NMDAR antagonists, such as memantine and ketamine, have demonstrated efficacy in treating neurodegenerative diseases and major depression. Our recent findings reveal that these antagonists significantly enhance 20S proteasome activity, which is essential for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins-key factors in neurodegenerative diseases like Alzheimer's and Parkinson's. Through the Ubiquitin-Independent 20S Proteasome pathway (UIPS), these drugs help maintain cellular protein homeostasis, a critical function that declines with age and contributes to protein aggregation and disease symptoms. Our findings provide a plausible explanation for how memantine alleviates symptoms of Alzheimer's and Parkinson's diseases by reducing or preventing protein aggregation in the brain. Furthermore, our data suggest that the dramatic changes in synaptic protein homeostasis induced by ketamine within 2 hours may contribute to its therapeutic effects in major depression.

The etiology and mechanisms of schizophrenia are not well understood, arising from complex interactions between genetic and environmental factors. Its pathophysiology reflects this complexity, with abnormalities in multiple brain functions. This review discusses the potential effects of NMDAR antagonists on the pathophysiology of schizophrenia and their therapeutic impact, supported by our data.