60 min) were associated with unaltered or increased p-MEK1/2 (up to +155%) and decreased p-ERK1/2 (up to −60%) contents, revealing disruption of MEK to ERK activation in mouse brain cortex. These anesthetic agents also upregulated cortical p-FADD (up to +110%), but not total FADD (moderately decreased), which resulted in increased neuroplastic/survival p-FADD/FADD ratios (up to +2.8 fold). The inhibition of pentobarbital metabolism with SKF525-A (a cytochrome P450 inhibitor) augmented barbiturate anesthesia (2.6 times) and induced a greater and sustained upregulation of p-MEK with p-ERK downregulation, as well as prolonged increases of p-FADD content and p-FADD/FADD ratio (effects lasting for more than 240 min). Pentobarbital also upregulated significantly the cortical contents of other markers of neuroplasticity such as the ERK inhibitor p-PEA-15 (up to +46%), the transcription factor NF-κB (up to +27%) and the synaptic density protein PSD-95 (up to +20%) during ‘sleep’. The results reveal a paradoxical stimulation of p-MEK without the concomitant (canonical) activation of p-ERK (e.g. with pentobarbital and isoflurane), for which various molecular mechanisms are discussed. The downregulation of brain p-ERK may participate in the manifestations of adverse effects displayed by most hypnotic/anesthetic agents in clinical use (e.g. amnesia).

  • Long-term challenge of methylphenidate changes the neuronal population and membrane property of dopaminergic neuron in rats
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-10
    Sanford PC. Hsu, Dao-Yuan Wang, Ming-Yuan Min, Yu-Show Fu

    Attention deficit hyperactivity disorder (ADHD) has a prevalence of 7.5% in school-age children in Taiwan. A number of ADHD patients start taking medications in elementary school and continue their treatment until they are in college or adulthood. Methylphenidate is the most frequently used medication prescribed for ADHD treatment. The influence of long-term treatment of methylphenidate on neuro-development, especially dopaminergic neurons, in rats would be explored. This study investigated the impact of long-term treatment of methylphenidate on different neurons. Rats aged 1 month were divided into three groups: Normal group receiving only sucrose solution, Low-dose group receiving 2 mg/kg methylphenidate, and High-dose group receiving 10 mg/kg methylphenidate; for each group, the drug was administreted twice per day. After 7 months of the treatment period, then the alterations in number of norepinephrine, serotonergic, cholinergic and dopaminergic neurons were quantified. The number of dopaminergic neurons in the substantia nigra (SN), the serotonergic neurons in the dorsal raphe nucleus, and the cholinergic neurons in the tegmental nucleus significantly decreased as compared with Normal group, whereas the noradrenergic neurons in the locus coeruleus substantially increased. The whole-cell recording was made from dopaminergic neurons residing in the SN for examination of their firing activity. The recorded dopaminergic neurons in SN were categorized into slow and fast firing using 10 Hz as a classified index. The results displayed that the ratio of dopaminergic neurons with fast firing in the High-dose group was less as compared with those in the Normal and the Low-dose group. Furthermore, the amplitude of action potential of the dopaminergic neurons with slow firing was higher in the High-dose group than those in the Normal and Low-dose groups. The firing behavior of dopaminergic neurons and dopamine concentration in the brain is affected by the long-term challenge of methylphenidate.

  • Microglia metabolism in health and disease
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-10
    Katharina Borst, Marius Schwabenland, Marco Prinz

    In the last decade tremendous progress has been made in understanding how the immune system reacts to insults. During this progress it became obvious that those immune responses are tightly regulated and cross-linked with distinct metabolic changes in immune cells. Extensive research has been conducted mainly on subtypes of T cells, which use different metabolic pathways during differentiation processes and activation states. In addition, it has also been established later, that the innate immune cell lineage of myeloid cells includes a variety of different subsets of bone marrow-derived as well as tissue-specific macrophages, which elicit much more functions than simply killing bacteria. To execute this high variety of functions, also macrophages use different metabolic pathways and are tightly regulated by key metabolic regulators, such as the mechanistic target of rapamycin (mTOR). Upon activation, metabolic changes within the cell occur to meet the requirements of the phenotypic switch. In addition, metabolic changes correlate with the ability of innate immune cells to show hallmarks of adaptive immune responses. Little is known about specific metabolic changes of myeloid cells and specifically microglia in vivo. Microglia are key players in neurodegenerative and neuroinflammatory diseases and have become a major target of medical research. Here, we review the existing data on microglia metabolism and the connection of microglia phenotypes with neuroinflammatory and neurodegenerative diseases. Lastly, we will discuss how our knowledge about the cellular metabolism might be used to develop new treatment options for neurological diseases.

