Objective To investigate the protective effect and regulatory mechanism of ciprofol on Parkinson′s disease (PD) rats based on the adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) signaling pathway.
Methods Wistar rats were divided into blank control group, model group, ciprofol group, and ciprofol+AMPK inhibitor dorsomorphin group (ciprofol+Dor group), with 10 rats in each group. Except for the blank control group, PD models were established in the other three groups. Behavioral experiments were used to assess the motor and cognitive functions of rats in each group. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) in the rat brain striatum. Immunofluorescence staining was conducted to measure the level of tyrosine hydroxylase (TH) in the rat brain substantia nigra. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was applied to detect the relative mRNA expression levels of ULK1, beclin1, LC3, Bcl-2 , and Bax in the rat brain striatum. Western blot was used to determine the relative protein expression levels of ULK1, beclin1, Bcl-2, Bax, phosphorylated (p)-AMPK, SIRT1, PGC1α, and the ratio of LC3Ⅱ to LC3Ⅰ(LC3Ⅱ/LC3Ⅰ) in the rat brain striatum.
Results Compared with the blank control group, the motor and cognitive functions of rats in the model group were reduced, the levels of DA and 5-HT in the brain striatum decreased, the fluorescence intensity of TH in the brain substantia nigra weakened, and the relative mRNA expression levels of ULK1, beclin1, LC3, Bcl-2 , as well as the relative protein expression levels of ULK1, beclin1, Bcl-2, p-AMPK, SIRT1, PGC1α, and LC3Ⅱ/LC3Ⅰ in the brain striatum were reduced. In contrast, the relative mRNA expression level of Bax and the relative protein expression level of Bax increased, with statistically significant differences (P < 0.05). Compared with the model group, the motor and cognitive functions of rats in the ciprofol group were improved, the levels of DA and 5-HT in the brain striatum increased, the fluorescence intensity of TH in the brain substantia nigra strengthened, and the relative mRNA expression levels of ULK1, beclin1, LC3, Bcl-2 , as well as the relative protein expression levels of ULK1, beclin1, Bcl-2, p-AMPK, SIRT1, PGC1α, and LC3Ⅱ/LC3Ⅰ in the brain striatum were elevated. Meanwhile, the relative mRNA expression level of Bax and the relative protein expression level of Bax decreased, with statistically significant differences (P < 0.05). The comparison between the ciprofol+Dor group and the ciprofol group revealed that the AMPK inhibitor dorsomorphin could reverse the effects of ciprofol (P < 0.05).
Conclusion Ciprofol may exert neuroprotective effects for PD rats by promoting autophagy through activating the AMPK/SIRT1/PGC1α signaling pathway.
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