Patton State Hospital, 3102 Highland Ave., Patton, CA 92369, USA.
University of California Riverside, Riverside 900 University Ave., Riverside, CA 92521, USA.
Int J Mol Sci. 2024 May 28;25(11):5904. doi: 10.3390/ijms25115904.
For the past 70 years, the dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling and antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there has been limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal senescence, brain volume loss, the attenuation of gamma oscillations in electroencephalograms, and the oxidation of lipids in the plasma and mitochondrial membranes. We surmise that the aberrant activation of the aryl hydrocarbon receptor by toxins derived from gut microbes or the environment drives premature cellular and neuronal senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including the impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: (1) to summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders, and (2) to discuss novel strategies for improving long-term outcomes in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor antagonists.
在过去的 70 年中，多巴胺假说一直是精神分裂症的关键工作模型。这促成了许多多巴胺能信号抑制剂和抗精神病药物的开发，这些药物导致症状迅速缓解，但仅有轻微的疗效改善。在过去几十年中，针对精神分裂症的可量化病理变化的研究非常有限，包括过早的细胞/神经元衰老、脑容量损失、脑电图中γ 振荡的衰减以及血浆和线粒体膜中脂质的氧化。我们推测，源自肠道微生物或环境的毒素对芳烃受体的异常激活会导致过早的细胞和神经元衰老，这是精神分裂症的一个标志。早期大脑衰老会导致继发性变化，包括线粒体损伤和丧失、灰质耗竭、γ 振荡减少以及代谢向乳酸和乳酰化的代偿性转变。本综述的目的有两个：（1）总结已知的与精神分裂症或类似精神分裂症的疾病中的过早细胞/神经元衰老有关的知识；（2）讨论使用天然衰老治疗、膜脂质替代、线粒体移植、微生物苯并嗪、新型抗氧化苯并噻嗪、糖原合酶激酶-3β抑制剂和芳烃受体拮抗剂等新型策略来改善严重精神疾病的长期预后。
