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  • The effects of manganese overexposure on brain health
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-20
    Mahfuzur R. Miah; Omamuyovwi M. Ijomone; Comfort O.A. Okoh; Olayemi K. Ijomone; Grace T. Akingbade; Tao Ke; Bárbara Krum; Airton da Cunha Martins; Ayodele Akinyemi; Nicole Aranoff; Felix Alexandre Antunes Soares; Aaron B. Bowman; Michael Aschner

    Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity.

  • Fluoxetine improves behavioural deficits induced by chronic alcohol treatment by alleviating RNA editing of 5-HT2C receptors
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-20
    Zexiong Li; Yan Lu; Shanshan Liang; Shuai Li; Beina Chen; Manman Zhang; Maosheng Xia; Dawei Guan; Alexei Verkhratsky; Baoman Li
  • Preclinical testing of the ketogenic diet in fragile X mice
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-17
    Pamela R. Westmark; Alejandra Gutierrez; Aaron K. Gholston; Taralyn M. Wilmer; Cara J. Westmark
  • Estrogen protects neuroblastoma cell from amyloid-β 42 (Aβ42)-induced apoptosis via TXNIP/TRX axis and AMPK signaling
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-10
    Qiong Pan; Ke Guo; Min Xue; Qiuyun Tu

    Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-β 42 (Aβ42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In Aβ42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued Aβ42-suppressed cell viability and protein level of TRX while inhibited Aβ42-induced increases in ROS production, cell apoptosis, ΔΨm, and the protein levels of PERK, IREα, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve Aβ42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.

  • Chronic constriction injury of the sciatic nerve in rats causes different activation modes of microglia between the anterior and posterior horns of the spinal cord
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-09
    Tasuku Nishihara; Junya Tanaka; Keisuke Sekiya; Yuki Nishikawa; Naoki Abe; Taisuke Hamada; Sakiko Kitamura; Keizo Ikemune; Shinichiro Ochi; Mohammed E. Choudhury; Hajime Yano; Toshihiro Yorozuya

    Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68+ phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.

  • Involvement of TRPV1 and the efficacy of α-spinasterol on experimental fibromyalgia symptoms in mice
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-08
    Susana Paula Moreira Fischer; Indiara Brusco; Evelyne da Silva Brum; Maria Fernanda Pessano Fialho; Camila Camponogara; Rahisa Scussel; Ricardo Andrez Machado-de-Ávila; Gabriela Trevisan; Sara Marchesan Oliveira
  • Polydatin protects SH-SY5Y in models of Parkinson's disease by promoting Atg5-mediated but parkin-independent autophagy
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-08
    Hua Bai; Yaqi Ding; Xin Li; Deqin Kong; Chenqi Xin; Xue-Kang Yang; Cheng-wu Zhang; Ziqiang Rong; Chuanhao Yao; Shenci Lu; Lei Ji; Lin Li; Wei Huang
  • Metabolomic analysis of serum using proton NMR in 6-OHDA experimental PD model and patients with PD
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-07
    Sadhana Kumari; S. Senthil Kumaran; Vinay Goyal; Samrat Bose; Suman Jain; S.N. Dwivedi; Achal Kumar Srivastava; N.R. Jagannathan
  • Iron overload induced by IRP2 gene knockout aggravates symptoms of Parkinson's disease
    Neurochem. Int. (IF 3.994) Pub Date : 2020-01-02
    Yun-Zhe Ci; Haiyan Li; Lin-Hao You; Yu Jin; Rui Zhou; Guofen Gao; Pui Man Hoi; Chunyan Wang; Yan-Zhong Chang; Peng Yu

    Parkinson's disease (PD) is accompanied by iron overload in the brain. However, whether iron accumulation is the cause or effect of PD is still unknown. Iron regulatory protein 2 (IRP2) plays a critical role in keeping iron homeostasis, and our previous data showed that the deletion of the IRP2 gene caused iron deposits in organs of mice. Therefore, we further investigated the role of iron overload induced by IRP2 gene deletion in the development of the MPTP-induced PD mouse model in vivo, and the underlying regulatory mechanisms in primary cultures of astrocytes in vitro. Data from neurobehavioral, immunohistochemistry, TUNEL and Elisa studies showed that MPTP treatment enhanced the symptoms of PD in vivo, increased cell apoptosis and decreased dopamine levels in IRP2−/− mice. In addition, the expression of L-ferritin and iron contents increased significantly in the substantia nigra (SN) of IRP2−/− mice. Moreover, MPTP treatment significantly increased the expression of DMT1 (-IRE) and decreased the expression of TfR1 in IRP2−/− mice. Further investigations with primary cultures of astrocytes from IRP2−/− mice showed that MPP+ increased the expression of L-ferritin and DMT1 (-IRE), and decreased the expression of TfR1. Our results demonstrated that IRP2 gene deletion induced iron accumulation in the SN, which exacerbated the neuronal apoptosis and Parkinsonism symptoms. At the same time, IRP2 gene deletion increased the iron contents in astrocytes around neurons, which further decreased their protection for neurons and increased the cell apoptosis, ultimately forming a vicious cycle that leads to the onset and progression of PD.

  • Intranasal wnt-3a alleviates neuronal apoptosis in early brain injury post subarachnoid hemorrhage via the regulation of wnt target PPAN mediated by the moonlighting role of aldolase C
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-31
    Wu Ruan; Junwen Hu; Hang Zhou; Yin Li; Chaoran Xu; Yujie Luo; Ting Chen; Bangliang Xu; Feng Yan; Gao Chen

    Neuronal apoptosis is one of the main pathophysiological events in the early brain injury (EBI) post subarachnoid hemorrhage (SAH). Wnt-3a, one of the endogenous wnt ligands crucial in neurogenesis, has been proven to be efficacious in neuroprotection in traumatic brain injury and ischemic stroke. The glycolytic enzyme aldolase C and ribosome biogenesis protein PPAN were revealed to be linked to wnt signaling pathway. The aim of the study was to explore the antiapoptotic effects of intranasal wnt-3a through Frizzled-1 (Frz-1)/aldolase C/PPAN pathway in SAH. Approaches for assessment included SAH grade, Garcia test, brain water content evaluation, rotarod test, Morris water maze test, Western blot, immunofluorescence and transmission electron microscopy. The results showed that wnt-3a improved the neurological scores, brain water content and long-term neurobehavioral functions after SAH. Wnt-3a increased the level of Frz-1, aldolase C, β-catenin, PPAN and the Bcl-2/Bax ratio; and decreased the level of axin and cleaved caspase-3 (CC-3). The anti-apoptotic effect of wnt-3a was further evidenced by TUNEL staining and subcellular structure imaging. Frz-1 siRNA and aldolase C siRNA offset the effects of wnt-3a; and restoration of aldolase C by aldolase C CRISPR in Frz-1 siRNA preconditioned SAH rats salvaged the level of Frz-1, aldolase C, PPAN and reduced axin and CC-3. In summary, intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats. The feasible intranasal route and the long-lasting neuroprotective property of wnt-3a is of great clinical relevance.

  • Glutamate treatment mimics LTP- and LTD-like biochemical activity in viable synaptosome preparation
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-31
    Kusumika Gharami; Subhas C. Biswas

    Long-term potentiation (LTP) and long-term depression (LTD) are considered to be the cellular mechanisms behind the increase or decrease of synaptic strength respectively. Electrophysiologically induced LTP/LTD is associated with the activation of glutamate receptors in the synaptic terminals resulting in the initiation of biochemical processes in the postsynaptic terminals and thus propagation of synaptic activity. Isolated nerve endings i.e. synaptosome preparation was used to study here, the biochemical phenotypes of LTP and LTD, and glutamate treatment in varying concentration for different time was used to induce those biochemical phenomena. Treatment with 200 μM glutamate showed increased GluA1 phosphorylation at serine 831 and activation of CaMKIIα by phosphorylation at threonine 286 like LTP, whereas 100 μM glutamate treatment showed decrease in GluA1 phosphorylation level at both pGluA1(S831) and pGluA1(S845), and activation of GSK3β by de-phosphorylating pGSK3β at serine 9 like LTD. The 200 μM glutamate treatment was associated with an increase in the local translation of Arc, BDNF, CaMKIIα and Homer1, whereas 100 μM glutamate treatments resulted in decrease in the level of the said synaptic proteins and the effect was blocked by the proteasomal inhibitor, Lactasystin. Both, the local translation and local degradation was sensitive to the Ca2+ chellator, Bapta-AM, indicating that both the phenomena were dependent on the rise in intra-synaptosomal Ca2+, like LTP and LTD. Overall the results of the present study suggest that synaptosomal preparations can be a viable alternative to study mechanisms underlying the biochemical activities of LTP/LTD in short term.

