Characterization of molecular mechanisms underlying the neuroprotective and neurotrophic activities of Chinese medicinal compound puerarin and electroacupuncture : implications for the therapy of Parkinson's disease

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide. Current applied treatments are undesirable, therapies that target disease modification are in high demand. Traditional Chinese medicine (TCM) has long been documented as having beneficial protection against neurodegeneration. Based on the theory of TCM, the pathogen of PD can be attributed to the deficiency in Liver and Kidney. The effectiveness of TCM approaches has been extensively investigated currently, whereas the molecular mechanisms remain obscure.

The current study was designed to determine the regulation mechanism of representative TCM therapeutic approaches from experimental perspective. Therefore, it was accomplished by three parts, 1) in Chapter 3, the therapeutic benefit and molecular basis of bioactive compound puerarin was determined; 2) In Chapter 4, the neuroprotective capacity of EA in the management of PD was identified; 3) In Chapter 5, the combination effect of puerarin and EA was tested in PD mouse model.

Considering the complexity in herbal formula and the herbal extracts, the benefits of bioactive compound puerarin, isolated from Gegen (葛根), was strategically observed against MPTP-induced neurotoxicity in mice. As expected, the motor impairments and the dopamine depletion triggered by MPTP can be effectively reversed by puerarin. Additionally, puerarin could effectively enhance the neurite extension in PC12 cells, which was dramatically abolished with the co-administration of a progesterone receptor inhibitor. The transient transfection of progesterone receptor siRNA and progesterone receptor luciferase promoter activity further confirmed the involvement of the progesterone receptor activation in the neuroprotective effect of puerarin against neurotoxicity.

As the other important therapies in TCM, acupuncture also has been reported with diverse therapeutic benefits. The neurotrophic activity of EA was next observed on MPTP mice model. As expected, pretreatment with EA on GV21 and GV29 could effectively recover motor function as well as dopaminergic neuron loss in the toxin-based PD model. The regulatory effect of EA on the regulation of brain derived neurotrophic factor (BDNF) and activation of the related signaling transduction, particularly on isoforms of the TrkB receptor, was determined. EA treatment could effectively enhance the expression of functional TrkB, resulting in a reversed ratio of functional TrkB versus the truncated structure which impaired under the MPTP challenge. The additional administration with TrkB receptor inhibitor further confirmed the regulatory role of TrkB in the neuroprotective effect of EA.

To mimic the TCM daily practice situation, the combination benefits was determined. The combination of puerarin and EA was assessed. However, combining them does not bring superior benefits compared with either the EA treated alone or just a high dose of puerarin treatment.

Taken together, based on the current results, puerarin exerts neuroprotective and neurotrophic effect against parkinsonism neurotoxicity mainly via activation progesterone receptor. EA could ameliorate MPTP injury mainly via the regulation of BDNF/TrkB signaling. These findings showed that both puerarin and EA could act as neuroprotective and neurotrophic agents in the neurotoxin-based animal model, however their combination benefits needs to be further determined.