Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Pain. 2023 May 1;164(5):1106-1117. doi: 10.1097/j.pain.0000000000002807. Epub 2022 Oct 19.
The increased presence of senescent cells in different neurological diseases suggests the contribution of senescence in the pathophysiology of neurodegenerative disorders. Microglia can adapt to any type of disturbance of the homeostasis of the central nervous system, and its altered activity can lead to permanent and unresolvable damage. The aim of this work was to characterize the behavioural phenotype of spared nerve injury mice and then associate it with senescence-related mechanisms. In this work, we investigated the timing of the onset of anxiety, depression, or memory decline associated with peripheral neuropathic pain and their correlation with the presence of microglial cellular senescence. Spared nerve injury mice showed a persistent pain hypersensitivity from 3 days after surgery. Twenty-eight days after nerve injury, they also developed anxiety, depression, and cognitive impairment. The appearance of these symptoms was coincident to a significant increase of senescence markers, such as β-galactosidase and senescent-associated secretory phenotype, at the microglial level in the spinal cord and hippocampus of spared nerve injury animals. These markers were unaltered at previous time points. In murine immortalized microglial cells (BV2) stimulated with LPS 500 ng/mL for 10 days (4 hours/day) every other day, we observed an increase of β-galactosidase and senescent-associated secretory phenotype appearance, a reduction of cell viability, and an increase of senescence-associated heterochromatin foci. Therefore, present findings could represent an important step to a better understanding of the pathophysiological cellular mechanisms in comorbidities related to neuropathic pain states.
衰老细胞在不同神经疾病中的大量存在表明衰老在神经退行性疾病的病理生理学中的贡献。小胶质细胞可以适应中枢神经系统内稳态的任何类型的干扰，其活性改变会导致永久性和不可逆转的损伤。本工作的目的是描述 spared nerve injury 小鼠的行为表型，然后将其与衰老相关的机制相关联。在本工作中，我们研究了与周围神经性疼痛相关的焦虑、抑郁或记忆减退的发病时间及其与小胶质细胞衰老相关机制的相关性。spared nerve injury 小鼠在手术后 3 天表现出持续的痛觉过敏。神经损伤 28 天后，它们还出现焦虑、抑郁和认知障碍。这些症状的出现与小胶质细胞水平上衰老标志物（如β-半乳糖苷酶和衰老相关分泌表型）的显著增加同时发生，在 spared nerve injury 动物的脊髓和海马中。这些标志物在前几个时间点没有改变。在 LPS 500ng/ml 刺激的永生化小鼠小胶质细胞（BV2）中，每隔一天刺激 10 天（每天 4 小时），我们观察到β-半乳糖苷酶和衰老相关分泌表型的出现增加，细胞活力降低，衰老相关异染色质焦点增加。因此，目前的发现可能是更好地理解与神经病理性疼痛状态相关的共病的病理生理细胞机制的重要一步。