  • mTORC1 is involved in DGKβ-induced neurite outgrowth and spinogenesis
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-28
    Hiroko Nakai; Ryosuke Tsumagari; Kenta Maruo; Akio Nakashima; Ushio Kikkawa; Shuji Ueda; Minoru Yamanoue; Naoaki Saito; Nobuyuki Takei; Yasuhito Shirai

    Diacylglycerol kinase β (DGKβ) is an enzyme converting DG to phosphatidic acid (PA) and is specifically expressed in neurons, especially those in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain function including emotion and memory, and plasma membrane localization of DGKβ via the C1 domain and a cluster of basic amino acids at the C-terminus is necessary for its function. To clarify the mechanisms involved in neuronal development by DGKβ, we investigated whether DGKβ activity induces neurite outgrowth using human neuroblastoma SH-SY5Y cells. DGKβ induced neurite outgrowth by activation of mammalian target of rapamycin complex 1 (mTORC1) through a kinase-dependent pathway. In addition, in primary cultured cortical and hippocampal neurons, inhibition of mTORC1 abolished DGKβ induced-neurite outgrowth, branching and spinogenesis. These results indicated that DGKβ induces neurite outgrowth and spinogenesis by activating mTORC1 in a kinase-dependent pathway.

  • 更新日期:2019-12-29
  • Phosphoproteomic analysis reveals Akt isoform-specific regulation of cytoskeleton proteins in human temporal lobe epilepsy with hippocampal sclerosis
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-27
    Rajesh Ramanna Valmiki; Subhashini Venkatesalu; Ari George Chacko; Krishna Prabhu; Maya Mary Thomas; Vivek Mathew; Sangeetha Yoganathan; Karthik Muthusamy; Geeta Chacko; Harshad Arvind Vanjare; Srinivasa Babu Krothapalli

    Akt is one of the most important downstream effectors of phosphatidylinositol 3-kinase/mTOR pathway. Hyper activation and expression of this pathway are shown in a variety of neurological disorders including human temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Nevertheless, the expression and activation profiles of the Akt isoforms, Akt1, Akt2, and Akt3 and their functional roles in human TLE-HS have not been studied. We examined the protein expression and activation (phosphorylation) patterns of Akt and its isoforms in human hippocampal tissue from TLE and non-TLE patients. A phosphoproteomic approach followed by interactome analysis of each Akt isoform was used to understand protein-protein interactions and their role in TLE-HS pathology. Our results demonstrated activation of the Akt/mTOR pathway as well as activation of Akt downstream substrates like GSK3β, mTOR, and S6 in TLE-HS samples. Akt1 isoform levels were significantly increased in the TLE-HS samples as compared to the non-TLE samples. Most importantly, different isoforms were activated in different TLE-HS samples, Akt2 was activated in three samples, Akt2 and Akt1 were simultaneously activated in one sample and Akt3 was activated in two samples. Our phosphoproteomic screen across six TLE-HS samples identified 183 proteins phosphorylated by Akt isoforms, 29 of these proteins belong to cytoskeletal modification. Also, we were able to identify proteins of several other classes involved in glycolysis, neuronal development, protein folding and excitatory amino acid transport functions as Akt substrates. Taken together, our data offer clues to understand the role of Akt and its isoforms in underlying the pathology of TLE-HS and further, modulation of Akt/mTOR pathway using Akt isoforms specific inhibitors may offer a new therapeutic window for treatment of human TLE-HS.

  • Purification, characterization and identification of rat brain cytosolic tyrosine transaminase as glutamine Transaminase-K
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-23
    Ronald R. Bowsher; David P. Henry

    The current study was undertaken to investigate the spectrum of tyrosine transaminases enzymes in a cytosolic fraction of rat brain and to specifically purify and characterize a previously identified cytosolic brain enzyme possessing tyrosine/glyoxylate transaminase activity. Based upon extensive biochemical and immunochemical characterization of purified brain tyrosine/glyoxylate transaminase, we concluded the purified enzyme is glutamine transaminase-K (EC This conclusion was based on: 1.) a concurrent enrichment in the tyrosine/glyoxylate and glutamine/phenylpyruvate transaminase activities during purification, 2.) demonstration of a co-substrate specificity for amino acids and α-keto acids that was highly consistent with published information for glutamine transaminase-K, 3.) results from detailed kinetic analysis, 4.) glutamine was a potent inhibitor of in vitro tyrosine/glyoxylate transamination, 5.) biochemical characterization, including pH optimum of 8.5 and spectrophotometric analysis and 6.) immunoanalytical analysis using a specific antiserum to rat renal glutamine transaminase-k. In addition, immunochemical characterization of a crude soluble extract of whole brain suggests that the in vitro tyrosine transaminase activity for several different α-keto acid co-substrates likely reflect the activity of glutamine transaminase-K. In conclusion, this investigation confirmed the presence of multiple tyrosine transaminase enzymes in a cytosolic extract of rat brain. Moreover, we concluded glutamine transaminase-K represents a predominant cytosolic enzyme in rat brain that's capable of catalyzing in vitro transamination of p-tyrosine and other aromatic amino acids, including the neurotransmitter precursors L-dopa and 5-hydroxytryptophan. The purified transaminase possesses a broad co-substrate specificity with preferential reactivity with α-keto acids derived from neutral aliphatic and aromatic amino acids. Lastly, we identified a heterogeneous regional distribution of tyrosine/glyoxylate transaminase (glutamine transaminase-K) in rat brain with a significantly higher level of in vitro activity in cerebellum.

  • Indole-3-guanylhydrazone hydrochloride mitigates long-term cognitive impairment in a neonatal sepsis model with involvement of MAPK and NFκB pathways
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-23
    Luana Heimfarth; Alexandra Maria Santos Carvalho; Jullyana de Souza Siqueira Quintans; Erik Willyame Menezes Pereira; Natália Teles Lima; Mikaella Tuanny Bezerra Carvalho; Rosana de Souza Siqueira Barreto; José Cláudio Fonseca Moreira; Edeildo F. da Silva-Júnior; Martine Schmitt; Jean-Jacques Bourguignon; Thiago M. de Aquino; João X. de Araújo-Júnior; Lucindo J. Quintans-Júnior
  • Hydrogen peroxide triggers an increase in cell surface expression of system xc− in cultured human glioma cells
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-23
    Leah A. Chase; Mary VerHeulen Klyen; NaTasha Schiller; Abby Goltz King; Guillermo Flores; Sasha Balcazar Engelsman; Christina Bowles; Sara Lang Smith; Anne E. Robinson; Jeffrey Rothstein

    System xc− exchanges extracellular cystine for intracellular glutamate across the plasma membrane of many cell types. One of the physiological roles of System xc− is to provide cystine for synthesis of the antioxidant glutathione. Here we report that hydrogen peroxide (H2O2) triggers the translocation of System xc− to the plasma membrane within 10 min of the initial exposure. Specifically, we observed a three-fold increase in 35S-l-cystine uptake following a 10 min exposure to 0.3 mM H2O2. This effect was dose-dependent with an EC50 for H2O2 of 65 μM. We then used cell surface biotinylation analysis to test the hypothesis that the increase in activity is due to an increased number of transporters on the plasma membrane. We demonstrated that the amount of transporter protein, xCT, localized to the plasma membrane doubles within 10 min of H2O2 exposure as a result of an increase in its delivery rate and a reduction in its internalization rate. In addition, we demonstrated that H2O2 triggered a rapid decrease in total cellular glutathione which recovered within 2 h of the oxidative insult. The kinetics of glutathione recovery matched the time course for the recovery of xCT cell surface expression and System xc− activity following removal of the oxidative insult. Collectively, these results suggest that oxidants acutely modulate the activity of System xc− by increasing its cell surface expression, and that this process may serve as an important mechanism to increase de novo glutathione synthesis during periods of oxidative stress.

  • Age-related insult of cochlear ribbon synapses: An early-onset contributor to D-galactose-induced aging in mice
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-20
    Zheng-De Du; Shu-Guang Han; Teng-Fei Qu; Bin Guo; Shu-Kui Yu; Wei Wei; Shuai Feng; Ke Liu; Shu-Sheng Gong

    Presbycusis results from age-related degeneration of the auditory system. D-galactose (D-gal)-induced aging is an ideal and commonly used animal model in aging research. Previous studies demonstrate that administration of D-gal can activate mitochondria-dependent apoptosis in the cochlear stria vascularis. However, D-gal-induced changes to cochlear inner (IHCs) and outer (OHCs) hair cells, spiral ganglion cells (SGCs), and ribbon synapses connecting IHCs and SGCs have not been systematically reported. The current study investigated changes in the numbers of hair cells, SGCs, and ribbon synapses in the mouse model of aging. We found that in comparison to control mice, the numbers of ribbon synapses and their nerve fibers were significantly decreased in D-gal-treated mice, whereas the numbers of OHCs, IHCs, and SGCs were almost unchanged. Moreover, hair cell stereocilia were also not obviously influenced by D-gal administration. Although D-gal-induced aging did not significantly shift the auditory brainstem response (ABR) thresholds in the 8, 16, and 32 kHz frequency bands, the amplitude and latency of the ABR wave I, reflecting ribbon synapse functions, were abnormal in D-gal-treated mice compared to control mice. We also found that 8-hydroxy-2-deoxyguanosine, a marker of oxidative DNA damage, was significantly increased in mitochondria of cochleae from mice exposed to D-gal-induced aging in comparison to control mice. Moreover, D-gal administration increased the levels of H2O2 and mitochondrial 3860-bp common deletion, and decreased superoxide dismutase activity and ATP production in the cochlea. Furthermore, compared with control mice, the protein levels of NADPH oxidase 2 and uncoupling protein 2 were significantly increased in the cochlea of D-gal-treated mice. Taken together, these findings support that the cochlear ribbon synapse is the primary insult site in the early stage of presbycusis, and mitochondrial oxidative damage and subsequent dysfunctions might be responsible for this insult.

