Topiramate Treatment Is Neuroprotective and Reduces Oligodendrocyte Loss after Cervical Spinal Cord Injury John C. Gensel 1 *, C. Amy Tovar 1 , Jacqueline C. Bresnahan 2 , Micheal S. Beattie 2 1 Center for Brain and Spinal Cord Repair, Department of Neuroscience, The Ohio State University College of Medicine, Columbus, Ohio, United States of America, 2 Brain and Spinal Injury Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America Abstract Excess glutamate release and associated neurotoxicity contributes to cell death after spinal cord injury (SCI). Indeed, delayed administration of glutamate receptor antagonists after SCI in rodents improves tissue sparing and functional recovery. Despite their therapeutic potential, most glutamate receptor antagonists have detrimental side effects and have largely failed clinical trials. Topiramate is an AMPA-specific, glutamate receptor antagonists that is FDA-approved to treat CNS disorders. In the current study we tested whether topiramate treatment is neuroprotective after cervical contusion injury in rats. We report that topiramate, delivered 15-minutes after SCI, increases tissue sparing and preserves oligodendrocytes and neurons when compared to vehicle treatment. In addition, topiramate is more effective than the AMPA-receptor antagonist, NBQX. To the best of our knowledge, this is the first report documenting a neuroprotective effect of topiramate treatment after spinal cord injury. Citation: Gensel JC, Tovar CA, Bresnahan JC, Beattie MS (2012) Topiramate Treatment Is Neuroprotective and Reduces Oligodendrocyte Loss after Cervical Spinal Cord Injury. PLoS ONE 7(3): e33519. doi:10.1371/journal.pone.0033519 Editor: Hyoung-gon Lee, Case Western Reserve University, United States of America Received June 14, 2011; Accepted February 15, 2012; Published March 13, 2012 Copyright: ß 2012 Gensel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by NIH grants NS 031193 and NS 038079. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gensel.1@osu.edu Introduction Tissue loss after spinal cord injury (SCI) is the result of primary physical damage and secondary apoptotic and necrotic cell death. Cytokines, neurotransmitters, and blood products released by the initial physical trauma create a toxic environment for neurons and oligodendrocytes. For example, levels of the pro-inflammatory cytokine, TNF-a, increase acutely after injury. Neurons, in response to high levels of TNF-a, traffic glutamate receptors to their cell membrane thereby becoming more sensitive to excitotoxic cell death [1]. TNF-a also increases the susceptibility of oligodendrocytes to excitoxic cells death [2]. Levels of pro- inflammatory cytokines and glutamate increase after injury coincident with neuron and oligodendrocyte loss [3]. Although extracellular levels of glutamate reach toxic levels shortly after SCI [4,5], delayed administration of drugs that directly antagonize glutamate receptors reduces cell loss and improves motor recovery [6]. Even when delayed by 4 hrs after SCI, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainic acid (KA) glutamate receptor antagonist NBQX improves functional recovery and tissue sparing [7]. Unfortunately, this drug, and many other glutamate receptor antagonists, have detrimental side effects and have largely failed clinical trials [8–10]. In an effort to find clinically feasible approaches for limiting excitotoxic cell death after SCI we tested the neuroprotective potential of topiramate treatment in a model of cervical SCI. Topiramate is a potent AMPA receptor antagonist FDA approved for clinical treatment of epileptic seizures and migraines. Topiramate treatment is also neuroprotective and rescues oligodendrocytes in models of traumatic brain injury, stroke, epilepsy, and Periventricular leukomalacia [11–14]. We report that topiramate delivery 15 minutes after SCI increases tissue sparing, preserves oligodendrocytes, and saves motor neurons compared to vehicle and NBQX controls. To the best of our knowledge this is the first report examining the neuroprotective potential of topiramate in a SCI model. Methods Animals and Surgery Fifty-two female, Long-Evans rats (Simonsen Laboratories, CA, USA) 75–85 days old and weighing an average of 236+/22 grams were anesthetized with sodium pentobarbital (Nembutal, Abbott Laboratories, IL, USA; 45–60 mg/kg) and received prophylactic antibiotics (cefazolin; Ancef, Novation, LCC, TX, USA; 25 mg/ kg). Body temperatures were monitored throughout the surgical procedure and maintained at 37+/22uC. Cervical contusion injuries were performed as described in detail previously [15]. Briefly, a single level laminectomy was performed at C5 and right unilateral SCI produced using the MASCIS/NYU injury device [16,17]. Two severities of injury were produced by dropping a 10- gram weight from a height of either 12.5 mm or 6.25 mm. The 12.5 mm weight drop damages .80% of the tissue ispilateral to the injury and is hereafter referred to as a severe injury [15]. The 6.25 mm weight drop damages ,50% of the hemicord and is hereafter referred to as a moderate injury [15]. Drug administration The dura was opened immediately after SCI and the animal was placed in a stereotaxic frame. Twelve minutes and thirty PLoS ONE | www.plosone.org 1 March 2012 | Volume 7 | Issue 3 | e33519