Glutamate Receptor Modulation as a Therapeutic Strategy in Neurodegenerative Diseases: Mechanisms, Pharmacological Targets, and Future Perspectives

Abstract

Glutamate is the principal excitatory neurotransmitter in the central nervous system and plays a crucial role in synaptic transmission, neuronal development, memory formation, and synaptic plasticity. However, dysregulation of glutamatergic signaling can lead to excitotoxicity, a pathological process characterized by excessive calcium influx, oxidative stress, mitochondrial dysfunction, and neuronal damage. This mechanism has been strongly implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Glutamate receptors are broadly classified into ionotropic receptors (NMDA, AMPA, and kainate) and metabotropic glutamate receptors, both of which play essential roles in neuronal communication. Pharmacological modulation of these receptors using antagonists, agonists, and allosteric modulators has shown promising neuroprotective and disease-modifying effects in experimental studies. Nevertheless, clinical translation remains limited due to issues related to receptor selectivity, adverse effects, and incomplete understanding of glutamatergic pathways. Future research focusing on receptor subtype–selective modulators, improved safety profiles, and personalized therapeutic approaches may enhance the clinical potential of glutamate receptor–targeted therapies.