  • Sex differences in miRNA as therapies for ischemic stroke
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-02
    Farida Sohrabji, Amutha Selvamani

    MicroRNAs, a subset of non-coding RNAs, are present in virtually all tissues including body fluids and are global regulators of the transcriptome. In view of the expanding number of microRNAs and the large number of gene targets that each microRNA can potentially regulate, they have been compared to hormones in the scope of their effects. MicroRNA have been implicated as biomarkers for several diseases including stroke, as well as chronic conditions that are associated with stroke. Recent research has focused on manipulating miRNA to improve stroke outcomes. Although several miRNAs have been shown to have neuroprotective properties, the overwhelming majority of these studies have employed only male animals. This review will focus on two miRNAs, Let7f and mir363–3p, whose effectiveness as a stroke neuroprotectant is sex-specific.

  • Protein disulfide-isomerase A3 significantly reduces ischemia-induced damage by reducing oxidative and endoplasmic reticulum stress
    Neurochem. Int. (IF 3.603) Pub Date : 2018-11-03
    Dae Young Yoo, Su Bin Cho, Hyo Young Jung, Woosuk Kim, Kwon Young Lee, Jong Whi Kim, Seung Myung Moon, Moo-Ho Won, Jung Hoon Choi, Yeo Sung Yoon, Dae Won Kim, Soo Young Choi, In Koo Hwang

    Ischemia causes oxidative stress in the endoplasmic reticulum (ER), accelerates the accumulation of unfolded and misfolded proteins, and may ultimately lead to neuronal cell apoptosis. In the present study, we investigated the effects of protein disulfide-isomerase A3 (PDIA3), an ER-resident chaperone that catalyzes disulfide-bond formation in a subset of glycoproteins, against oxidative damage in the hypoxic HT22 cell line and against ischemic damage in the gerbil hippocampus. We also confirmed the neuroprotective effects of PDIA3 by using PDIA3-knockout HAP1 cells. The HT22 and HAP1 cell lines showed effective (dose-dependent and time-dependent) penetration and stable expression of the Tat-PDIA3 fusion protein 24 h after Tat-PDIA3 treatment compared to that in the control-PDIA3-treated group. We observed that the fluorescence for both 2′,7′-dichlorofluorescein diacetate (DCF-DA) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), which are markers for the formation of hydrogen peroxide (H2O2)-induced reactive oxygen species and apoptosis, respectively, was higher in HAP1 cells than in HT22 cells. The administration of Tat-PDIA3 significantly reduced the (1) DCF-DA and TUNEL fluorescence in HT22 and HAP1 cells, (2) ischemia-induced hyperactivity that was observed 1 day after ischemia/reperfusion, (3) ischemia-induced neuronal damage and glial (astrocytes and microglia) activation that was observed in the hippocampal CA1 region 4 days after ischemia/reperfusion, and (4) lipid peroxidation and nitric oxide generation in the hippocampal homogenates 3–12 h after ischemia/reperfusion. Transient forebrain ischemia significantly elevated the immunoglobulin-binding protein (BiP) and C/EBP-homologous protein (CHOP) mRNA levels in the hippocampus at 12 h and 4 days after ischemia, relative to those in the time-matched sham-operated group. Administration of Tat-PDIA3 ameliorated the ischemia-induced upregulation of BiP mRNA levels versus the Tat peptide- or control-PDIA3-treated groups, and significantly reduced the induction of CHOP mRNA levels, at 12 h or 4 days after ischemia. Collectively, these results suggest that Tat-PDIA3 acts as a neuroprotective agent against ischemia by attenuating oxidative damage and blocking the apoptotic pathway that is related to the unfolded protein response in the ER.

  • The GSK3β inhibitor, TDZD-8, rescues cognition in a zebrafish model of okadaic acid-induced Alzheimer's disease
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-28
    Daniel Koehler, Zahoor A. Shah, Frederick E. Williams

    Currently, no treatments exist that are able to directly treat against Alzheimer's disease (AD), and we are facing an inevitable increase in the near future of the amount of patients who will suffer from AD. Most animal models of AD are limited by not being able to recapitulate the entire pathology of AD. Recently an AD model in zebrafish was established by using the protein phosphatase 2A inhibitor, okadaic acid (OKA). Administering OKA to zebrafish was able to recapitulate most of the neuropathology associated with AD. Therefore, providing a drug discovery model for AD that is also time and cost efficient. This study was designed to investigate the effects of GSK3β inhibition by 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8) on this newly developed AD model. Fish were divided into 4 groups and each group received a different treatment. The fish were divided into a control group, a group treated with 1 μM TDZD-8 only, a group treated with 1 μM TDZD-8 + 100 nM OKA, and a group treated with 100 nM OKA only. Administering the GSK3β inhibitor to zebrafish concomitantly with OKA proved to be protective. TDZD-8 treatment reduced the mortality rate, the ratio of active: inactive GSK3β, pTau (Ser199), and restored PP2A activity. This further corroborates the use of GSKβ inhibitors in the treatment against AD and bolsters the use of the OKA-induced AD-like zebrafish model for drug discovery.

