Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

Abstract

Background/Aims: Uncaria rhynchophylla, known as “Gou-teng”, is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP⁺-induced SH-SY5Y cells and MPTP-induced mice. Methods: MPP⁺-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson’s disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP⁺-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. Results: URE dose-dependently increased the cell viability in MPP⁺-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP⁺-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨ_m). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. Conclusions: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment.

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

“…is finding was supported by the study done by Pal and Kumar [185] that demonstrated that Uncaria rhynchophylla exhibited anti-Parkinson's activity in 6-OHDA rat model. In another model of Parkinson's disease, Uncaria rhynchophylla has been reported to increase cell viability, attenuate dopaminergic neuronal loss of substantia nigra and striatum, inhibit heat-shock protein 90 and apoptosis, and thereby induce autophagy through MAPKs and PI3K-serine/threonine protein kinase (Akt) pathways in MPP + -induced SH-SY5Y cells and MPTP-induced mouse model [186].…”

Tissue Distribution of Hirsutine and Hirsuteine in Mice by Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry

“…Pharmacological studies show that Uncaria rhynchophylla has an antagonistic effect on Ca 2+ , which can block external Ca 2+ influx and release of internal Ca 2+ [4]. It has a strong inhibitory effect on the cardiovascular system and significantly reduces blood pressure; it has obvious nerve conduction block infiltration anesthesia and spinal canal anesthesia; it has a significant inhibitory effect on the synaptic transmission process of the central nervous system and has antiepileptic effects [5][6][7]. It can be used to treat hypertension, sedation, sleeping, and antispasmodic effects [8][9][10][11][12].…”

Neuroprotective Effects of Gagam-Sipjeondaebo-Tang, a Novel Herbal Formula, against MPTP-Induced Parkinsonian Mice and MPP+-Induced Cell Death in SH-SY5Y Cells

“…The two herbs were reported to have positive effect on PD [8, 9] and have been used for patients who have motor dysfunctions in East Asia countries. Furthermore, Uncaria rhynchophylla extract has shown neuroprotective effect in MPP + -induced SH-SY5Y cells and MPTP-induced mice by increasing cell viability and ameliorating behavioral impairment through dopamine and tyrosine hydroxylase (TH) expression elevation [10]. Anti-apoptotic and antioxidative aspects of Gastrodia elata Blume in MPP + -induced cytotoxicity dopaminergic cells were also suggested [11].…”