  • MiR-340-5p alleviates oxygen-glucose deprivation/reoxygenation-induced neuronal injury via PI3K/Akt activation by targeting PDCD4
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-20
    Yake Zheng; Peng Zhao; Yajun Lian; Shuang Li; Yuan Chen; Lihao Li

    MicroRNA-340-5p (miR-340-5p), a suppressor of certain target genes in brain, reportedly is decreased in peripheral circulation of acute stroke patients. However, little is known regarding its role in regulating cerebral ischemia/reperfusion injury. This study explores the effect of miR-340-5p on ischemia/reperfusion insults by exposing rat hippocampal neurons to oxygen-glucose deprivation/reoxygenation (OGDR) in vitro. We found miR-340-5p to be poorly expressed in these neurons after OGDR stimulation. OGDR stimulation decreased cell viability, increased lactate dehydrogenase (LDH) activity and cell apoptosis, all of which were significantly inhibited by miR-340-5p overexpression and enhanced by miR-340-5p inhibition. Using bioinformatics analysis, we identified mRNA encoding the pro-apoptotic factor, programmed cell death 4 (PDCD4) as a putative target of miR-340-5p. A dual-luciferase reporter assay suggested that miR-340-5p targeted the 3′-UTR of PDCD4. PDCD4 was upregulated in cells exposed to OGDR, and miR-340-5p negatively modulated expression of PDCD4. PDCD4 overexpression partly reversed the neuroprotective effect of miR-340-5p during OGDR-induced injury. MiR-340-5p overexpression significantly promoted the activation of PI3K/Akt signaling pathway (P < 0.05) in OGDR-exposed cells, and PDCD4 overexpression attenuated this effect (P < 0.05). Collectively, our results indicate that miR-340-5p might exerted neuroprotective effects during OGDR injury by targeting PDCD4 and then activating the PI3K/Akt pathway. These results indicated a novel target for treating cerebral ischemic injury.

  • Upregulation of spinal glucose-dependent insulinotropic polypeptide receptor induces membrane translocation of PKCγ and synaptic target of AMPA receptor GluR1 subunits in dorsal horns in a rat model of incisional pain
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-20
    Ruijuan Guo; Yuqing Sun; Huili Li; Danxu Ma; Yun Wang

    It is unclear whether glucose-dependent insulinotropic polypeptide (GIP) receptor signaling plays an important role in spinal nociception. We hypothesized that the spinal GIPR is implicated in central sensitization of postoperative pain. Our data showed that the cumulative pain scores peaked at 3 h, kept at a high level at 1 d after incision, gradually decreased afterwards and returned to the baseline values at 5 day after incision. Correspondingly, the expression of GIPR in spinal cord dorsal horn peaked at 1 d after incision, and returned to the baseline value at 5 d after incision. The double-labeling immunofluorescence demonstrated that spinal GIPR was expressed in dorsal horn neurons, but not in astrocyte or microglial cells. At 1 d after incision, the effects of intrathecal saline, GIPR antagonist (Pro3)GIP on pain behaviors were investigated. Our data showed that at 30 min and 60 min following intrathecal treatments of 300 ng (Pro3)GIP, the cumulative pain scores were decreased and paw withdrawal thresholds to mechanical stimuli were increased when compared to those immediately before intrathecal treatments. Accordingly, at 30 min after intrathecal injections, the membrane translocation levels of PKCγ and the GluR1 expression in postsynaptic membrane in ipsilateral dorsal horns to the incision were significantly upregulated in rats with intrathecal saline injections, as compared to normal control group. At 30 min after intrathecal treatment, (Pro3)GIP inhibited the membrane translocation levels of PKCγ and the GluR1 expression in postsynaptic membrane in ipsilateral dorsal horns. Our study indicates that upregulation of spinal GIPR may contribute to pain hypersensitivity through inducing membrane translocation level of PKCγ and synaptic target of AMPA receptor GluR1 subunits in ipsilateral dorsal horns of rats with plantar incision.

  • Short review: Air pollution, noise and lack of greenness as risk factors for Alzheimer's disease- epidemiologic and experimental evidence
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-19
    Anna Oudin

    The number of patients with Alzheimer's disease (AD) is likely to triple in a few decades as the world's population ages. Given the high personal and societal burden of this disease, it is imperative to identify its risk factors. The etiology of AD is still not fully understood, but environmental factors have emerged as plausible important risk factors on the population-level. In this short review, the author summarizes literature on air pollution, noise and (lack of) greenness as risk factors for AD. In conclusion, a link between air pollution and AD is supported by experimental studies as well as epidemiological studies, although a multi-exposure approach is lacking in most epidemiological studies. Although evidence is much more limited regarding noise and (lack of) greenness as risk factors for AD, future epidemiological studies should have a multi-exposure approach in order to separate potential effects of air pollution, noise and lack of greenness. Given the heavy toll of AD on individuals and society, as well as the ubiquitous nature of environmental factors, a link between environmental stressors and AD deserves special attention.

  • LncRNA RMST-mediated miR-107 transcription promotes OGD-induced neuronal apoptosis via interacting with hnRNPK
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-15
    Hong Cheng; Mei Sun; Zhao-Lu Wang; Qian Wu; Juan Yao; Guang Ren; Xiu-Lan Sun

    The long noncoding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (RMST) silencing has been demonstrated to protect against ischemic brain injury in vivo and neuron injury in vitro. However, its underlying mechanisms in the progression of ischemic stroke have not been well explored. The expression of RMST in oxygen-glucose deprivation (OGD)-treated HT-22 hippocampal neuron cell line was examined using quantitative Real-Time PCR (qRT-PCR). CCK-8 cell viability and apoptotic cell detection using Annexin V-FITC and PI staining coupled with flow cytometry were performed to determine the pro-apoptotic role of RMST in HT-22 hippocampal neuron cell line. Furthermore, RNA pull-down, RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and dual-Luciferase reporter assays were performed to determine the mechanism of RMST in OGD-induced HT-22 cell apoptosis. In the results, RMST was highly expressed in OGD-treated HT-22 cells. Altered RMST expression led to marked changes in HT-22 cell proliferation and apoptosis. Mechanistically, RMST indirectly activated p53/miR-107 signaling pathway via interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and fulfilled its pro-apoptotic function in HT-22 cells. In conclusion, our data indicated that the RMST/hnRNPK/p53/miR-107/Bcl2l2 axis plays an important role in regulating neuronal apoptosis.

  • Epigenetic mechanisms of neurodegenerative diseases and acute brain injury
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-12
    Mario J. Bertogliat; Kahlilia C. Morris-Blanco; Raghu Vemuganti

    Epigenetic modifications are emerging as major players in the pathogenesis of neurodegenerative disorders and susceptibility to acute brain injury. DNA and histone modifications act together with noncoding RNAs to form a complex gene expression machinery that adapts the brain to environmental stressors and injury response. These modifications influence cell-level operations like neurogenesis and DNA repair to large, intricate processes such as brain patterning, memory formation, motor function and cognition. Thus, epigenetic imbalance has been shown to influence the progression of many neurological disorders independent of aberrations in the genetic code. This review aims to highlight ways in which epigenetics applies to several commonly researched neurodegenerative diseases and forms of acute brain injury as well as shed light on the benefits of epigenetics-based treatments.

  • The regulative effects of levetiracetam on adult hippocampal neurogenesis in mice via Wnt/β-catenin signaling
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-11
    Kuo Zhang, Fan Wang, Yang Zhao, Meiyao He, Yuanchao Luo, Yue Cheng, Jing Luo, Zhimei Li, Jingyu Yang

    Adult hippocampal neurogenesis plays the pivotal roles in central nervous system diseases. Recently, it has been reported that levetiracetam (LEV), a new antiepileptic drug with novel chemical construction and unique pharmacological properties, suppressed aberrant adult subventricular zone (SGZ) neurogenesis in kainite-induced epileptic mice, while promoted adult SGZ neuroblast differentiation in normal mice. These studies indicate LEV can modulate adult hippocampal neurogenesis, but the exact mechanism remained unknown. Thus, the present study aimed to investigate the effects of subchronic and chronic LEV treatments on neural stem cell by lineage tracing in adult hippocampal dentate gyrus of mice, as well as the potential mechanism related to Wnt/β-catenin signaling pathway. The data showed that both subchronic and chronic LEV treatments had no effects on body weight, locomotor activity and anxiety-like behavior in mice. Notably, subchronic LEV treatment significantly suppressed the proliferation of intermediate progenitor cell and neuroblast, decreased the number of intermediate progenitor cell and neuroblast, but increased the number of quiescent neural stem cell. On the contrary, chronic LEV treatment promoted the proliferation of neural stem cell, intermediate progenitor cell and neuroblast, increased the number of neural stem cell, intermediate progenitor cell and neuroblast, and promoted differentiation of newborn immature neuron and mature neuron. Furthermore, subchronic LEV treatment decreased the level of Wnt 3a and nuclear β-Catenin expression, which led to the inhibition on Wnt/β-catenin signaling pathway. Chronic LEV treatment increased the level of Wnt 3a, cytosolic β-catenin and nuclear β-Catenin, decreased the expression of GSK-3β, p-Tyr216-GSK-3β and Axin2, resulting in the enhancement of Wnt/β-catenin signaling pathway. These results demonstrated that LEV significantly suppressed or promoted adult hippocampal neurogenesis in mice by subchronic or chronic treatment possibly through the regulation of Wnt/β-catenin signaling pathway. Our findings provided the new perspectives of LEV on adult hippocampal neurogenesis underlying its clinical application.

