Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement.
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 limb-placing 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.
Lee
Soon-Tae
ST
Department of Neurology, Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Seoul National University Hospital, Seoul, South Korea.
Chu
Kon
K
Jung
Keun-Hwa
KH
Kim
Juhyun
J
Kim
Eun-Hee
EH
Kim
Se-Jeong
SJ
Sinn
Dong-In
DI
Ko
Song-Yi
SY
Kim
Manho
M
Roh
Jae-Kyu
JK
D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006406:Hematoma / Q000188:drug therapy*; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000235:genetics; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases; D008559:Memantine