Sahin Fikret, Gunel Aslihan, Atasoy Buse Turegun, Guler Ulku, Salih Bekir, Kuzu Isinsu, Taspinar Mehmet, Cinar Ozgur, Kahveci Selda
Department of Medical Microbiology, Ankara University School of Medicine, Ankara, Turkey.
Faculty of Arts and Science Department of Chemistry-Biochemistry, Kırşehir Ahi Evran University, Kırşehir, Turkey.
Sci Rep. 2025 Jan 13;15(1):1165. doi: 10.1038/s41598-024-84479-w.
NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer's and Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer's and Parkinson's diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling-a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.
N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，如美金刚和氯胺酮，已显示出在治疗神经退行性疾病和重度抑郁症方面的疗效。这些药物纠正上述疾病的机制仍然未知。我们的研究表明，这些拮抗剂显著增强了20S蛋白酶体的活性，这对于降解内在无序、氧化损伤或错误折叠的蛋白质至关重要，而这些蛋白质是阿尔茨海默病和帕金森病等神经退行性疾病中的关键因素。在我们的小鼠模型实验中，给予氯胺酮在两小时内显著改变了大脑突触蛋白谱，显著下调了与阿尔茨海默病和帕金森病密切相关的蛋白质。此外，这些改变的蛋白质在与可塑性和增强相关的方面表现出富集，包括逆行内源性大麻素信号传导——这是短期和长期可塑性中的关键途径，可能解释了氯胺酮在重度抑郁症中的持久作用。通过不依赖泛素的20S蛋白酶体途径（UIPS），这些药物维持细胞蛋白质稳态，这至关重要，因为蛋白酶体活性会随着年龄的增长而下降，导致蛋白质聚集和疾病症状。因此，这些发现不仅为脑部疾病，也为与未折叠或错误折叠蛋白质相关的其他全身性疾病带来了新的治疗选择的希望。