  • Phosphoglycerate mutase 1 reduces neuronal damage in the hippocampus following ischemia/reperfusion through the facilitation of energy utilization
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-10
    Woosuk Kim, Hyun Jung Kwon, Hyo Young Jung, Dae Young Yoo, Dae Won Kim, In Koo Hwang

    In a previous study, we observed the effect of phosphoglycerate mutase 1 (PGAM1) on proliferating cells and neuroblasts in the subgranular zone of mouse dentate gyrus. In the present study, we examined the roles of PGAM1 in the HT22 hippocampal cell line and in gerbil hippocampus after H2O2-induced oxidative stress and after ischemia/reperfusion, respectively. Control-PGAM1 and Tat-PGAM1 proteins were synthesized using Tat-1 expression vector since Tat-1 fusion proteins can easily cross the blood-brain barrier and cell membranes. We found that transduction of Tat-PGAM1 protein into HT22 cells was dose- and time-dependent. Delivery of the protein to the cytoplasm was confirmed by western blotting and immunocytochemistry. Treatment of HT22 cells with Tat-PGAM1 protein showed a concentration-dependent reduction in cell damage and decreased formation of reactive oxygen species after H2O2 exposure. Tat-PGAM1 administration significantly ameliorated the ischemia-induced hyperactivity in gerbils at 1 day after ischemia/reperfusion. Additionally, a pronounced decrease in neuronal damage and reactive gliosis were observed in the hippocampal CA1 region of the Tat-PGAM1-treated group at 4 days after ischemia/reperfusion compared to that in the vehicle (Tat peptide) or control-PGAM1-treated groups. Administration of Tat-PGAM1 mitigated the changes in ATP content, succinate dehydrogenase activity, pH, and 4-hydroxynonenal levels in the hippocampus at 4 and 7 days after ischemia/reperfusion compared to that in the vehicle-treated group. In addition, administration of Tat-PGAM1 significantly ameliorated the ischemia-induced increases of lactate levels in the hippocampus at 15 min and 6 h after ischemia/reperfusion than in the vehicle or control-PGAM1-treated groups. These results suggest that Tat-PGAM1 can be used as a therapeutic agent to prevent neuronal damage from oxidative stress or ischemia.

  • Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-09
    Susan C. Campbell, Carmen Muñoz-Ballester, Lata Chaunsali, William A. Mills, Jennifer H. Yang, Harald Sontheimer, Stefanie Robel

    Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.

  • PDE9 inhibition promotes proliferation of neural stem cells via cGMP-PKG pathway following oxygen-glucose deprivation/reoxygenation injury in vitro
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-09
    Xiao Huan, Cheng Oumei, Qiu Hongmei, Yang Junxia, Ma Xiaojiao, Jiang Qingsong

    Cerebral ischemia is one of leading causes of death and long-term disability worldwide. Stem cell-based therapy is promising some valuable strategies for the structural and functional recovery after ischemic insult. The inhibition of phosphodiesterases (PDEs) has wide spectrum neuroprotective properties by stimulating proliferation of neural stem cells (NSCs). However, the potential role of PDE9 on NSCs proliferation after cerebral ischemia is not well investigated. The present study aimed to assess the contribution of PDE9 inhibition on the proliferation of NSCs and to determine the details of its underlying mechanisms against cerebral ischemia. The survival and proliferation of NSCs were assessed by CCK-8 assay and BrdU immunofluorescence staining, respectively. PDE9 activity and cGMP level were measured by ELISA kits. The protein expression of PKG and BDNF was detected by Western blot. Exposing NSCs of cultured primary hippocampus to oxygen-glucose deprivation/reoxygenation (OGD/R) significantly decreased the survival rate, but increased the proliferation of NSCs. Meanwhile, PDE9 activity was decreased, cGMP level was increased, PKG and BDNF protein expression was increased. PF-04447953, a PDE9 inhibitor, increased the survival rate of NSCs, moreover, PDE9 activity reduced more, and NSCs proliferation, cGMP level, PKG and BDNF protein expression were increased further, compared with OGD/R model group. These effects of PF-04447953, except for PDE9 activity and cGMP level, were reversed by treatment with KT5823, a PKG inhibitor. Taken together, the inhibition of PDE9 can promote the proliferation of NSCs following OGD/R injury, which may be, at least partly, mediated by cGMP-PKG pathway.

  • Xanthohumol, an active constituent from hope, affords protection against kainic acid-induced excitotoxicity in rats
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-06
    Che Chuan Wang, Yu Hsuan Ho, Chi Feng Hung, Jinn Rung Kuo, Su Jane Wang

    Excitotoxicity induced by excessive glutamate has been implicated in many brain disorders. Xanthohumol is a natural product derived from hops (Humulus lupulus L.), which is reported to have glutamate release-inhibiting activity. However, it is unknown whether xanthohumol has protective effects against glutamate-induced excitotoxicity. This study investigated the potential action of xanthohumol in a rat model of excitotoxicity induced by intraperitoneal injection of kainic acid (KA). Xanthohumol (10 or 50 mg/kg) administrated intraperitoneally 30 min prior to KA (15 mg/kg) considerably ameliorated KA-induced seizures, glutamate concentration elevation, and CA3 neuron death. The decrease of mitochondrial fusion protein Mfn-2 and antiapoptotic protein Bcl-2 expression in hippocampal tissues following KA injection were reversed by xanthohumol. Moreover, apoptotic protease activating factor 1 (Apaf-1) expression and caspase-3 activation in the hippocampus were inhibited by xanthohumol. These results suggest that xanthohumol up-regulates Mfn-2 and Bcl-2 to preserve mitochondrial function and suppress Apaf-1 and caspase-3 activation, thereby increasing neuron survival in rats after KA treatment. Therefore, xanthohumol has great potential for development into a therapeutic agent for improving glutamate-related nervous system diseases.

  • The role of linagliptin, a selective dipeptidyl peptidase-4 inhibitor, in the morphine rewarding effects in rats
    Neurochem. Int. (IF 3.994) Pub Date : 2019-12-03
    Małgorzata Łupina, Sylwia Talarek, Jolanta Kotlińska, Ewa Gibuła-Tarłowska, Piotr Listos, Joanna Listos

    Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor which suppresses the rapid degradation of endogenous glucagon-like peptide-1 (GLP-1). In clinical practice, it is used as an antidiabetic drug, but recent studies have confirmed its role in the activity of the central nervous system (CNS). The reported study focused on the role of linagliptin (10 and 20 mg/kg, ip) in the morphine rewarding effect, analyzing how the agent had influenced the conditioned place preference (CPP) in rats via the expression, acquisition, extinction and reinstatement of the morphine rewarding effect. The obtained results clearly demonstrated linagliptin to inhibit the expression and acquisition, to accelerate the extinction and, eventually, to reduce the reinstatement of morphine-induced CPP. The undertaken experiments significantly extended our knowledge on the mechanisms behind the morphine rewarding effect.

  • 更新日期:2019-12-03
  • Protective effect of Liraglutide on diabetic retinal neurodegeneration via inhibiting oxidative stress and endoplasmic reticulum stress
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-30
    Junli Liu, Limin Wei, Zhizhou Wang, Shiyu Song, Zhongyi Lin, Jiaxu Zhu, Xiang Ren, Li Kong

    Diabetes-induced retinal neurodegeneration occurs before visible microvascular abnormalities. Hyperglycemia-induced endoplasmic reticulum (ER) stress (ERS) and oxidative stress(OS) were considered as the important factors during diabetic retinopathy development. Liraglutide (LIRA), a glucagon-like peptide-1 (GLP-1) analogue, is widely used in the clinic and also proved having protective effect on neurodegenerative diseases. The purpose of this study was to evaluate the neuroprotective effect of LIRA on diabetes-induced retinal neurodegeneration and underlying mechanisms. In vivo, a high-fat diet and streptozotocin (STZ) injection were used inducing diabetes model. Hematoxylin-eosin staining was used for morphological observation and measuring retinal thickness. In vitro, Neuro2a cells were cultured in normal and high-glucose conditions. Flow cytometry was performed to analyze apoptosis. Additionally, Western blotting and Immunohistochemistry were carried out to detect proteins expression. The retinal thickness was decreased in diabetes. However, the retinal thickness reducing was delay after LIRA treatment in diabetes. In vitro, the apoptosis percentage, ROS production and the expression of ERS related protein GRP78, ASK1, p-IRE1α was increased and the expression of Nrf2, p-Erk1/2, Trx was decreased after HG treatment, However, the apoptosis percentage, generation of ROS and the expression of GRP78, ASK1, p-IRE1 were decreased. The expression of Nrf2, p-Erk1/2, Trx was increased significantly after LIRA treatment. Taken together, our results indicated that LIRA can alleviates diabetes-induced retinal neurodegeneration which activated Erk pathway inhibiting OS and regulated the Trx-ASK1complex inhibiting ERS.

