The role of circadian rhythm proteins Rev-Erb? and ? in the development of neuronal injury after traumatic brain injury

Abstract

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-Erb alpha/(3 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. Materials and methods: 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-Erb alpha and Rev-Erb(3 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. Results: Our observations indicate that Rev-Erb(3 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-Erb alpha and Rev-Erb(3 improved BBB permeability and neuronal survival significantly, which were reversed by their inhibitions. Conclusion: Our results show that Rev-Erb alpha and particularly Rev-Erb(3 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.