  • Methoxetamine: A foe or friend?
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-24
    Chrislean Jun Botanas, June Bryan de la Peña, Hee Jin Kim, Yong Sup Lee, Jae Hoon Cheong

    Methoxetamine (MXE) is an N-methyl-D-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to other dissociative substances, such as ketamine and phencyclidine. There are reports on the misuse of MXE, which sometimes resulted in adverse consequences and death. Studies have also shown that MXE has abuse liability and stimulates dopamine neurotransmission in the mesolimbic reward pathway in the brain. These findings have contributed to the negative impression on MXE. However, recent preclinical studies have identified the antidepressant properties of MXE, which are attributed to its ability to affect the glutamatergic and serotonergic systems. MXE is also reported to have analgesic effects. These findings show some of the “redeeming qualities” of MXE and indicate its possible therapeutic uses. In this paper, we have reviewed the findings that provide insights into the adverse and potential therapeutic effects of MXE. We compiled studies on the toxicity, psychotomimetic effects, and abuse liability of MXE, as well as its promising antidepressant and analgesic properties. We also have discussed the mechanism of action that might mediate the somewhat paradoxical effects observed. Importantly, this review provides valuable information on MXE for future research and will enable a better understanding of its psychopharmacological properties and the mechanisms responsible for its unique effects.

  • Clinical spectrum of inflammatory central nervous system demyelinating disorders associated with antibodies against myelin oligodendrocyte glycoprotein
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-23
    Tetsuya Akaishi, Douglas Kazutoshi Sato, Toshiyuki Takahashi, Ichiro Nakashima

    Immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) are detected in the serum of some patients with demyelinating diseases. These patients are known to show repeated clinical episodes of inflammatory demyelinating attacks in the central nervous system. Although the associated pathogenicity and mechanism of inflammatory demyelination remains inconclusive, it is known that patients with MOG-IgG antibodies have a different clinical spectrum from those with other demyelinating diseases, such as multiple sclerosis. Based on our database of 85 MOG-IgG antibody positive (+) cases, the most frequently associated clinical episodes were isolated optic neuritis (67.5%), encephalitis (26.5%), and myelitis (19.3%). Optic neuritis in MOG-IgG (+) disease usually involves the long segment of optic nerves and sometimes happens bilaterally, but visual acuity usually recovers with proper treatment in the acute phase. Brain and brainstem lesions usually present vague and focal appearances with irregular margins, typically in subcortical or brainstem regions, but occasionally in the cortex or corpus callosum. Due to these characteristics, MOG-IgG (+) cases with brain or brainstem lesions are sometimes diagnosed with acute disseminated encephalomyelitis, meningitis, or symptomatic epilepsy. The myelitis in MOG-IgG (+) typically shows longitudinally extensive lesions as seen in neuromyelitis optica spectrum disorders. Acute treatment to reduce attack-related disability is recommended in MOG-IgG (+) disease, and long-term immunosuppression may be considered in patients with a high frequency of relapses and/or high risk of neurological disability.

  • MiR-34a and stroke: Assessment of non-modifiable biological risk factors in cerebral ischemia
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-23
    Xuefang Ren, Elizabeth B. Engler-Chiurazzi, Ashley E. Russell, Saumyendra N. Sarkar, Stephanie L. Rellick, Sara Lewis, Deborah Corbin, Jared Clapper, James W. Simpkins

    Aging of the nervous system, and the occurrence of age-related brain diseases such as stroke, are associated with changes to a variety of cellular processes controlled by many distinct genes. MicroRNAs (miRNAs), short non-coding functional RNAs that can induce translational repression or site-specific cleavage of numerous target mRNAs, have recently emerged as important regulators of cellular senescence, aging, and the response to neurological insult. Here, we focused on the assessment of the role of miR-34a in stroke. We noted increases in miR-34a expression in the blood of stroke patients as well as in blood and brain of mice subjected to experimental stroke. Our methodical genetic manipulation of miR-34a expression substantially impacted stroke-associated preclinical outcomes and we have in vitro evidence that these changes may be driven at least in part by disruptions to blood brain barrier integrity and mitochondrial oxidative phosphorylation in endothelial cells. Finally, aging, independent of brain injury, appears to be associated with shifts in circulating miRNA profiles. Taken together, these data support a role for miRNAs, and specifically miR-34a, in brain aging and the physiological response to age-related neurological insult, and lay the groundwork for future investigation of this novel therapeutic target.

