Objective: Our aim is to investigate whether the altered expression of clock genes is associated with the dysfunction of the anti-oxidative ability in Parkinson’s disease.

Background: The altered expression of clock genes and disturbance of circadian rhythm are reported in the animal models and patients with PD. And the dysfunction of anti-oxidative system is important pathology mechanism of Parkinson’s disease.

Methods: In vivo, 6-OHDA was injected stereotactically in the striatum of SD rat. After three weeks, the striatum were harvested at 6am, 12am, 6pm, 12pm.The expression of clock genes(bmal, clock, per2, cry1, rora) and anti-oxidative genes (sod, cat, gst, gpx)were calculated by the quantitative polymerase chain reaction (QPCR). The method of western blotting was applied to access the ratio of acetylation BMAL/BMAL and the expression of SIRT1. In vitro, the SH-SY5Y cell was treated by 6-OHDA for 24 hours. And the clock genes and anti-oxidative genes were accessed by QPCR. In addition, the ratio of acetylation BMAL/BMAL and the expression of SIRT1 were detected by western blotting. And the binding of the CRY1and BMAL were detected by the CO-IP.

Results: Compared to the sham group, the expressions of bmal, clock, per2, cry1,rora decreased the expression pattern of clock gene was also altered in the 6-OHDA induced PD model. At the same time, the anti-oxidative genes (sod, cat, gpx)were down-regulated in 6-OHDA group. The expression of SIRT1 and BMAL was also decreased in the PD group, but the ratio of acetylation BMAL/BMAL was increased. And in vivo, the change of clock genes and anti-oxidative genes was similar with the aminal model. Then, the decrease of clock genes and anti-oxidative genes was partially rescued by Resveratrol treatment. The binding of the CRY1and BMAL was elevated in the 6-OHDA group and can be normalized by the Resveratrol treatment.

Conclusions: In PD model induced by 6-OHDA, the expression of the clock genes and SIRT1 are decreased. As a result, the level of acetylation BMAL was high in the 6-OHDA group, especially when compared to the total BMAL. Further, acetylation BMAL may promote the binding with CRY, which may induce the inhibition of the transcription of the downstream gene containing the E-BOX in the promoter. Thus, the expression of the anti-oxidative gene was down-regulated in the PD. Our result suggest that SIRT1 accelerating the progress of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/disruption-of-circadian-rhythm-function-and-anti-oxidation-via-sirt1-bmal1-pathway-in-6-ohda-induced-parkinsons-disease-model/