Background/Aim:Circadian rhythm proteins (CRP) play critical roles in both physiological and pathophysiological conditions, including neurodegenerative disorders. As member of CRP, the nuclear receptors REV-ERBα/β regulates circadian rhythm particularly by inhibiting Bmal1 protein and 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, which were investigated in the present study.Materials and Methods: For the induction of TBI, animals were submitted 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 RevErbα and RevErbβ proteins were activated or deactivated, and their expression profiles were determined by Western blot analyzes. 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 RevErbβ significantly reduced brain injury after TBI, which was reversed by inhibiting this protein. Not activation but the inhibition of both RevErb proteins increased brain swelling significantly. In addition, both RevErbα and RevErbβ improved BBB permeability and neuronal survival significantly, which were reversed by their inhibitions.Conclusion: Our results show that both RevErbα and particularly RevErbβ 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.

REV-ERB α/β proteins play critical roles in circadian rhythm regulation and are considered to be specialized members of the nuclear receptor family. These so-called "orphan" proteins, whose endogenous ligands were initially unidentified, have become exogenously interferable through synthetic agents with the discovery of their endogenous ligands. This feature has made them an important target for clinical research in recent years. Unlike other nuclear receptors, the unique structure of REV-ERB proteins allows them to perform only transcription inhibition, which makes them even more intriguing. This review summarizes the structural features of REV-ERB α/β proteins and their role in the circadian cycle. We also discuss findings in the literature on the function of REV-ERB α/β proteins in the metabolic and immune systems, emphasizing their importance in these systems.