  • Docosahexaenoic acid protection in a rotenone induced Parkinson's model: Prevention of tubulin and synaptophysin loss, but no association with mitochondrial function
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-19
    Norma Serrano-García, Francisca Fernández-Valverde, Erika Rubi Luis-Garcia, Leticia Granados-Rojas, Tarsila Elizabeth Juárez-Zepeda, Sandra Adela Orozco-Suárez, José Pedraza-Chaverri, Marisol Orozco-Ibarra, Anabel Jiménez-Anguiano

    Rotenone, a classic mitochondrial complex I inhibitor, leads to dopaminergic neuronal death resulting in a Parkinson's-like-disease. Docosahexaenoic acid (DHA) has shown neuroprotective effects in other experimental models of Parkinson's disease, but its effect on the rotenone-induced parkinsonism is still unknown. We tested whether DHA in vivo exerts a neuroprotective effect on rotenone-induced parkinsonism and explored the mechanisms involved, including mitochondrial function and ultrastructure as well as the expression of tubulin and synaptophysin. We pretreated eighty male Wistar rats with DHA (35 mg/kg/day) for 7 days and then administered rotenone for either 8 or 14 days. We then measured rearing behavior, number of dopaminergic neurons, tyrosine hydroxylase content, tubulin and synaptophysin expression, mitochondrial complex I, respiratory control ratio, mitochondrial transmembrane potential, ATP production activity and mitochondrial ultrastructure. We found that in vivo DHA supply exerted a neuroprotective effect, evidenced by decreased dopaminergic neuron cell death. Although we detected rotenone induced mitochondrial ultrastructure alterations, these were not associated with mitochondrial dysfunction. Rotenone had no effect on mitochondrial complex I, respiratory control ratio, mitochondrial transmembrane potential or ATP production activity. DHA also prevented a rotenone-induced decrease in tubulin and synaptophysin expression. Our results support the neuroprotective effect of DHA on rotenone-induced parkinsonism, and a possible effect on early stage Parkinson's disease. This protective effect is not associated with mitochondrial function improvement, but rather with preventing loss of tubulin and synaptophysin, proteins relevant to synaptic transmission.

  • Adrenergic control of lymphocyte trafficking and adaptive immune responses
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-19
    Akiko Nakai, Kazuhiro Suzuki

    Since the beginning of the last century, substantial evidence has suggested that various aspects of the immune system are influenced by the activity of the nervous system. However, the cellular and molecular basis for the neural control of immune responses has emerged only in the past decade. Recent studies have shown that adrenergic nerves control trafficking of immune cells through cell-type-specific mechanisms. Activation of the β2-adrenergic receptor expressed on lymphocytes enhances signals mediated by a particular set of chemokine receptors, and consequently inhibits their exit from lymph nodes. This mechanism is involved in the diurnal variation of adaptive immune responses and the progression of inflammatory diseases. In the present review, we focus on the role of adrenergic nerves in the control of lymphocyte trafficking and adaptive immune responses in physiological and pathological conditions.

  • Inflammation and neural repair after ischemic brain injury
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-19
    Seiichiro Sakai, Takashi Shichita

    Stroke causes neuronal cell death and destruction of neuronal circuits in the brain and spinal cord. Injury to the brain tissue induces sterile inflammation triggered by the extracellular release of endogenous molecules, but cerebral inflammation after stroke is gradually resolved within several days. In this pro-resolving process, inflammatory cells adopt a pro-resolving or repairing phenotype in the injured brain, activating endogenous repairing programs. Although the mechanisms involved in the transition from inflammation to neural repair after stroke remain largely unknown to date, some of the mechanisms for inflammation and neural repair have been clarified in detail. This review focuses on the molecular or cellular mechanisms involved in sterile inflammation and neural repair after stroke. This accumulation of evidence may be helpful for speculating about the endogenous repairing mechanisms in the brain and identifying therapeutic targets for improving the functional prognoses of stroke patients.

  • Knockdown of RTN1-C attenuates traumatic neuronal injury through regulating intracellular Ca2+ homeostasis
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-21
    Xiao-xuan Fan, Yu-ying Hao, Shi-wen Guo, Xiao-ping Zhao, Yi Xiang, Fei-xue Feng, Ge-ting Liang, Yu-wei Dong

    Reticulons (RTNs) are a family of membrane-bound proteins that are dominantly localized to the endoplasmic reticulum (ER) membrane. RTN1-C is one member of RTNs abundantly expressed in the brain and has been shown to mediate neuronal injury in cerebral ischemia models. In the present study, we investigated the role of RTN1-C in an in vitro brain trauma model mimicked by traumatic neuronal injury (TNI) in primary cultured cortical neurons. TNI increased the expression of RTN1-C in cortical neurons but had no effect on RTN1-A and RTN1-B. Knockdown of RTN1-C with specific siRNA (Si-RTN1-C) significantly decreased cytotoxicity and apoptosis after TNI. The results of Ca2+ imaging showed that intracellular Ca2+ overload induced by TNI was attenuated by RTN1-C knockdown. Furthermore, the activation of metabotropic glutamate receptor 1 (mGluR1)-induced Ca2+ response was partially prevented by Si-RTN1-C transfection. We also evaluated the role of RTN1-C in store-operated Ca2+ entry (SOCE) in cortical neurons using the ER Ca2+ inducer thapsigargin (Tg). The results showed that knockdown of RTN1-C alleviated the SOCE-mediated Ca2+ influx and decreased the expression of stromal interactive molecule 1 (STIM1). In summary, the present study found that knockdown of RTN1-C protected neurons against TNI via preservation of intracellular Ca2+ homeostasis, which was associated with the inhibition of mGluR1-mediated ER Ca2+ release and suppression of STIM1-related SOCE. Thus, RTN1-C might represent a therapeutic target for traumatic brain injury (TBI) research.

