NEUROPROTECTIVE CONCENTRATIONS OF THE N -METHYL--ASPARTATE OPEN-CHANNEL BLOCKER MEMANTINE ARE EFFECTIVE WITHOUT CYTOPLASMIC VACUOLATION FOLLOWING POST-ISCHEMIC ADMINISTRATION AND DO NOT BLOCK MAZE LEARNING OR LONG-TERM POTENTIATION H.-S. V. CHEN,* Y. F. WANG,* P. V. RAYUDU,* P. EDGECOMB,² J. C. NEILL,² M. M. SEGAL,*§S. A. LIPTON*§and F. E. JENSEN²‡§¶ *CNS Research Institute, Neurosurgical Service and Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, U.S.A. ²Division of Neuroscience, Children’s Hospital, Boston, MA 02115, U .S.A. §Program in Neuroscience, Harvard Medical School, Boston, MA 02115, U.S.A. Abstract––The potential of most N -methyl--aspartate antagonists as neuroprotectants is limited by side effects. We previously reported that memantine is an open-channel N -methyl--aspartate blocker with a faster off-rate than many uncompetitive N -methyl--aspartate antagonists such as dizocilpine maleate. This parameter correlated with memantine’s known clinical tolerability in humans with Parkinson’s disease. Memantine is the only N -methyl--aspartate antagonist that has been used clinically for excitotoxic disorders at neuroprotective doses. Therefore, we wanted to investigate further the basis of its clinical efficacy, safety, and tolerability. Here we show for the first time for any clinically-tolerated N -methyl--aspartate antagonist that memantine significantly reduces infarct size when administered up to 2 h after induction of hypoxia/ischemia in immature and adult rats. We found that at neuroprotective concentrations memantine results in few adverse side effects. Compared to dizocilpine maleate, memantine displayed virtually no effects on Morris water maze performance or on neuronal vacuolation. At concentrations similar to those in brain following clinical administration, memantine (6–10 μM) did not attenuate long-term potentiation in hippocampal slices and substantially spared the N -methyl--aspartate component of excitatory postsynaptic currents, while dizocilpine maleate (6–10 μM) or -2-amino-5- phosphovalerate (50 μM) completely blocked these phenomena. We suggest that the favorable kinetics of memantine interaction with N -methyl--aspartate channels may be partly responsible for its high index of therapeutic safety, and make memantine a candidate drug for use in many N -methyl--aspartate receptor-mediated human CNS disorders.  1998 IBRO. Published by Elsevier Science Ltd. Key words: memantine, MK-801, glutamate, NMDA receptors, hypoxia/ischemia, rat. Excitotoxic neuronal injury in focal hypoxia/ ischemia, epilepsy, trauma, and certain degenerative diseases is largely mediated by overactivation of the N -methyl--aspartate (NMDA) glutamate receptor subtype (for reviews see Refs 9, 37 and 41). There is extensive literature regarding neuroprotection by NMDA antagonists in disease models in vivo and in vitro. However, the clinical potential of many experimental drugs is hampered by the fact that they indiscriminately block physiologic effects of NMDA receptor activation at neuroprotective doses. 37,41 Adverse effects range from hallucinations and sedation to learning and memory deficits. NMDA receptors are important for the induction of long-term potentiation (LTP), and a number of NMDA antagonists have been shown to block this phenomenon. 29,50 In addition to neurobehavioral effects, dizocilpine maleate (MK-801) and other NMDA antagonists have been shown to cause acute but reversible neuronal vacuolation when systemi- cally administered at neuroprotective doses. 45,46 In the immature brain, the potential for adverse effects ¶To whom correspondence should be addressed. These authors contributed equally to the work. A bbreviations: ACA, anterior cerebral artery; ACSF, artificial cerebrospinal fluid; ANOVA, analysis of variance; -APV, -2-amino-5-phosphovalerate; EGTA, ethyleneglycolbis(aminoethylether)tetra-acetate; EPSC, excitatory postsynaptic currents; EPSP, excitatory postsynaptic potentials; HEPES, N -2-hydroxyethyl- piperazine-N 1 -2-ethanesulphonic acid; HSP-70, heat shock protein; ICA, internal carotid artery; LTP, long- term potentiation; MCAO, middle cerebral artery occlu- sion; MK-801, dizocilpine maleate; MRI, magnetic resonance images; NMDA, N -methyl--aspartate; PBS, phosphate-buffered saline; TTC, 2,3,5-triphenyl- tetrazolium chloride. Pergamon N euroscience Vol. 86, No. 4, pp. 1121–1132, 1998 Copyright  1998 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306–4522/98 $19.00+ 0.00 PII: S0306-4522(98)00163-8 1121