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.

Correlates of Post-Stroke Brain Plasticity, Relationship to Pathophysiological Settings and Implications for Human Proof-of-Concept Studies

“…The intrinsic capacity of brain repair can be efficiently stimulated by exogenous therapeutic interventions, e.g., by physical exercise, delivery of growth factors, cell-based biologicals or pharmacological compounds, which in rodent and primate models of stroke were shown to enhance neurological recovery (Bacigaluppi et al, 2009 ; Reitmeir et al, 2011 , 2012 ; Jaeger et al, 2015 ; Wang et al, 2016 ). Neurological recovery in the experimental setting can be defined as regain of lost function of the paretic limb as compared to a baseline defined previous to the stroke, which should not be confused with neurological compensation (Murphy and Corbett, 2009 ), in which other parts of the limbs (e.g., shoulder or the non-paretic limb) are recruited to complete a task.…”

Prenatal Deltamethrin Exposure-Induced Cognitive Impairment in Offspring Is Ameliorated by Memantine Through NMDAR/BDNF Signaling in Hippocampus

“…Memantine, a non-competitive, partial NMDAR antagonist, inhibits NMDA glutamate receptors to regulate the glutamatergic system and relieve cognitive and memory deficits in several diseases, such as Alzheimer’s disease, Parkinson’s disease, and ischemia ( Olivares et al, 2012 ; Wang et al, 2016 ). Previous studies have suggested that memantine prevents excitotoxicity induced by Ca 2+ overload in neurons via NMDARs and then upregulates BDNF, thereby enhancing cognitive ability ( Olivares et al, 2012 ; Ranju et al, 2015 ; Liu et al, 2016 ).…”

“…Moreover, NMDA receptor antagonists, such as MK-801, have neuroprotective properties in pyrethroid-treated neurons, which suggests the involvement of NMDARs in the mechanism of pyrethroid-induced neurotoxicity ( Chugh et al, 1992 ; Umeda et al, 2016 ). Memantine, which is a non-selective, non-competitive antagonist of NMDA receptors, has been proved to improve cognitive abilities in several conditions, such as Parkinson’ disease, ischemia dementia, through regulating NMDA glutamate receptors ( Olivares et al, 2012 ; Wang et al, 2016 ).…”

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders.

“…On the other hand, astrocytes were shown to produce VEGF upon brain injury, ischemia and neuroinflammation for regulating vascular remodeling and angiogenesis during the repair process [39,40]. Memantine improved stroke outcomes via increasing BDNF, GDNF and VEGF levels, reducing reactive astrogliosis, and enhancing vascular density [41,42]. In a rat model of chronic cerebral hypoperfusion, memantine enhanced neovascularization with increases in BDNF and VEGF expressions [43].…”