  • Associations between long-term exposure to ambient air pollution and Parkinson's disease prevalence: A cross-sectional study
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-29
    Farhad Salimi, Ivan Hanigan, Bin Jalaludin, Yuming Guo, Margaret Rolfe, Jane S. Heyworth, Christine T. Cowie, Luke D. Knibbs, Martin Cope, Guy B. Marks, Geoffrey G. Morgan

    Background Epidemiological studies have reported contradictory results regarding the effects of ambient air pollution on Parkinson's disease (PD). This study investigated the associations between long-term exposure to particulate matter <2.5 μm in diameter (PM2.5) and nitrogen dioxide (NO2) and PD among participants in the 45 and Up Study, which comprised adults older than 45 years living in New South Wales, Australia. Methods We conducted a cross-sectional analysis of long-term exposure to PM2.5 and NO2 concentrations and prevalence of PD using data from around 240,000 cohort members from the 45 and Up Study, NSW. Annual average concentrations of NO2 and PM2.5 were estimated at the participants’ residential address using satellite-based land use regression models. Logistic regression was used to quantify the associations between these pollutants and ever physician-diagnosed PD, after adjusting for a range of individual- and area-level covariates. Results Among the 236,390 participants with complete data, 1,428 (0.6%) reported physician-diagnosed PD. Annual mean PM2.5 and NO2 concentrations for the cohort were 5.8 and 11.9 μg m−3, respectively, and were positively, but not statistically significantly associated with PD. The odds ratio for a 1 μg m−3 increase in PM2.5 was 1.01 (95% confidence interval (CI): 0.98–1.04). The adjusted odds ratio for a 5 μg m−3 increase in NO2 was 1.03 (95% CI: 0.98–1.08). In subgroup analyses, larger associations for NO2 were observed among past smokers (OR 1.11 (95% CI: 1.02–1.20) per 5 μg m−3 increase). Conclusions Overall, we found limited evidence of associations between long-term exposure to NO2 or PM2.5 and PD. The associations observed among past smokers require further corroboration.

  • Upregulation of Cdh1 in the trigeminal spinal subnucleus caudalis attenuates trigeminal neuropathic pain via inhibiting GABAergic neuronal apoptosis
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-28
    Jiayan Li, Xuhui Chen, Xuan Li, Rong Hu, Wenlong Yao, Wei Mei, Li Wan, Lingli Gui, Chuanhan Zhang

    Trigeminal neuropathic pain (TNP) remains a tremendous clinical challenge due to its elusive mechanisms. Previous studies showed that peripheral nerve injury facilitated a selective GABAergic neuronal apoptosis in the superficial dorsal horn and contributed to the development and maintenance of neuropathic pain. It has also demonstrated that downregulation of the anaphase-promoting complex/cyclosome(APC/C) and its coactivator Cdh1 contribute to neuronal apoptosis in diverse neurodegenerative diseases. However, whether APC/C-Cdh1 downregulation could induce GABAergic neuronal apoptosis in trigeminal caudalis nucleus (Vc), and then contribute to the development and maintenance of TNP remains unknown. In this study, we aimed to investigate the role of APC/C-Cdh1 in a TNP rat model and its underlying mechanisms. Our results showed that Cdh1 was primarily distributed in superficial laminae of Vc and significantly downregulated in Vc at day 14 post trigeminal nerve injury. Furthermore, trigerminal nerve injury leads to neuronal apoptosis, especially GABAergic interneurons in the superficial of Vc. Upregulating Cdh1 in Vc ameliorated mechanical allodynia and inhibited GABAergic neuronal apoptosis induced by chronic constriction injury of trigeminal infraorbital nerve (CCI-ION).

  • Neuroprotective potential of chrysin in Parkinson's disease: Molecular mechanisms and clinical implications
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-27
    Efthalia Angelopoulou, Efstratios-Stylianos Pyrgelis, Christina Piperi

    Parkinson's disease (PD) is the most common neurodegenerative movement disorder, with current treatment being mainly symptomatic and often accompanied by serious side effects. In search of novel and safe therapeutic agents for PD, natural flavonoids have been shown to exert significant neuroprotective effects. Among them, chrysin (5,7-dihydroxyflavone) has been demonstrated to exhibit anti-oxidative effects to dopaminergic neurons mainly by increasing the expression of Nuclear Factor Erythroid 2 -related factor 2 (NRF2) which reduces intracellular nitric oxide (NO) levels and regulates anti-oxidant pathways. Moreover, chrysin activates Myocyte Enhancer factor 2D (MEF2D), a critical transcription factor involved in dopaminergic survival. It suppresses the MPP-induced upregulation of c-caspase and Bax as well as the downregulation of anti-apoptotic protein Bcl 2. Chrysin also enhances the production of neurotrophic factors, contributing to neuronal survival. Of interest, the combination of chrysin with protocatechuic acid (PCA) has been demonstrated to inhibit neuronal loss in PD animal models. Along with anti-inflammatory properties, chrysin has also been shown to increase dopamine levels in the striatum via monoamino-oxidase B (MAO-B) inhibition while it restores the behavioral deficits in PD animal models. In this review, we discuss the molecular mechanisms that underlie the potentially neuroprotective effects of chrysin in PD pathogenesis along with its therapeutic potential.

  • Therapeutic strategies for ketosis induction and their potential efficacy for the treatment of acute brain injury and neurodegenerative diseases
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-27
    Lucy Camberos-Luna, Lourdes Massieu

    The therapeutic use of ketone bodies (KB) against acute brain injury and neurodegenerative disorders has been lately suggested by many studies. Several mechanisms responsible for the protective action of KB have been described, including metabolic, anti-inflammatory and epigenetic. However, it is still not clear whether a specific mechanism of action can be associated with a particular neurological disorder. Different strategies to induce ketosis including the ketogenic diet (KD), caloric restriction (CR), intermittent fasting (IF), as well as the administration of medium chain triglycerides (MCTs), exogenous ketones or KB derivatives, have been used in animal models of brain injury and in humans. They have shown different degrees of success to prevent neuronal damage, motor alterations and cognitive decline. However, more investigation is needed in order to establish safe protocols for clinical application. Throughout the present review, we describe the different approaches that have been used to elevate blood KB and discuss their effectiveness considering their advantages and limitations, as tested in models of brain injury, neurodegeneration and clinical research. We also describe the mechanisms of action of KB in non-pathologic conditions and in association with their protective effect against neuronal damage in acute neurological disorders and neurodegenerative diseases.

  • The temporal pattern of brachial plexus root avulsion-induced lncRNA and mRNA expression prior to the motoneuron loss in the injured spinal cord segments
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-26
    Guangyin Yu, Prince Last Mudenda Zilundu, Xiaoying Xu, Yingqin Li, Yingying Zhou, Ke Zhong, Rao Fu, Li-Hua Zhou

    The neuronal mechanisms underlying brachial plexus roots avulsion-induced motoneuron death are unknown. Our previous studies showed that the avulsion induced obvious temporal and spatial expression of both degenerative and regenerative genes in the injured spinal cord tissue. Therefore, we hypothesized that lncRNAs (responsible for epigenetic molecular mechanisms) are altered (resulting in altered gene expression patterns) at days 3 and 14 after avulsion. In the present microarray study, 121 lncRNAs (83 up/38 down) and 844 mRNAs (726 up/118 down) were differentially expressed (ipsilateral vs contralateral) after avulsion. We further used qRT-PCR as a validation tool to confirm the expression patterns of 5 lncRNAs and 5 mRNAs randomly selected from our microarray analysis data. The gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the critical biological processes and pathways. The noted downregulation of the AF128540 (which targets the nNOS gene) is consistent with the high expression of nNOS protein observed at day 14 post-avulsion. The downregulation of MRAK034299, whose target is the Adra1d gene, is consistent with the downregulation of Adra1d mRNA and protein at days 3 and 14 post avulsion. Immunofluorescence evaluation showed cytoplasmic translocation of ECEL1 after avulsion injury. Moreover, we also found that IL6 and Rac2 are the core genes at days 3 and 14 after unilateral brachial plexus roots avulsion, respectively. Overall, our present data suggest that the altered LncRNAs (avulsion-induced), via unknown epigenetic mechanisms, certainly contribute to the molecular mechanism underpinning motoneuron death or survival. Therefore, the avulsion-induced differentially expressed lncRNAs and mRNAs may offer potential diagnostic and therapeutic targets for BPRA.

