Nakagawa Yutaka, Yamada Shizuo
Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Cell Mol Neurobiol. 2023 Apr;43(3):963-989. doi: 10.1007/s10571-022-01234-3. Epub 2022 May 30.
While alterations in the locus coeruleus-noradrenergic system are present during early stages of neuropsychiatric disorders, it is unclear what causes these changes and how they contribute to other pathologies in these conditions. Data suggest that the onset of major depressive disorder and schizophrenia is associated with metal dyshomeostasis that causes glial cell mitochondrial dysfunction and hyperactivation in the locus coeruleus. The effect of the overactive locus coeruleus on the hippocampus, amygdala, thalamus, and prefrontal cortex can be responsible for some of the psychiatric symptoms. Although locus coeruleus overactivation may diminish over time, neuroinflammation-induced alterations are presumably ongoing due to continued metal dyshomeostasis and mitochondrial dysfunction. In early Alzheimer's and Parkinson's diseases, metal dyshomeostasis and mitochondrial dysfunction likely induce locus coeruleus hyperactivation, pathological tau or α-synuclein formation, and neurodegeneration, while reduction of glymphatic and cerebrospinal fluid flow might be responsible for β-amyloid aggregation in the olfactory regions before the onset of dementia. It is possible that the overactive noradrenergic system stimulates the apoptosis signaling pathway and pathogenic protein formation, leading to further pathological changes which can occur in the presence or absence of locus coeruleus hypoactivation. Data are presented in this review indicating that although locus coeruleus hyperactivation is involved in pathological changes at prodromal and early stages of these neuropsychiatric disorders, metal dyshomeostasis and mitochondrial dysfunction are critical factors in maintaining ongoing neuropathology throughout the course of these conditions. The proposed mechanistic model includes multiple pharmacological sites that may be targeted for the treatment of neuropsychiatric disorders commonly.
虽然在神经精神疾病的早期阶段蓝斑 - 去甲肾上腺素能系统会发生改变，但尚不清楚是什么导致了这些变化以及它们如何在这些疾病中导致其他病理状况。数据表明，重度抑郁症和精神分裂症的发病与金属稳态失衡有关，金属稳态失衡会导致神经胶质细胞线粒体功能障碍和蓝斑过度激活。蓝斑过度激活对海马体、杏仁核、丘脑和前额叶皮质的影响可能是一些精神症状的原因。虽然蓝斑过度激活可能会随着时间推移而减弱，但由于持续的金属稳态失衡和线粒体功能障碍，神经炎症引起的改变可能仍在持续。在早期阿尔茨海默病和帕金森病中，金属稳态失衡和线粒体功能障碍可能会导致蓝斑过度激活、病理性tau蛋白或α-突触核蛋白的形成以及神经退行性变，而在痴呆症发作前，嗅球区域的类淋巴系统和脑脊液流动减少可能是β-淀粉样蛋白聚集的原因。过度活跃的去甲肾上腺素能系统可能会刺激细胞凋亡信号通路和致病蛋白的形成，导致进一步的病理变化，无论是否存在蓝斑低激活情况都可能发生。本综述中的数据表明，虽然蓝斑过度激活参与了这些神经精神疾病前驱期和早期的病理变化，但金属稳态失衡和线粒体功能障碍是在这些疾病整个病程中维持持续神经病理学的关键因素。所提出的机制模型包括多个药理学靶点，这些靶点可能是常见神经精神疾病治疗的目标。
