title: Post-acute delivery of memantine promotes post-ischemic neurological recovery, peri-infarct tissue remodeling, and contralesional brain plasticity.
abstract: The NMDA antagonist memantine preferentially inhibits extrasynaptic NMDA receptors, which are overactivated upon stroke and thought to disturb neuroplasticity. We hypothesized that memantine enhances post-ischemic neurological recovery, brain remodeling, and plasticity. C57BL6/j mice were exposed to intraluminal middle cerebral artery occlusion. Starting 72 hours post-stroke, vehicle or memantine (4 or 20 mg/kg/day) were subcutaneously delivered over 28 days. Neurological recovery, perilesional tissue remodeling and contralesional pyramidal tract plasticity were evaluated over 49 days. Memantine, delivered at 20 but not 4 mg/kg/day, persistently improved motor-coordination and spatial memory. Secondary striatal atrophy was reduced by memantine. This delayed neuroprotection was associated with reduced astrogliosis and increased capillary formation around the infarct rim. Concentrations of BDNF, GDNF, and VEGF were bilaterally elevated by memantine in striatum and cortex. Anterograde tract tracing studies revealed that memantine increased contralesional corticorubral sprouting across the midline in direction to the ipsilesional red nucleus. In the contralesional motor cortex, the NMDA receptor subunit GluN2B, which is predominantly expressed in extrasynaptic NMDA receptors, was transiently reduced by memantine after 14 days, whereas GluN2A and PSD-95, which preferentially co-localize with synaptic NMDA receptors, were increased after 28 days. Our data suggest the utility of memantine for enhancing post-acute stroke recovery.
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Ya-Chao
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Sanchez-Mendoza
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D020520:Brain Infarction; D002545:Brain Ischemia; D020244:Infarction, Middle Cerebral Artery; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D018696:Neuroprotective Agents; D020127:Recovery of Function / Q000187:drug effects*
chemical_list: D018696:Neuroprotective Agents; D008559:Memantine
keywords: Brain plasticity; brain remodeling; cerebral angiogenesis; focal cerebral ischemia; neurological recovery