Pharmacological Rescue with SR8278, a Circadian Nuclear Receptor REV-ERB alpha Antagonist as a Therapy for Mood Disorders in Parkinson's Disease

Abstract

Parkinson's disease is a neurodegenerative disease characterized by progressive dopaminergic 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. We demonstrated that 6-hydroxydopamine (6-OHDA)-lesioned mice, as Parkinson's disease mouse model, exhibit increased depression- and anxiety-like behaviors only at dawn (the equivalent of dusk in human). Administration of REV-ERB alpha antagonist, SR8278, exerted antidepressant and anxiolytic effects in a circadian time-dependent manner in 6-OHDA-lesioned mice and restored the circadian rhythm of mood-related behaviors. 6-OHDA-lesion altered DAergic-specific Rev-erb alpha and Nurr1 transcription, and atypical binding activities of REV-ERB alpha and NURR1, which are upstream nuclear receptors for the discrete tyrosine hydroxylase promoter region. SR8278 treatment restored the binding activities of REV-ERB alpha and NURR1 to the tyrosine hydroxylase promoter and the induction of enrichment of the R/N motif, recognized by REV-ERB alpha and NURR1, as revealed by ATAC-sequencing; therefore, tyrosine hydroxylase expression was elevated in the ventral tegmental area of 6-OHDA-injected mice, especially at dawn. These results indicate that REV-ERB alpha 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.