2005 - NATURE - Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement
Journal of Cerebral Blood Flow & Metabolism
Journal of Cerebral Blood Flow & Metabolism advance online publication 17 August 2005; doi: 10.1038/sj.jcbfm.9600213
Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement
This research was supported by a grant (SC3060) from Stem Cell Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea.
Soon-Tae Lee1,2,5, Kon Chu1,2,3,5, Keun-Hwa Jung1,2,4, Juhyun Kim1, Eun-Hee Kim1, Se-Jeong Kim1, Dong-In Sinn1,2, Song-Yi Ko1, Manho Kim1,2 and Jae-Kyu Roh1,2
1Department of Neurology, Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Seoul National University Hospital, Seoul, South Korea
2Program in Neuroscience, Neuroscience Research Institute of SNUMRC, Seoul National University, Seoul, South Korea
3Center for Alcohol and Drug Addiction Research, Seoul National Hospital, Seoul, South Korea
4Division of Epidemic Intelligence Service, Korea Center for Disease Control and Prevention, Seoul, South Korea
Correspondence: Dr J-K Roh, Department of Neurology, Seoul National University Hospital, 28, Yongon-Dong, Chongro-Gu, Seoul 110-744, South Korea. E-mail: rohjk@snu.ac.kr
5The first two authors contributed equally to this work.
Received 14 April 2005; Revised 01 July 2005; Accepted 18 July 2005; Published online 17 August 2005.
Top of pageAbstract
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.
Keywords: glutamate, intracerebral hemorrhage, memantine, MMP-9, tPA
nature.com |
