Research Paper
Acute administration of perampanel, an AMPA receptor antagonist, reduces cognitive impairments after traumatic brain injury in rats

https://doi.org/10.1016/j.expneurol.2020.113222Get rights and content

Abstract

Traumatic brain injury (TBI) is a major cause of death and physical as well as cognitive disability for which an effective treatment option remains to be identified. Evidence in preclinical models has indicated that antagonists of the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor exert neuroprotective effects after mechanical injury in vitro and in vivo. In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel), a selective AMPA receptor antagonist with good bioavailability, was recently shown to therapeutically protect against the sequelae of TBI in the rodent controlled cortical impact model. However, this model induces a largely focal injury and is less representative of diffuse injury components that occur in TBI resulting from acceleration/deceleration forces. Here, we investigated the neuroprotective effects of perampanel in the rodent lateral fluid percussion injury model (LFPI), which produces both focal and diffuse injury. Pre- or post-injury administration of perampanel in male adult rats attenuated the injury-induced increase in the pro-apoptotic bax/bcl-xL ratio in the hippocampus; reduced impairments in learning and memory, assessed by the Morris water maze test; and reduced impairments in reward-seeking behavior, assessed by a female encounter test. Although additional studies are needed to determine the sex-related differences in the neuroprotective effects, these results provide support for the therapeutic potential of perampanel in TBI.

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.

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  • Cited by (6)

    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.

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