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.