Neuroprotective effect of the herbal pair Coptidis Rhizoma-Cinnamomi Cortex against 6-OHDA-induced Parkinson's disease rats through promotion of autophagy via the PI3K/AKT/mTOR pathway.

Parkinson's disease (PD) is a common neurodegenerative disorder with a universal and fast-growing increase in both prevalence and incidence worldwide. Coptidis Rhizoma-Cinnamomi Cortex (CR-CC), a classic herbal pair comprising the Jiaotai Pill, has been widely used in clinical practice to improve PD and its associated symptoms including anxiety and insomnia. However, the mechanism of the action of CR-CC in improving PD remains to be fully elucidated. To investigate the therapeutic effect of CR-CC against PD rats and the relevant mechanism. A rat model of PD was established through unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum. The therapeutic effects were evaluated by three kinds of behavioral tests, the levels of oxidative stress markers, and tyrosine hydroxylase (TH). The neurotransmitters and their metabolites were determined by UPLC-MS/MS. Immunohistochemistry, immunofluorescence, and western blotting were conducted to detect the TH expression and α-Synuclein (α-Syn) level in the substantia nigra (SN). The potential targets and related signaling pathways were analyzed and predicted using network pharmacology analysis and molecular docking, and the expression of LC3II/LC3I, p62, and the proteins related to PI3K/AKT/mTOR pathways in the SN of PD rats was assessed by western blotting. CR-CC ameliorated motor dysfunction and oxidative damage in the serum of PD rats and modulated the neurotransmitter levels of the striatum on the injured side. It also attenuated the dopaminergic neuronal loss and abnormal aggregation of α-Syn in the SN, showing similar effects compared with CR and CC administration alone. Network pharmacology and molecular docking analysis suggested that MTOR, PIK3CA, and MAPK3 related to autophagy would be the core targets for the active compounds of CR-CC. Further studies showed that CR-CC increased the LC3II/LC3I ratio, decreased the p62 level, and regulated the expression of proteins related to the PI3K/AKT/mTOR pathway in PD rats. The results showed that CR-CC exerted neuroprotective effects by regulating autophagy through the PI3K/AKT/mTOR pathway to reduce the α-Syn level in the SN of PD rats and showed similar effects to those of CR and CC alone.