Pençe Mahmud E, Doğan Enes, Koç Halil I, Bayraktaroğlu Çiğdem, Altunay Serdar, Balçikanli Zeynep, Kiliç Ertuğrul, Beker Mustafa Ç
Research Institute for Health Sciences and Technologies (SABITA), İstanbul Medipol University, İstanbul, Turkiye.
Department of Physiology, Faculty of Medicine, İstanbul Medipol University, İstanbul, Turkiye.
Turk J Med Sci. 2024 Sep 19;54(6):1409-1418. doi: 10.55730/1300-0144.5924. eCollection 2024.
BACKGROUND/AIM: Circadian rhythm proteins (CRPs) play critical roles in both physiological and pathophysiological conditions, including neurodegenerative disorders. As members of CRPs, the nuclear receptors Rev-Erbα/β regulate circadian rhythm particularly by inhibiting Bmal1 protein and are involved in the neuroinflammation and cell death processes. However, their roles in the development of neuronal injury after traumatic brain injury (TBI) were largely unexplored, and so were investigated in the present study.
For the induction of TBI, animals were subjected to the cryogenic model of TBI, which is a commonly used animal model and shares essential similarities with cerebral ischemia in terms of pathophysiological cascades. To assess the impact of Rev-Erb proteins on TBI, both Rev-Erbα and Rev-Erbβ proteins were activated or deactivated, and their expression profiles were determined by western blot analyses. Infarct volume and brain swelling were analyzed by cresyl violet staining. Blood-brain barrier (BBB) permeability was analyzed by immunoglobulin G extravasation. Neuronal survival was analyzed by NeuN immunohistochemistry.
Our observations indicate that Rev-Erbβ significantly reduced brain injury after TBI, which was reversed by inhibiting this protein. Not activation but the inhibition of both Rev-Erb proteins increased brain swelling significantly. In addition, both Rev-Erbα and Rev-Erbβ improved BBB permeability and neuronal survival significantly, which were reversed by their inhibitions.
Our results show that Rev-Erbα and particularly Rev-Erbβ play significant roles in the development of neuronal injury after TBI. Our findings suggest that Rev-Erb proteins would be a potential therapeutic target for the treatment of neurodegenerative diseases.
背景/目的：昼夜节律蛋白（CRPs）在生理和病理生理状况中发挥关键作用，包括神经退行性疾病。作为CRPs的成员，核受体Rev-Erbα/β尤其通过抑制Bmal1蛋白来调节昼夜节律，并参与神经炎症和细胞死亡过程。然而，它们在创伤性脑损伤（TBI）后神经元损伤发展中的作用在很大程度上尚未得到探索，因此在本研究中进行了调查。
为诱导TBI，对动物采用TBI低温模型，这是一种常用的动物模型，在病理生理级联反应方面与脑缺血有本质相似之处。为评估Rev-Erb蛋白对TBI的影响，激活或失活Rev-Erbα和Rev-Erbβ蛋白，并通过蛋白质免疫印迹分析确定它们的表达谱。通过甲酚紫染色分析梗死体积和脑肿胀。通过免疫球蛋白G外渗分析血脑屏障（BBB）通透性。通过NeuN免疫组织化学分析神经元存活情况。
我们的观察结果表明，Rev-Erbβ显著减轻了TBI后的脑损伤，抑制该蛋白可逆转这一作用。并非激活而是抑制这两种Rev-Erb蛋白会显著增加脑肿胀。此外，Rev-Erbα和Rev-Erbβ均显著改善了BBB通透性和神经元存活情况，抑制它们可逆转这些作用。
我们的结果表明，Rev-Erbα尤其是Rev-Erbβ在TBI后神经元损伤的发展中发挥重要作用。我们的研究结果表明，Rev-Erb蛋白可能是治疗神经退行性疾病的潜在治疗靶点。
