TY - JOUR
T1 - Pharmacological Rescue with SR8278, a Circadian Nuclear Receptor REV-ERBα Antagonist as a Therapy for Mood Disorders in Parkinson’s Disease
AU - Kim, Jeongah
AU - Park, Inah
AU - Jang, Sangwon
AU - Choi, Mijung
AU - Kim, Doyeon
AU - Sun, Woong
AU - Choe, Youngshik
AU - Choi, Ji Woong
AU - Moon, Cheil
AU - Park, Sung Ho
AU - Choe, Han Kyoung
AU - Kim, Kyungjin
N1 - Funding Information:
This work was supported by the NRF grant (NRF-2021R1A2C1004803) and DGIST start-up fund Program of the Ministry of Science and ICT (2020010055) awarded to KK, by Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science and ICT (NRF-No.2017M3A9G8084463) to JWC, by the basic science research program through the NSF funded by the Ministry of Education (2020R1A6A1A03040516) to CM, and by the NRF grant (NRF-2017M3C7A1048089), KBRI Basic Research Program (KBRI-21-BR-02–04) to YC.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - 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-ERBα 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-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 treatment 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, 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-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.
AB - 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-ERBα 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-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 treatment 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, 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-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.
KW - Circadian mood regulation
KW - Dopaminergic neuronal loss
KW - Nurr1
KW - Parkinson’s disease
KW - Rev-erbα
KW - Sundowning syndrome
UR - http://www.scopus.com/inward/record.url?scp=85126909145&partnerID=8YFLogxK
U2 - 10.1007/s13311-022-01215-w
DO - 10.1007/s13311-022-01215-w
M3 - Article
C2 - 35322351
AN - SCOPUS:85126909145
SN - 1933-7213
VL - 19
SP - 592
EP - 607
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 2
ER -