Research PaperAcute administration of perampanel, an AMPA receptor antagonist, reduces cognitive impairments after traumatic brain injury in rats
Introduction
Traumatic brain injury (TBI) remains a major cause of disability and death in the United States. In 2013, approximately 2.8 million people sustained a TBI in the United States alone, and approximately 69 million TBIs occur worldwide each year (Dewan et al., 2018; Taylor et al., 2017). TBI usually requires long-term care and therefore conveys a substantial economic cost to health systems. In the United States, the direct and indirect costs of TBI amount to more than 76 billion dollars annually (Centers for Disease Control and Prevention, 2017).
The long-term consequences of TBI result from the primary injury and the subsequent secondary injury. Primary injury constitutes the initial mechanical deformation caused by an external force and results in numerous physiological, cellular, and molecular responses such as contusion, laceration, intracranial hemorrhage, cerebral ischemia, and intracranial hypertension (Smith et al., 1997; Werner and Engelhard, 2007). Acceleration and deceleration inertial forces are likely to result in the diffuse axonal injury pathology that is observed in 40–50% of individuals who sustain fatal TBI (Bennett et al., 1995).
Secondary injury refers to the pathophysiologic biochemical cascade initiated as a result of the primary injury. A key component in this secondary injury cascade is glutamate excitotoxicity, which results from the indiscriminate and excessive release of excitatory amino acids from the impaired neurons (Krishnamurthy and Laskowitz, 2016). Glutamate mediates fast excitatory transmission predominantly through ionotropic glutamate receptors such as the N-methyl-d-aspartate (NMDA) receptor and the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor. The expression and function of NMDA and AMPA receptors are often altered after injury (Spaethling et al., 2008; Sta Maria et al., 2017), and these receptors are the focus of much of the research seeking to identify therapeutic options for patients with TBI. In particular, excessive NDMA receptor activation and the consequent increased calcium influx observed immediately after the primary injury has been implicated as a predominant pathophysiological mechanism of excitotoxicity (Kalia et al., 2008; Waxman and Lynch, 2005). This increase in NMDA receptor activation subsequently triggers phosphorylation, subunit modification, and activation of AMPA receptors (Spaethling et al., 2012; Spaethling et al., 2008). Unfortunately, however, NMDA receptor antagonists, such as selfotel, aptiganel, eliprodil, licostinel, and gavestinal, have failed to show efficacy in patients with TBI when evaluated in clinical trials (Ikonomidou and Turski, 2002).
AMPA receptor blockade, however, has recently emerged as a potential alternative strategy for providing neuroprotection in TBI (Belayev et al., 2001; Chen et al., 2017; Spaethling et al., 2008). In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel [PER]; marketed as Fycompa, Esai, Co, Woodcliff Lake NJ), an orally active noncompetitive AMPA receptor antagonist utilized in seizure management in the United States and approved in more than 40 countries world-wide (Hanada et al., 2011), was found to exert protective effects in the controlled cortical impact (CCI) TBI model in rats (Chen et al., 2017). However, the CCI model produces a predominately focal injury, without the diffuse axonal injury that is observed clinically in TBI and is associated with acceleration/deceleration forces (Albert-Weissenberger and Siren, 2010; Bennett et al., 1995; Meythaler et al., 2001). In this study, we evaluated the neuroprotective effects of PER in the rodent lateral fluid percussion injury (LFPI) model, a model that produces both focal and diffuse injury (Lin et al., 2015). Importantly, fluid percussion injury also reproduces the cognitive effects of TBI observed in patients, and is therefore considered to be of high clinical relevance (Dixon et al., 1987). We hypothesize that either pre- or post-TBI administration of the AMPA antagonist will show efficacy in reducing injury-induced deficits in a rodent model of LFPI.
Section snippets
Animals
All experimental protocols and animal handling procedures were reviewed and approved by the University of Alabama at Birmingham (UAB) Institutional Animal Care and Use Committee in compliance with the National Research Council of the National Academies Guide for the Care and Use of Laboratory Animals (Council, 2011). A total of 239 adult male, gonad-intact, Sprague-Dawley (SD) rats weighing 250–300 g were obtained from Charles River Laboratories, Inc. (Wilmington, MA) and used for these
Return of righting reflex
Loss of consciousness is a preclinical and clinical indicator of TBI severity (Floyd et al., 2002; Lyeth et al., 1988). Consequently, we used the duration of loss of consciousness, as indicated by the suppression of the righting reflex, to evaluate injury severity after LFPI. Of note, the pre-injury administration cohort received PER for 7 days before LFPI, but the post-injury administration cohort had not received PER at the time of LFPI, when the duration of transient unconsciousness was
Discussion
No multicenter phase III randomized controlled trial of a neuroprotective agent has shown improvement for patients with TBI, despite the strides that have been made in TBI management (Nichol et al., 2015). Thus, interest in elucidating effective approaches for conferring neuroprotection after TBI remains high. Notably, AMPA receptor antagonism has shown promise as a potential neuroprotective strategy in preclinical models of ischemia (Follett et al., 2000; Gaspary et al., 1994; Kawasaki-Yatsugi
Conclusion
Our data in a clinically relevant model of TBI indicate that preventative or therapeutic administration of PER is neuroprotective and reduces injury-induced deficits in cognition and behavior. This AMPA receptor antagonist, which has already been approved by the United States Food and Drug administration for the treatment of epilepsy, may have therapeutic potential in the treatment of patients with TBI.