  • Expression and secretion of synaptic proteins during stem cell differentiation to cortical neurons
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-18
    Faisal Hayat Nazir, Bruno Becker, Ann Brinkmalm, Kina Höglund, Åsa Sandelius, Petra Bergström, Tugce Munise Satir, Annika Öhrfelt, Kaj Blennow, Lotta Agholme, Henrik Zetterberg
  • Blockade of IL-6 signaling in neuromyelitis optica
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-17
    Manabu Araki

    Neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune diseases associated with a disease-specific autoantibody directed against the water channel protein aquaporin-4. Standard immunotherapy, immunosuppressive agents, and corticosteroids can prevent acute attacks and maintain remission in most patients with NMOSD. However, there is a strong need for additional options for patients who are refractory to standard treatments. Emerging therapies targeting specific molecules related to the pathogenicity of NMOSD are currently being developed. The review focuses on improving preventive treatments for NMOSD, including ongoing randomized clinical trials using biological drugs targeting CD19 and CD20 on B cells, interleukin-6, and complement protein C5. The anti-IL-6 receptor monoclonal antibody tocilizumab (TCZ), which can block IL-6 signaling, was shown to be highly effective for refractory patients with NMOSD. Notably, TCZ has marked effects on chronic neuropathic pain and general fatigue in patients refractory to standard medications. TCZ is a promising drug for preventing acute attacks in patients with NMOSD.

  • Assessment of neuroprotective effects of Gallic acid against glutamate-induced neurotoxicity in primary rat cortex neuronal culture
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-17
    S. Maya, T. Prakash, Krishna Das

    Glutamate excitotoxicity plays a crucial role in the pathogenesis behind the development and progression of several neurodegenerative diseases. The study aimed to investigate the neuroprotective activity of Gallic acid (GA) against glutamate-induced neurotoxicity in primary rat cortex neurons (RCN). Treated the RCNs with GA 25 & 50 μg/ml for 2 h and later treated the cells with 100 μM glutamate (GLU) and incubated for 24 h at 37 °C. The results demonstrated that, the GA improved the antioxidant profile in the cortex neurons and inhibited the production of the proinflammatory cytokine. GA also maintained the Ca2+ homeostasis, IGF-1 expression, and protected the neurons from glutamate-induced neuronal toxicity. The neuroprotective activity of GA has further confirmed from the results of N-acetylaspartate and expression of microtubule-associated protein-2 expression. The reports suggest that, GA is significantly attenuated the glutamate-induced neurotoxicity and protected neurons from various chemical events that are involved in the pathogenesis of neurotoxicity.

  • Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-15
    Péter Hertelendy, Dániel P. Varga, Ákos Menyhárt, Ferenc Bari, Eszter Farkas

    Secondary injury following acute brain insults significantly contributes to poorer neurological outcome. The spontaneous, recurrent occurrence of spreading depolarization events (SD) has been recognized as a potent secondary injury mechanism in subarachnoid hemorrhage, malignant ischemic stroke and traumatic brain injury. In addition, SD is the underlying mechanism of the aura symptoms of migraineurs. The susceptibility of the nervous tissue to SD is subject to the metabolic status of the tissue, the ionic composition of the extracellular space, and the functional status of ion pumps, voltage-gated and other cation channels, glutamate receptors and excitatory amino acid transporters. All these mechanisms tune the excitability of the nervous tissue. Aging has also been found to alter SD susceptibility, which appears to be highest at young adulthood, and decline over the aging process. The lower susceptibility of the cerebral gray matter to SD in the old brain may be caused by the age-related impairment of mechanisms implicated in ion translocations between the intra- and extracellular compartments, glutamate signaling and surplus potassium and glutamate clearance. Even though the aging nervous tissue is thus less able to sustain SD, the consequences of SD recurrence in the old brain have proven to be graver, possibly leading to accelerated lesion maturation. Taken that recurrent SDs may pose an increased burden in the aging injured brain, the benefit of therapeutic approaches to restrict SD generation and propagation may be particularly relevant for elderly patients.

  • Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal medium spiny neurons
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-15
    Xinjian Zhang, Taku Nagai, Rijwan Uddin Ahammad, Keisuke Kuroda, Shinichi Nakamuta, Takashi Nakano, Naoto Yukinawa, Yasuhiro Funahashi, Yukie Yamahashi, Mutsuki Amano, Junichiro Yoshimoto, Kiyofumi Yamada, Kozo Kaibuchi
  • Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione homeostasis via NGF/TrkA and mTOR signaling in the cerebellum
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-06
    Carla Garza-Lombó, Pavel Petrosyan, Miguel Tapia-Rodriguez, Cesar Valdovinos-Flores, María E. Gonsebatt
  • Bacopa monnieri alleviates paraquat induced toxicity in Drosophila by inhibiting jnk mediated apoptosis through improved mitochondrial function and redox stabilization
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-05
    Saurabh Srivastav, Mahino Fatima, Amal Chandra Mondal

    Paraquat (PQ) is an organic chemical compound and a member of redox active family of heterocycles. In spite of its high toxicities, it is used as one of the potent herbicide throughout the world. Though its toxic manifestations are observed in different organs, its principal toxic effect is manifested in the brain leading to the development of Parkinsonian symptoms. PQ exposure adversely affects dopaminergic (DA-ergic) neuron-rich region in the substantia nigra pars compacta (SNPC) of brain in the animal models of Parkinson's disease (PD), thereby mimicking PD like symptoms. Currently, lack of a potential drug to counter the toxic effect of PQ makes the management difficult. Bacopa monnieri extract (BME) has been shown to have promising effect against neurodegenerative disorders. Therefore, the present study evaluated the role of BME against PQ induced toxicity in Drosophila model of PD, the results of which are reproducible in higher animal models including human subjects. Here, we showed that BME treatment attenuates acute PQ induced toxicity in Drosophila by decreasing mortality and improving climbing ability. BME functions by optimizing redox equilibrium, mitochondrial function and depreciating apoptosis level. The underlying mechanisms were attributed to optimization of active JNK and cleaved Caspase-3 activity along with transcriptional stabilization of the genes regulating oxidative stress and apoptosis (jnk, caspase-3, damb and nrf-2). These results showed therapeutic efficacy of BME against PQ toxicity in the brain. Our results pave the way for further detailed analysis of BME to combat the development of Parkinson's like symptoms following exposure to PQ toxicity in the brain of higher animal models.

  • TRPV1 modulates morphine self-administration via activation of the CaMKII-CREB pathway in the nucleus accumbens
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-04
    Shi-Xun Ma, Hyoung-Chun Kim, Seok-Yong Lee, Choon-Gon Jang

    Opioid addiction is a growing problem for public health, and opioids have correspondingly become more heavily regulated over time. We have previously shown that TRPV1 plays a critical role in morphine addiction using a self-administration paradigm in rats, and the current study evaluates the effects of the TRPV1 signaling pathway on morphine self-administration (SA). We found that treatment with a selective TRPV1 antagonist, SB366791, significantly decreased the morphine SA-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), Akt and the cAMP response element binding protein (CREB) in the nucleus accumbens (NAc). In addition, phospho-PKA and phospho-PKC expression levels were significantly increased in the NAc of the morphine-SA groups, regardless of SB366791 treatment. Finally, local microinjection of SB366791 into the NAc significantly suppressed the maintenance of morphine SA. Taken together, our findings highlight that TRPV1 plays an important role in morphine addiction, likely via activation of the CaMKII-CREB pathway in the NAc.

  • The effect of age, sex and strains on the performance and outcome in animal models of stroke
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-03
    Hongxia Zhang, Siyang Lin, Xudong Chen, Lei Gu, Xiaohong Zhu, Yinuo Zhang, Kassandra Reyes, Brain Wang, Kunlin Jin

    Stroke is one of the leading causes of death worldwide, and the majority of cerebral stroke is caused by occlusion of cerebral circulation, which eventually leads to brain infarction. Although stroke occurs mainly in the aged population, most animal models for experimental stroke in vivo almost universally rely on young-adult rodents for the evaluation of neuropathological, neurological, or behavioral outcomes after stroke due to their greater availability, lower cost, and fewer health problems. However, it is well established that aged animals differ from young animals in physiology, neurochemistry, and behavior. Stroke-induced changes are more pronounced with advancing age. Therefore, the overlooked role of age in animal models of stroke could impact on data quality and hinder the translation of rodent models to humans. In addition to aging, other factors also influence the performance after ischemic stroke. In this article, we summarize the differences between young and aged animals, the impact of age, sex and animal strains on performance and outcome in the animal models of stroke and emphasize age as a key factor in preclinical stroke studies in animal models of stroke.

