Brain Research 911 (2001) 96–100 www.elsevier.com / locate / bres Short communication Neuroprotection by memantine, a non-competitive NMDA receptor antagonist after traumatic brain injury in rats a,b a d a Vemuganti L. Raghavendra Rao , Aclan Dogan , Kathryn G. Todd , Kellie K. Bowen , a,c, * Robert J. Dempsey a Department of Neurological Surgery, University of Wisconsin-Madison, H4 /336 CSC, 600 Highland Avenue, Madison, WI 53792, USA b Cardiovascular Research Center, University of Wisconsin-Madison, Madison, WI, USA c William S. Middleton Memorial Veterans Administration Hospital, Madison, WI, USA d Department of Psychiatry, University of Alberta, Edmonton, Canada Accepted 1 May 2001 Abstract This study investigated whether memantine, a non-competitive NMDA receptor antagonist is neuroprotective after traumatic brain injury (TBI) induced in adult rats with a controlled cortical impact device. TBI led to significant neuronal death in the hippocampal CA2 and CA3 regions (by 50 and 59%, respectively), by 7 days after the injury. Treatment of rats with memantine (10 and 20 mg / Kg, i.p.) immediately after the injury significantly prevented the neuronal loss in both CA2 and CA3 regions. This is the first study showing the neuroprotective potential of memantine to prevent the TBI-induced neuronal damage.  2001 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Trauma Keywords: Excitotoxicity; Glutamate antagonist; Memantine; Neuroprotection; Secondary neuronal death; Traumatic brain injury The biochemical mechanisms responsible for the sec- NMDA open channel blocker memantine (3,5-dimethyl-1- ondary neuronal death after traumatic brain injury (TBI) adamantanamine) was recently shown to be neuroprotec- are not completely understood. Available evidence sug- tive without adverse side effects in animal models of gests a pivotal role for the excitatory amino acid neuro- cerebral and spinal cord ischemia [1,3,5,7,12]. The present transmitter glutamate in this process [14,17]. Previous study evaluated its usefulness in decreasing hippocampal studies showed an acute increase in glutamate release [19], neuronal death and cortical contusion volume after con- a chronic down-regulation of glutamate transporters [23] trolled cortical impact (CCI) induced TBI. and decreased densities of ionotropic (NMDA and kainate All surgical procedures were conducted, and animals subtypes) glutamate receptors [15] following TBI. NMDA were cared for according to the animal welfare guidelines receptor overactivation leads to increased calcium influx, (1985 Principles of the Guide for the Care and Use of which starts many calcium dependent processes leading to Laboratory Animals, U.S. Department of Health and cell death [28]. Several NMDA receptor antagonists have Human Services Pub. 85-23) and were approved by the received attention as therapeutic agents to limit the sec- animal care committee of the University of Wisconsin- ondary neuronal damage after trauma [18]. However, as Madison. Through a craniectomy (6 mm in diameter; most of them produce undesirable side effects at their between bregma and lambda and 1 mm lateral to midline), putative therapeutic doses, the search for a clinically viable a moderate grade CCI injury was induced in adult, male NMDA antagonist is continuing [16]. The non-competitive Sprague–Dawley rats (250–280 g) at a velocity of 3-m/s and 2 mm deformation under halothane anesthesia as described earlier [23,24]. Sham-operated rats underwent *Corresponding author. Tel.: 11-608-263-9585; fax: 11-608-263- craniectomy without the impact. During the surgery, body 1728. E-mail address: dempsey@neurosurg.wisc.edu (R.J. Dempsey). and cranial temperatures were monitored using rectal and 0006-8993 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0006-8993(01)02617-8