Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases.
Scientific reports January 13, 2025 Fikret Sahin, Aslihan Gunel, Buse Turegun Atasoy et al. 10 citations
Drugs that block the N-methyl-D-aspartate receptor, such as memantine and ketamine, increase the activity of the 20S proteasome, a cellular machine that degrades damaged or misfolded proteins. In a mouse model, ketamine changed the levels of many brain proteins within two hours, notably reducing proteins linked to Alzheimer's and Parkinson's diseases. The altered proteins were involved in synaptic plasticity and retrograde endocannabinoid signaling, a pathway that may explain ketamine's lasting effects in major depression. Because proteasome activity declines with age, leading to protein aggregation, these findings suggest new treatment possibilities for brain diseases and other conditions involving misfolded proteins.