  • Tyrosol attenuates pro-inflammatory cytokines from cultured astrocytes and NF-κB activation in in vitro oxygen glucose deprivation
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-04
    Gang Luo, Yinuo Huang, Dapeng Mo, Ning Ma, Feng Gao, Ligang Song, Xuan Sun, Xiaotong Xu, Lian Liu, Xiaochuan Huo, Bo Wang, Xiaoqing Li, Baixue Jia, Yiming Deng, Xuelei Zhang, Alejandro Fernandez-Escobar, Guangge Peng, Zhongrong Miao

    Subsequent inflammation in stroke plays an important role in the damage of neurons in the perilesional area. Therapeutic intervention targeting inflammation may be a promising complementary strategy to current treatments of stroke. Here, we explored the possible beneficial effects of tyrosol, a derivative of phenethyl alcohol and natural antioxidant, playing an anti-inflammatory role in astrocyte culture and in vitro oxygen glucose deprivation (OGD) model. MTT, western blot, ELISA and EMSA assays were carried out to investigate cell viability, protein expression level, cytokine expression and NF-κB activity. We found tyrosol protected cultured astrocytes against OGD-induced cell viability loss in MTT test. Meanwhile, tyrosol attenuated the released TNF-α and IL-6 level from astrocyte via regulating Janus N-terminal kinase (JNK). The reduction of cytokines from astrocyte might be due to its inhibition of astrocyte activation and regulation of STAT3 signaling pathway since tyrosol attenuated the expression level of GFAP (glial fibrillary acidic protein) and the phosphorylation of STAT3. Additionally, we demonstrated that tyrosol prevented the degradation of IκBα and the increase of IκBα phosphorylation in astrocytes exposed to OGD, which led to the suppression of NF-κB function during ischemia. Collectively, our results showed that tyrosol may be a promising complementary treatment compound for stroke via modulating the inflammatory response in astrocytes during ischemia.

  • Interactions of the tricyclic antidepressant drug amitriptyline with L-DOPA in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Relevance to motor dysfunction in Parkinson's disease
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-02
    Kinga Kamińska, Tomasz Lenda, Jolanta Konieczny, Jadwiga Wardas, Elżbieta Lorenc-Koci

    Antidepressant drugs are recommended for the treatment of Parkinson's disease (PD)-associated depression but their role in the modulation of L-DOPA-induced behavioral and neurochemical markers is poorly explored. The aim of the present study was to examine the impact of the tricyclic antidepressant amitriptyline and L-DOPA, administered chronically alone or in combination, on rotational behavior, monoamine levels and binding of radioligands to their transporters in the dopaminergic brain structures of unilaterally 6-OHDA-lesioned rats. Binding of [3H]nisoxetine to noradrenaline transporter (NET), [3H]GBR 12,935 to dopamine transporter (DAT) and [3H]citalopram to serotonin transporter (SERT) were analyzed by autoradiography. Amitriptyline administered alone did not induce rotational behavior but in combination with L-DOPA increased the number of contralateral rotations much more strongly than L-DOPA alone. The combined treatment also significantly increased the tissue dopamine (DA) content in the ipsilateral striatum and substantia nigra (SN) vs. L-DOPA alone. 6-OHDA-mediated lesion of nigrostriatal DA neurons drastically reduced DAT and NET bindings in the ipsilateral striatum. In the ipsilateral SN, DAT binding decreased while NET binding rose. SERT binding increased significantly mainly in the SN. Amitriptyline administered alone or jointly with L-DOPA had no effect on DAT binding on the lesioned side, significantly decreased SERT binding in the striatum and SN while NET binding only in the SN. Since in the DA-denervated striatum, SERT is mainly responsible for reuptake of L-DOPA-derived DA while in the SN, SERT and NET are involved, the inhibition of these transporters by antidepressant drugs may improve dopaminergic transmission and consequently motor behavior.

  • Behavioral response to imipramine under chronic mild stress corresponds with increase of mRNA encoding somatostatin receptors sst2 and sst4 expression in medial habenular nucleus
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-03
    Faron-Górecka Agata, Kuśmider Maciej, Solich Joanna, Kolasa Magdalena, Gruca P, Pabian Paulina, Szlachta Marta, Dziedzicka-Wasylewska Marta
  • Uncaria rhynchophylla ameliorates amyloid beta deposition and amyloid beta-mediated pathology in 5XFAD mice
    Neurochem. Int. (IF 3.603) Pub Date : 2018-10-03
    Soo Jung Shin, Yuon Jeong, Seong Gak Jeon, Sujin Kim, Seong-kyung Lee, Hong Seok Choi, Cheong Su Im, Seong Hee Kim, Soo Hwan Kim, Jae Ho Park, Jin-il Kim, Jwa-Jin Kim, Minho Moon

    One of the pathological hallmarks of Alzheimer's disease (AD) is the abnormal aggregation of amyloid beta (Aβ) peptides. Uncaria rhynchophylla (UR), one of the Uncaria species, has long been used to treat neurodegenerative disease. In particular, it has been reported that UR inhibits aggregation of Aβ in vitro. However, little is known about the histological effects of UR treatment on Aβ pathology in AD animal models. In the present study, we investigated the effect of UR on Aβ aggregation, Aβ-mediated pathologies and adult hippocampal neurogenesis in the brain of 5XFAD mice. First, using the thioflavin T assay and amyloid staining, we demonstrated that UR treatment effectively inhibited Aβ aggregation and accumulation in the cortex and subiculum. Second, immunofluorescence staining showed that administration of UR attenuated gliosis and neurodegeneration in the subiculum and cortex. Third, UR treatment ameliorated impaired adult hippocampal neurogenesis. The present results indicate that UR significantly alleviates Aβ deposition and Aβ-mediated neuropathology in the brain in 5XFAD mice, suggesting the potency of UR as a preventive and therapeutic agent for AD.

