Pharmacological Rescue with SR8278, A Circadian Nuclear Receptor REV-ERBα Antagonist as a Therapy for Mood Disorders in Parkinson’s Disease

Background: Parkinson’s disease is a neurodegenerative disease characterized by progressive dopaminergic (DAergic) neuronal loss. Motor deficits experienced by patients with Parkinson’s disease are well documented, but non-motor symptoms, including mood disorders associated with circadian disturbances, are also frequent features. One common phenomenon is “sundowning syndrome,” which is characterized by the occurrence of neuropsychiatric symptoms at a specific time (dusk), causing severe quality of life challenges. This study aimed to elucidate the underlying mechanisms of sundowning syndrome in Parkinson’s disease and their molecular links with the circadian clock.Methods: To induce the Parkinson’s disease mouse model, a single injection of 6-hydroxydopamine (6-OHDA) was administered into the left dorsal striatum. Five weeks post injection, mood-related behavioral tests were performed at the indicated time of day (circadian time 22-01 vs. 10-13). Local injection of a REV-ERBα antagonist, SR8278, into the ventral tegmental area, was performed 3 h before each behavioral test. To determine the molecular mechanism of behavioral deficits, fluorescent in situ hybridization, chromatin immunoprecipitation assay, western blot analysis, and ATAC-sequencing were performed.Results: Our study demonstrated that 6-OHDA-lesioned mice exhibited increased depression- and anxiety-like behaviors only at dawn. SR8278 treatment exerted antidepressant and anxiolytic effects in a circadian time-dependent manner in 6-OHDA-lesioned mice, restoring the circadian rhythm of mood-related behaviors. 6-OHDA-lesion altered DAergic-specific Rev-erbα and Nurr1 transcription, and atypical binding activities of REV-ERBα and NURR1, which are upstream nuclear receptors for the discrete tyrosine hydroxylase promoter region SR8278, restored the binding activities of REV-ERBα and NURR1 to the tyrosine hydroxylase promoter and the induction of enrichment of the R/N motif, recognized by REV-ERBα and NURR1 only at dawn, as revealed by ATAC-sequencing; therefore, tyrosine hydroxylase expression was elevated in the ventral tegmental area of 6-OHDA-injected mice, especially at dawn.Conclusions: These results indicate that REV-ERBα is a potential therapeutic target, and its antagonist, SR8278, is a potential drug for mood disorders related to circadian disturbances, namely sundowning syndrome, in Parkinson’s disease.