Mechanistic description
REVISED MECHANISM (post-Skeptic critique): Constitutive GluN2B signaling combined with age-related oxidative stress leads to excessive nNOS-derived superoxide and peroxynitrite (ONOO⁻) formation, causing vasomotor uncoupling, AQP4 oxidation, and endothelial glycocalyx damage. Original NO-vasoconstriction mechanism was mechanistically flawed (NO produces vasodilation). Memantine data explained by reduced excitotoxic oxidative stress. Targeting downstream astrocyte/vascular pathways may be superior to direct GluN2B inhibition.
Evidence for (2)
Memantine enhances CSF tracer clearance in mice (mechanism reinterpreted)
GluN2B upregulation in aged cortex correlates with reduced glymphatic influx
Evidence against (3)
NO produces vasodilation, not vasoconstriction; original mechanism mechanistically unsound
Ifenprodil has off-target effects on alpha1-adrenergic and sigma receptors
Memantine citation may be mismatched (per Skeptic)