  • DNMT1 and Sp1 competitively regulate the expression of BACE1 in A2E-mediated photo-oxidative damage in RPE cells
    Neurochem. Int. (IF 3.603) Pub Date : 2018-09-28
    Peirong Huang, Junran Sun, Fenghua Wang, Xueting Luo, Hong Zhu, Qing Gu, Xiangjun Sun, Te Liu, Xiaodong Sun

    Numerous studies have focused on the deteriorate role of amyloid-β (Aβ) on retina, implying the potential pathogenic mechanism underlying age-related macular degeneration (AMD). However, the mechanism underlying the Aβ deposition in AMD patients remains unknown. Beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), rate-limiting enzyme for Aβ production, plays an important role in Aβ deposition in the brain. In the current study, we aimed to clarify the regulation mechanism of BACE1 and explore potential drug targets using a lipofuscinfluorophore A2E-mediated photo-oxidation model. In this model, Aβ1-40 and Aβ1-42 levels increased simultaneously with the enhanced BACE1 expression. These changes were associated with the hypomethylation of specific loci within the BACE1 gene promoter and the decreased levels of DNA methyltransferase 1 (DNMT1). Furthermore, we noticed overlapping regions of differentially methylated CpG islands and specificity protein (Sp1) binding sites within the BACE1 promoter. We employed chromatin immunoprecipitation (ChIP) assay to verify that the decreased BACE1 promoter methylation by DNMT1 enabled increased binding between Sp1 and the BACE1 promoter, which further enhanced BACE1 transcription. The inhibition of Sp1 with mithramycin A (MTM) could down-regulate the expression of BACE1 as well as alleviate the RPE barrier morphology and function impairment. Our results for the first time show the competitive regulation of BACE1 by transcription factor Sp1 and DNMT1 after photo-oxidation and confirm the potential novel protective role of MTM on RPE cells.

  • Gateway reflex: Local neuroimmune interactions that regulate blood vessels
    Neurochem. Int. (IF 3.603) Pub Date : 2018-09-29
    Daisuke Kamimura, Takuto Ohki, Yasunobu Arima, Mitsutoshi Ota, Masaaki Murakami

    Neuroimmunology is a research field that intersects neuroscience and immunology, with the larger aim of gaining significant insights into the pathophysiology of chronic inflammatory diseases such as multiple sclerosis. Conventional studies in this field have so far mainly dealt with immune responses in the nervous system (i.e. neuroinflammation) or systemic immune regulation by the release of glucocorticoids. On the other hand, recently accumulating evidence has indicated bidirectional interactions between specific neural activations and local immune responses. Here we discuss one such local neuroimmune interaction, the gateway reflex. The gateway reflex represents a mechanism that translates specific neural stimulations into local inflammatory outcomes by changing the state of specific blood vessels to allow immune cells to extravasate, thus forming the gateway. Several types of gateway reflex have been identified, and each regulates distinct blood vessels to create gateways for immune cells that induce local inflammation. The gateway reflex represents a novel therapeutic strategy for neuroinflammation and is potentially applicable to other inflammatory diseases in peripheral organs.

  • Nicotinamide Mononucleotide Adenylyltransferase 2 maintains neuronal structural integrity through the maintenance of golgi structure
    Neurochem. Int. (IF 3.603) Pub Date : 2018-09-29
    Tana Pottorf, Alexis Mann, Shaneann Fross, Clayton Mansel, Bhupinder P.S. Vohra

    Golgi fragmentation and loss of Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) are the early key features of many neurodegenerative disorders. We investigated the link between NMNAT2 loss, Golgi fragmentation and axon degeneration. Golgi fragmentation in the cultured dorsal root ganglion (DRG) neurons resulted in caspase dependent axon degeneration and neuronal cell death. NMNAT2 depletion in the DRG neurons caused Golgi fragmentation and caspase dependent axon degeneration. NMNAT2 depletion did not cause ATP loss in the axons. These results indicate that NMNAT2 is required for maintenance of Golgi structure. Loss of Golgi structure or Nmnat2 depletion causes caspase dependent neurodegeneration. cytNmnat1 overexpression inhibited the axon degeneration induced by Golgi fragmentation or NMNAT2 depletion. These results also suggest that these degeneration signals converge on a common cytNmnat1 mediated axon protective program and are distinct from the SARM1 mediated caspase independent axon degeneration.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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