Phytochemicals with potential NMDAR-inhibitory activities: a review of neuroprotective mechanisms against excitotoxicity

The N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors in the central nervous system (CNS) that play a crucial role in synaptic plasticity, learning, and memory. However, NMDAR overstimulation is a critical pathological feature in neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. This excitotoxic cascade triggers massive intracellular calcium influx, oxidative stress, and mitochondrial dysfunction, ultimately driving neuronal apoptosis. In this regard, phytochemicals have emerged as safe, multitargeting NMDAR inhibitors with significant therapeutic potential. This review synthesizes current experimental evidence regarding the neuroprotective potential of major phytochemical classes, including glycosides (e.g., vitexin, ginsenosides), polyphenols (e.g., quercetin, resveratrol), alkaloids (e.g., cytisine, huperzine A), and terpenoids (e.g., bilobalide, fucoxanthin). The results of these studies demonstrate that these bioactive compounds mitigate excitotoxicity via multiple mechanisms, including direct receptor blockade, inhibiting specific subunits (such as GluN2B), and downregulating NMDAR expression. Furthermore, they restore neuronal homeostasis by modulating downstream signaling pathways; thereby suppressing neuroinflammation and apoptosis. It can be concluded that phytochemicals represent a vital reservoir of modulatory agents that protect against glutamate-induced neurotoxicity. Hence, they offer a compelling framework for future drug discovery in CNS therapeutics.