2005 - Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement
1] 1Department of Neurology, Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Seoul National University Hospital, Seoul, South Korea [2] 2Program in Neuroscience, Neuroscience Research Institute of SNUMRC, Seoul National University, Seoul, South Korea.
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.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 August 2005; doi:10.1038/sj.jcbfm.9600213.
ncbi.nlm.nih.gov
PMID: 16107786 [PubMed - as supplied by publisher] |