  • Tanshinone IIA ameliorates cognitive deficits by inhibiting endoplasmic reticulum stress-induced apoptosis in APP/PS1 transgenic mice
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-26
    Yingying He, John Bosco Ruganzu, Chengheng Lin, Bo Ding, Quzhao Zheng, Xiangyuan Wu, Ruiyang Ma, Qian Liu, Yang Wang, Hui Jin, Yihua Qian, Xiaoqian Peng, Shengfeng Ji, Liangliang Zhang, Weina Yang, Xiaomei Lei

    Our previous data indicated that tanshinone IIA (tan IIA) improves learning and memory in a mouse model of Alzheimer's disease (AD) induced by streptozotocin via restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. This study aims to estimate whether tan IIA inhibits endoplasmic reticulum (ER) stress-induced apoptosis to prevent cognitive decline in APP/PS1 transgenic mice. Tan IIA (10 mg/kg and 30 mg/kg) was intraperitoneally administered to the six-month-old APP/PS1 mice for 30 consecutive days. β-amyloid (Aβ) plaques were measured by immunohistochemisty and Thioflavin S staining, apoptotic cells were observed by TUNEL, ER stress markers and apoptosis signaling proteins were investigated by western blotting and RT-PCR. Our results showed that tan IIA significantly ameliorates cognitive deficits and improves spatial learning ability of APP/PS1 mice in the nest-building test, novel object recognition test and Morris water maze test. Furthermore, tan IIA significantly reduced the deposition of Aβ plaques and neuronal apoptosis, and markedly prevented abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), as well as suppressed the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways in the parietal cortex and hippocampus. Moreover, tan IIA induced an up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 protein activity. Taken together, the above findings indicated that tan IIA improves learning and memory through attenuating Aβ plaques deposition and inhibiting ER stress-induced apoptosis. These results suggested that tan IIA might become a promising therapeutic candidate drug against AD.

  • Sildenafil promotes the anti-amnesic activity of estrogen receptor alpha agonist in animals with estrogen insufficiency
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-25
    Ahsas Goyal, Debapriya Garabadu

    The cognitive function in the females is observed to modulate with the fluctuation in plasma estrogen level. The specific estrogen receptor alpha (ERα) agonist, (4,4′,4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT), exerts similar therapeutic activity to that of estrogen replacement therapy. It can also exert cyclic adenosine monophosphate (cAMP)-dependent carcinogenic activity in the uterus of the ovariectomized animals. However, there is no report of cGMP on the ERα-mediated phosphorylation of Akt in the experimental condition. Sildenafil increases the level of cGMP in most of the tissues including brain. Hence, the present study evaluated the therapeutic effect of Sildenafil with or without PPT in rats with experimentally-induced estrogen insufficiency. The condition of estrogen insufficiency was induced in female rats through bilateral ovariectomy on day-1 (D-1) of the experimental schedule. Sildenafil (1.0 and 10.0 mg/kg) and PPT attenuated ovariectomy-induced cognitive deficits in behavioural tests and increase in body weight in the rodents. Sildenafil and PPT increased the cholinergic function and the ratio of cGMP/cAMP in the hippocampus, pre-frontal cortex and amygdala of the animals. Further, the ovariectomy-induced decrease in the extent of phosphorylation of ERα in all the brain regions was attenuated with the monotherapy of either Sildenafil or PPT. Interestingly, the combination of Sildenafil and PPT exhibited better therapeutic effectiveness than their monotherapy. However, Sildenafil attenuated the PPT-induced increase in the level of expression of phosphorylated protein kinase-B (Akt) in the discrete brain regions and the weight of uterus of these rodents. Hence, it can be assumed that the combination could be a better therapeutic alternative with minimal side effect in the management of estrogen insufficiency-induced disorders.

  • Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-22
    Nami Isooka, Ikuko Miyazaki, Ryo Kikuoka, Kouichi Wada, Erika Nakayama, Kotaro Shin, Daichi Yamamoto, Yoshihisa Kitamura, Masato Asanuma
  • Iron chelators inhibit amyloid-β-induced production of lipocalin 2 in cultured astrocytes
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-21
    Doortje W. Dekens, Peter P. De Deyn, Friederike Sap, Ulrich L.M. Eisel, Petrus J.W. Naudé

    Lipocalin 2 (Lcn2) has been implicated to play a role in various neurodegenerative diseases, and normalizing its overexpression may be of therapeutic potential. Iron chelators were found to reduce Lcn2 levels in certain animal models of CNS injury. Focusing on Alzheimer's disease (AD), we found that the iron chelators deferoxamine and deferiprone inhibited amyloid-β (Aβ)-induced Lcn2 production in cultured primary astrocytes. Accordingly, Aβ-exposure increased astrocytic ferritin production, indicating the possibility that Aβ induces iron accumulation in astrocytes. This effect was not significantly modulated by Lcn2. Known neuroprotective effects of iron chelators may rely in part on normalization of Lcn2 levels.

  • A TrkB receptor agonist N-acetyl serotonin provides cerebral protection after traumatic brain injury by mitigating apoptotic activation and autophagic dysfunction
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-21
    Tongyu Rui, Zufeng Wang, Qianqian Li, Haochen Wang, Tao Wang, Mingyang Zhang, Luyang Tao, Chengliang Luo

    Tropomyosin-related kinase B (TrkB) has emerged as a key mediator in the pathophysiology of traumatic brain injury (TBI). However, it is not known whether TrkB's agonist N-acetyl serotonin (NAS) involves in neuronal damage and brain dysfunction caused by TBI that is known as one of the most important causes of disability and death worldwide. Here, we investigated the effects of NAS on brain edema, blood-brain barrier (BBB), apoptosis activation and autophagy dysfunction after experimental TBI. A mouse TBI model was applied, NAS and ANA-12 (an antagonist of TrkB) were administered. Here, we first found that NAS administration ameliorated TBI-induced brain edema, blood-brain barrier (BBB) disruption, increase of matrix metalloproteinase-9 (MMP-9) expression and decrease of claudin-5 expression. NAS treatment decreased TBI-induced cell death and apoptosis activation (detected by propidium iodide labeling, TUNEL staining, blots for Bcl-2, Bax and caspase-3). In addition, NAS treatment decreased the expression of Beclin-1 and LC3, along with ratio of Beclin-1/Bcl-2, but increased p62 expression following TBI. NAS also enhanced the activation of the TrkB/Akt pathway following TBI. Whereas, the above protective effect of NAS following TBI was blocked by ANA-12 addition. Thus, we conclude that NAS-initiating the TrkB/Akt signaling cascade provides neuroprotection after experimental TBI in mice, which at least in part through inhibiting apoptosis activation and autophagic dysfunction.

  • Pseudoginsenoside-F11 improves long-term neurological function and promotes neurogenesis after transient cerebral ischemia in mice
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-20
    Linlin Yuan, Shibo Sun, Xiaohan Pan, Liqin Zheng, Yuting Li, Jingyu Yang, Chunfu Wu

    Stroke is the leading cause of long-term motor disability and cognitive impairment beside the acute brain injury. Recently, neurogenesis has become an attractive strategy for the chronic recovery of stroke. Our previous study showed that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, isolated from leaves of Panax pseudoginseng subsp, exerted neuroprotective effects on stroke by alleviating autophagy/lysosomal defects and repressing calcium overload. The present study investigated whether PF11 improved long-term functional recovery and promoted neurogenesis after ischemic stroke induced by transient middle cerebral artery occlusion (tMCAO) in mice. The data showed that PF11 (16, 32 mg/kg, p.o.) administrated once daily one week before tMCAO significantly reduced brain infarction and brain edema on day 3 after tMCAO. Also, PF11 attenuated the mortality, sensorimotor dysfunction, cognitive impairment and hippocampal atrophy of stroke mice. Moreover, the migration of neuroblasts and the generation of newborn neurons in ipsilateral striatum and dentate gyrus (DG) were significantly enhanced by PF11. In line with this, PF11 prevented the decreased survival rate of newborn neurons on day 42 after tMCAO. In addition, PF11 promoted proliferation and differentiation of neural stem cells in vitro. Furthermore, PF11's pro-neurogenic effect was attributed to its activation of the BDNF/TrkB, which was evidenced by that the pharmacological effects of PF11 was abolished by ANA-12, a specific inhibitor of BDNF receptor. Thus, the present study showed that PF11 could improve long-term neurological impairment and promote neurogenesis after stroke possibly through activating BDNF/TrkB pathway, indicating its potential role on treating ischemic stroke, especially chronic recovery.

  • Neuroprotective potential of azilsartan against cerebral ischemic injury: Possible involvement of mitochondrial mechanisms
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-18
    Varun Gupta, Dinesh K. Dhull, Jyoti Joshi, Sukhbir Kaur, Anil Kumar
  • N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-ҡB axis
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-18
    Doaa I. Mohamed, Eman Khairy, Sara A. Khedr, Eman Habib, Wael M. Elayat, Omnyah A. El-kharashi

    Background and aim Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2. Methods Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-ҡB and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done. Results TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-ҡB and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner. Conclusions NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.

