Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement

• Published in: Journal of cerebral blood flow and metabolism Vol. 26; no. 4; pp. 536 - 544
• Main Authors: Lee, Soon-Tae, Chu, Kon, Jung, Keun-Hwa, Kim, Juhyun, Kim, Eun-Hee, Kim, Se-Jeong, Sinn, Dong-In, Ko, Song-Yi, Kim, Manho, Roh, Jae-Kyu
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.04.2006; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Cerebral Hemorrhage - drug therapy; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Gene Expression Regulation - drug effects; Hematoma - drug therapy; Male; Matrix Metalloproteinases - analysis; Medical sciences; Memantine - administration & dosage; Memantine - pharmacology; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; RNA, Messenger - genetics; Tissue Plasminogen Activator - genetics; Toxicity: nervous system and muscle; Treatment Outcome; Urokinase-Type Plasminogen Activator - genetics; Vascular diseases and vascular malformations of the nervous system; intracerebral hemorrhage; tPA; memantine; MMP-9; glutamate; Nervous system diseases; Enzyme; Cardiovascular disease; Metalloendopeptidases; Glutamate receptor; Antialzheimer agent; Glutamate; Antiparkinson agent; Gelatinase B; Cerebral disorder; Vascular disease; Peptidases; Memantine; Cerebral hemorrhage; Amantadine dérivatives; Central nervous system disease; Hematoma; Hydrolases; Antagonist; NMDA receptor; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/sj.jcbfm.9600213

Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limbplacing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.