Acknowledgements
This work was supported by an investigator initatied study (IIS) to JS from Eisai, Inc.
References (70)
- et al.
Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations
Brain Res.
(1989) - et al.
BW1003C87 and NBQX but not CGS19755 reduce glutamate release and cerebral ischemic necrosis
Eur. J. Pharmacol.
(1994) A review of the validity and variability of the elevated plus-maze as an animal model of anxiety
Pharmacol. Biochem. Behav.
(1996)- et al.
Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?
Lancet Neurol.
(2002) - et al.
NMDA receptors in clinical neurology: excitatory times ahead
Lancet Neurol.
(2008) - et al.
Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model
Neuropharmacology
(2000) - et al.
A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats
Neuroscience
(2006) - et al.
Neuroprotective effects of topiramate and memantine in combination with hypothermia in hypoxic-ischemic brain injury in vitro and in vivo
Neurosci. Lett.
(2018) - et al.
Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory
Cell
(2003) - et al.
Effects of anticholinergic treatment on transient behavioral suppression and physiological responses following concussive brain injury to the rat
Brain Res.
(1988)
Current concepts: diffuse axonal injury-associated traumatic brain injury
Arch. Phys. Med. Rehabil.
AMPA receptor antagonist Perampanel ameliorates post-stroke functional and cognitive impairments
Neuroscience
Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial
Lancet
Depression-like and anxiety-like behavioural aftermaths of impact accelerated traumatic brain injury in rats: a model of comorbid depression and anxiety?
Behav. Brain Res.
Cognitive sequelae of traumatic brain injury
Psychiatr Clin. North Am.
The AMPA antagonist NBQX protects thalamic reticular neurons from degeneration following cardiac arrest in rats
Brain Res.
NMDA receptor mediated phosphorylation of GluR1 subunits contributes to the appearance of calcium-permeable AMPA receptors after mechanical stretch injury
Neurobiol. Dis.
Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update
Neuroscience
Neuroprotective effect of a novel AMPA receptor antagonist, YM90K, in rat focal cerebral ischaemia
Brain Res.
Pathophysiology of traumatic brain injury
Br. J. Anaesth.
The female encounter test: a novel method for evaluating reward-seeking behavior or motivation in mice
Int. J. Neuropsychopharmacol.
Experimental traumatic brain injury
Exp. Transl. Stroke Med.
Executive functions deficits after severe traumatic brain injury: the GREFEX study
J. Head Trauma Rehabil.
Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats
J. Neurotrauma
Mild in vitro trauma induces rapid Glur2 endocytosis, robustly augments calcium permeability and enhances susceptibility to secondary excitotoxic insult in cultured Purkinje cells
Brain
Clinicopathologic observations in 100 consecutive patients with fatal head injury admitted to a neurosurgical unit
Ir. Med. J.
The effect of gender on patients with moderate to severe head injuries
J. Trauma
Severe TBI
The AMPAR antagonist perampanel attenuates traumatic brain injury through anti-oxidative and anti-inflammatory activity
Cell. Mol. Neurobiol.
Guide for the Care and Use of Laboratory Animals: Eighth Edition
Descartes' Error: Emotion, Reason and the Human Brain
Encoding, consolidation, and retrieval of contextual memory: differential involvement of dorsal CA3 and CA1 hippocampal subregions
Learn. Mem.
17beta-estradiol confers protection after traumatic brain injury in the rat and involves activation of G protein-coupled estrogen receptor 1
J. Neurotrauma
Estimating the global incidence of traumatic brain injury
J. Neurosurg.
A fluid percussion model of experimental brain injury in the rat
J. Neurosurg.
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- 1
Virginia Aida, MS, Auburn University, 153 Lee Road 953, Auburn, Alabama 36832.
- 2
Tracy Niedzielko, B.S., Research Associate, Physical Medicine and Rehabilitation, 383 Colorow Drive, room 298, University of Utah, Salt Lake City, Utah 84108 USA.
- 3
Jerzy P. Szaflarski, M.D., pH.D, Professor, Department of Neurology, Director of UAB Epilepsy Center, 1719 6th Avenue South, CIRC 132, University of Alabama at Birmingham, Birmingham, AL 35249 USA.