  • N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-18
    Suwarna Chakraborty, Sunil Jamuna Tripathi, B.N. Srikumar, T.R. Raju, B.S. Shankaranarayana Rao

    Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.

  • The pivotal role of glycogen synthase kinase 3 (GSK-3) in vomiting evoked by specific emetogens in the least shrew (Cryptotis parva)
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-15
    W. Zhong, N.A. Darmani

    Glycogen synthase kinase 3 (GSK-3) is a constitutively active multifunctional serine-threonine kinase which is involved in diverse physiological processes. GSK-3 has been implicated in a wide range of diseases including neurodegeneration, inflammation, diabetes and cancer. GSK-3 is a downstream target for protein kinase B (Akt) which phosphorylates GSK-3 and suppresses its activity. Based upon our preliminary findings, we postulated Akt's involvement in emesis. The aim of this study was to investigate the participation of GSK-3 and the antiemetic potential of two GSK-3 inhibitors (AR-A014418 and SB216763) in the least shrew model of vomiting against fully-effective emetic doses of diverse emetogens, including the nonselective and/or selective agonists of serotonin type 3 (e.g. 5-HT or 2-Methyl-5-HT)-, neurokinin type 1 receptor (e.g. GR73632), dopamine D2 (e.g. apomorphine or quinpirole)-, and muscarinic 1 (e.g. pilocarpine or McN-A-343) receptors, as well as the L-type Ca2+ channel agonist (FPL64176), the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, and the chemotherapeutic agent, cisplatin. We first determined if these emetogens could regulate the phosphorylation level of GSK-3 in the brainstem emetic loci of least shrews and then investigated whether AR-A014418 and SB216763 could protect against the evoked emesis. Phospho-GSK-3α/β Ser21/9 levels in the brainstem and the enteric nerves of jejunum in the small intestine were upregulated following intraperitoneal (i.p.) administration of all the tested emetogens. Furthermore, administration of AR-A014418 (2.5–20 mg/kg, i.p.) dose-dependently attenuated both the frequency and percentage of shrews vomiting in response to i.p. administration of 5-HT (5 mg/kg), 2-Methyl-5-HT (5 mg/kg), GR73632 (5 mg/kg), apomorphine (2 mg/kg), quinpirole (2 mg/kg), pilocarpine (2 mg/kg), McN-A-343 (2 mg/kg), FPL64176 (10 mg/kg), or thapsigargin (0.5 mg/kg). Relatively lower doses of SB216763 exerted antiemetic efficacy, but both inhibitors barely affected cisplatin (10 mg/kg)-induced vomiting. Collectively, these results support the notion that vomiting is accompanied by a downregulation of GSK-3 activity and pharmacological inhibition of GSK-3 protects against pharmacologically evoked vomiting.

  • Melatonin attenuates streptozotocin-induced Alzheimer-like features in hyperglycemic rats
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-12
    Utcharaporn Kamsrijai, Prapimpun Wongchitrat, Chutikorn Nopparat, Jutamaad Satayavivad, Piyarat Govitrapong

    Diabetes mellitus (DM) is increasingly recognized as a risk for developing of Alzheimer's disease (AD). Accordingly, it has been reported that melatonin level is disturbed in both DM and AD which indicates its involvement in the pathophysiology of these diseases. In this study, the neuroprotective activities and relevant mechanisms of melatonin were evaluated in diabetic rat model. Rats were subcutaneously injected with melatonin (10 mg/kg) for 42 consecutive days. Single dose of streptozotocin (60 mg/kg STZ) was intraperitoneally injected. Morris water maze, Western blot and immunohistochemistry analysis of proteins in the hippocampus were measured. We found that melatonin was effective in protecting against memory impairment and decreased formation of Aβ42 peptide and phosphorylated tau in the hippocampus of STZ-treated rats. Melatonin significantly restored the reduction in phospho-insulin receptor β (p-IRβ) and ameliorated the increase of inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) in STZ-treated rats. Furthermore, it restored the phosphorylation of glycogen synthase kinase 3β (GSK3β), indicating a decreased activity of GSK3β. Melatonin prevented amyloidogenic processing of β-amyloid precursor protein (βAPP) by significantly inhibited β-site APP cleaving enzyme (BACE1), presenilin 1 (PS1), and β-cleaved C-terminal fragment (C99). In conclusion, melatonin ameliorates memory deficits in STZ-induced hyperglycemia rats by restoring insulin signaling pathway which is independent of its effects on blood glucose and insulin levels. Thus, melatonin might be a therapeutic option for helping patients suffering from diabetes and contributed to Alzheimer's disease.

  • Polarized hemichannel opening of pannexin 1/connexin 43 contributes to dysregulation of transport function in blood-brain barrier endothelial cells
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-08
    Masanori Tachikawa, Koji Murakami, Ryo Akaogi, Shin-ichi Akanuma, Tetsuya Terasaki, Ken-ichi Hosoya

    Dysregulation of blood-brain barrier (BBB) transport exacerbates brain damage in acute ischemic stroke. Here, we aimed to investigate the mechanism of this BBB transport dysregulation by studying the localization and function of pannexin (Px) and connexin (Cx) hemichannels in blood-brain barrier endothelial cells of rat (TR-BBB13 cells) and human (hCMEC/D3 cells) under acute ischemic stroke-mimicking oxygen/glucose deprivation (OGD) and extracellular Ca2+ ([Ca2+]e)-free conditions. TR-BBB13 cells showed increased uptake of hemichannel-permeable sulforhodamine 101, and this increase was markedly inhibited by carbenoxolone, a hemichannel inhibitor. Transcripts of Px1 and Cx43 were detected in TR-BBB13 cells and freshly isolated brain microvascular endothelial cells. The basal-compartment-to-cell uptake of hemichannel-permeable propidium iodide was selectively enhanced in hCMEC/D3 cells under [Ca2+]e-free conditions in the basal Transwell chamber. Immunohistochemical analysis revealed the predominant localization of Cx43 on the lateral membranes of hCMEC/D3 cells. [3H]Taurine uptake by hCMEC/D3 cells was significantly reduced in the absence of [Ca2+]e. Functional knock-down of Px1 and Cx43 with mimetic peptides significantly inhibited the increase of ATP release from hCMEC/D3 cells under [Ca2+]e-free conditions. These results suggest that polarized Px1/Cx43 hemichannel opening in brain capillary endothelial cells under acute ischemic stroke-mimicking conditions contributes to dysregulation of BBB transport function, resulting in release of intracellular taurine and ATP.

  • Agonist binding of human mu opioid receptors expressed in the yeast Pichia pastoris: Effect of cholesterol complementation
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-06
    Franck Talmont, Chantal Lebrun, Jean-Marie Zajac

    This study compared pharmacological profiles between human mu opioid receptors (hMOR) overexpressed in the SH-SY5Y neuroblastoma cell line (SH-hMOR) and the methylotrophic yeast Pichia pastoris (Pp-hMOR). Affinity determinations were performed by direct binding with the tritiated agonist DAMGO and antagonist diprenorphine (DIP). Additionally, displacement of these drugs with agonists (morphine and DAMGO) and antagonists (β-funaltrexamine, naloxone and diprenorphine) was examined. Tritiated DAMGO could bind to membranes prepared from Pp-hMOR, although the receptor was not coupled with G-proteins. The data obtained with this yeast strain suggested that only 7.5% of receptors were in a high-affinity-state conformation. This value was markedly less than that estimated in SH-hMOR membranes, which reached 50%. Finally, to understand the pharmacological discrepancies between Pp-hMOR and SH-hMOR, the role of sterols was evaluated. The major sterol in P. pastoris is ergosterol, while hMOR naturally functions in a cholesterol-containing membrane environment. Cell membranes were sterol-depleted or cholesterol-loaded with methyl-β-cyclodextrine. The results indicated that cholesterol must be present to ensure Pp-hMOR function. The proportion of high-affinity-state conformation was reversibly increased by cholesterol complementation.

  • Possible involvement of DNA methylation in hippocampal synaptophysin gene expression during postnatal development of mice
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-04
    Shu Aizawa, Yutaka Yamamuro

    Synaptophysin (Syp) is an integral membrane protein of synaptic vesicles, and is ubiquitously expressed in neurons throughout the brain. As Syp expression is correlated with synaptogenesis during development of the central nervous system, the expression of Syp is considered to be a critical aspect of neuronal maturation and circuit formation. However, little information is available concerning the regulatory mechanisms of Syp gene expression during postnatal development of the brain. In the present study, we investigated changes in Syp mRNA in the hippocampus of mice during postnatal development, and examined the gene regulation mechanisms, focusing on DNA methylation. We found that hippocampal Syp expression involving both mRNA and protein levels increased during the first two weeks of life, and that this increase was accompanied by a transition from hypermethylation to hypomethylation at the CpG sites of the Syp gene upstream region. In addition, DNA demethylating agent 5-Aza-2′-deoxycytidine (5-aza-dC) de-repressed Syp gene expression both in vitro in Neuro-2a mouse neuronal cells and in vivo in the hippocampus of early postnatal mice. Furthermore, the methylation levels at upstream region of Syp gene in the hippocampus of developing mice was decreased by intraperitoneal injection of 5-aza-dC. These results suggest that Syp gene regulation, at least during postnatal brain development, could be mediated by DNA methylation. Our findings promote understanding of the molecular basis of synaptogenesis during postnatal brain development, and provide novel insight into therapeutic aspects of neurodevelopmental disorders involving synaptic dysfunction.

  • Rapid and persistent loss of TXNIP in HT22 neuronal cells under carbonyl and hyperosmotic stress
    Neurochem. Int. (IF 3.994) Pub Date : 2019-11-01
    Alcir Luiz Dafre, Ariana Ern Schmitz, Pamela Maher
  • Acute blockade of the Caenorhabditis elegans dopamine transporter DAT-1 by the mammalian norepinephrine transporter inhibitor nisoxetine reveals the influence of genetic modifications of dopamine signaling in vivo.
    Neurochem. Int. (IF 3.994) Pub Date : 2016-02-07
    Daniel P Bermingham,J Andrew Hardaway,Chelsea L Snarrenberg,Sarah B Robinson,Oakleigh M Folkes,Greg J Salimando,Hussain Jinnah,Randy D Blakely

    Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis (Swip), a phenotype first described in animals with loss of function mutations in the presynaptic DA transporter (dat-1). Swip has proven to be a phenotype suitable for the identification of novel dat-1 mutations as well as the identification of novel genes that impact DA signaling. Pharmacological manipulations can also induce Swip, though the reagents employed to date lack specificity and potency, limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent on DA release and signaling, and non-additive with Swip triggered by dat-1 deletion. Using nisoxetine in combination with genetic mutations that impact DA release, we further demonstrate the utility of the drug for demonstrating contributions of presynaptic DA receptors and ion channels to Swip. Together, these findings reveal nisoxetine as a powerful reagent for monitoring multiple dimensions of DA signaling in vivo, thus providing a new resource that can be used to evaluate contributions of dat-1 and other genes linked to DA signaling without the potential for compensations that attend constitutive genetic mutations.

  • Apoptosis by 2-chloro-2'-deoxy-adenosine and 2-chloro-adenosine in human peripheral blood mononuclear cells.
    Neurochem. Int. (IF 3.994) Pub Date : 1998-07-24
    D Barbieri,M P Abbracchio,S Salvioli,D Monti,A Cossarizza,S Ceruti,R Brambilla,F Cattabeni,K A Jacobson,C Franceschi

    Adenosine has profound effects on immune cells and has been implicated in the intrathymic apoptotic deletion of T-cells during development. In order to characterize adenosine effects on quiescent peripheral blood mononuclear cells (PBMC), we have evaluated the ability of the previously characterized adenosine receptor agonist 2-chloro-adenosine (2CA; Ceruti, Barbieri et al., 1997) and of the antineoplastic drug 2-chloro-2'-deoxy-adenosine (2CdA, cladribine) to trigger apoptosis of PBMC. Apoptosis was assessed by morphological changes, DNA fragmentation by agarose gel electrophoresis and appearance of hypodiploid DNA peak by flow cytometry. 2CA (10 microM) and 2CdA (1 microM) induced apoptosis in human PBMC, which are relatively insensitive to apoptosis. For both agents, the effect was concentration- and time-dependent, although 2CdA induced apoptosis more potently than 2CA. Evaluation of mitochondrial function in parallel samples using the mitochondrial membrane-potential-specific dye JC-1 showed that mitochondrial damage followed the same kinetics as apoptosis, hence an early damage of mitochondria is likely not responsible for adenosine-induced death of PBMC. The effect of 2CA was partially prevented by addition of dipyridamole (DP), a nucleoside transport inhibitor, hence some of the apoptotic effect of this nucleoside is, at least in part, due to intracellular action. Alternatively, DP did not affect 2CdA-induced apoptosis, suggesting that 2CdA may enter cells via a DP-insensitive transporter. 5-Iodotubercidin (5-Itu), a nucleoside kinase inhibitor, was also able to partially prevent the action of 2CA and was not able to affect 2CdA-induced apoptosis, suggesting a different role for phosphorylation in 2CA- vs 2CdA-induced apoptosis. To test the role of P1 receptors, agonists and antagonists selective at various P1 receptor subtypes were used. Data suggest that, for 2CA, apoptosis is partially sustained by activation of the A2A receptor subtype, whereas no role is exerted by P1 receptors in 2CdA-dependent apoptosis. Moreover, in these cells, apoptosis could also be triggered through intense activation of the A3 receptor via selective agonists such as 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA), but this mechanism plays no role in either 2CA- or 2CdA-induced apoptosis. On the whole, our results suggest that 2CA and 2CdA follow different pathways in inducing apoptosis of immune cells. Moreover, our data also suggest that there are at least three different ways by which adenosine derivatives may induce apoptosis of human PBMC: (i) through an A2A-like extracellular membrane receptor; (ii) through entry of nucleosides into cells and direct activation of intracellular events involved in the apoptotic process; or (iii) through activation of the A3 receptor.

  • The importance of the excitatory amino acid transporter 3 (EAAT3).
    Neurochem. Int. (IF 3.994) Pub Date : 2016-05-29
    Walden E Bjørn-Yoshimoto,Suzanne M Underhill

    The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.

  • Excitatory amino acid transporters: roles in glutamatergic neurotransmission.
    Neurochem. Int. (IF 3.994) Pub Date : 2014-01-15
    Christopher B Divito,Suzanne M Underhill

    Excitatory amino acid transporters or EAATs are the major transport mechanism for extracellular glutamate in the nervous system. This family of five carriers not only displays an impressive ability to regulate ambient extracellular glu concentrations but also regulate the temporal and spatial profile of glu after vesicular release. This dynamic form of regulation mediates several characteristic of synaptic, perisynaptic, and spillover activation of ionotropic and metabotropic receptors. EAATs function through a secondary active, electrogenic process but also possess a thermodynamically uncoupled ligand gated anion channel activity, both of which have been demonstrated to play a role in regulation of cellular activity. This review will highlight the inception of EAATs as a focus of research, the transport and channel functionality of the carriers, and then describe how these properties are used to regulate glutamatergic neurotransmission.

  • The physiology and pathophysiology of basal ganglia: From signal transduction to circuits.
    Neurochem. Int. (IF 3.994) Pub Date : 2019-09-07
    Nao Chuhma,Kenji F Tanaka,Taku Nagai

  • Antioxidant cascades confer neuroprotection in ethanol, morphine, and methamphetamine preconditioning.
    Neurochem. Int. (IF 3.994) Pub Date : 2019-08-31
    Shuang Lu,Lvshuang Liao,Bing Zhang,Weitao Yan,Liangpei Chen,He Yan,Limin Guo,Shanshan Lu,Kun Xiong,Jie Yan

  • Sex differences in microRNA expression during development in rat cortex.
    Neurochem. Int. (IF 3.994) Pub Date : 2014-06-28
    Stephanie J Murphy,Theresa A Lusardi,Jay I Phillips,Julie A Saugstad

    There are important sex differences in the risk and outcome of conditions and diseases between males and females. For example, stroke occurs with greater frequency in men than in women across diverse ethnic backgrounds and nationalities. Work from our lab and others have revealed a sex-specific sensitivity to cerebral ischemia whereby males exhibit a larger extent of brain damage following an ischemic event compared to females. Studies suggest that the difference in male and female susceptibility to ischemia may be triggered by innate variations in gene regulation and protein expression between the sexes that are independent of post-natal exposure to sex hormones. We have shown that there are differences in microRNA (miRNA) expression in adult male and female brain following focal cerebral ischemia in mouse cortex. Herein we examine a role for differential expression of miRNAs during development in male and female rat cortex as potential effectors of the phenotype that leads to sex differences to ischemia. Expression studies in male and female cortices isolated from postnatal day 0 (P0), postnatal day 7 (P7), and adult rats using TaqMan Low Density miRNA arrays and NanoString nCounter analysis revealed differential miRNA levels between males and females at each developmental stage. We focused on the miR-200 family of miRNAs that showed higher levels in females at P0, but higher levels in males at P7 that persisted into adulthood, and validated the expression of miR-200a, miR-200b, and miR-429 by individual qRT-PCR as these are clustered on chromosome 5 and may be transcriptionally co-regulated. Prediction analysis of the miR-200 miRNAs revealed that genes within the Gonadotropin releasing hormone receptor pathway are the most heavily targeted. These studies support that developmental changes in miRNA expression may influence phenotypes in adult brain that underlie sexually dimorphic responses to disease, including ischemia.

  • Neurovascular interaction.
    Neurochem. Int. (IF 3.994) Pub Date : 2019-07-20
    Mika Takarada-Iemata,Peter D Westenskow,Rieko Muramatsu

  • Redox regulation in hydrogen sulfide action: From neurotoxicity to neuroprotection.
    Neurochem. Int. (IF 3.994) Pub Date : 2019-04-25
    Xue Yang,Chudong Wang,Xudong Zhang,Siqi Chen,Liangpei Chen,Shanshan Lu,Shuang Lu,Xisheng Yan,Kun Xiong,Fengxia Liu,Jie Yan

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上海纽约大学William Glover