Targeting the differentiation of astrocytes by Bilobalide in the treatment of Parkinson’s disease model

Abstract

Background: The etiology of Parkinson’s disease (PD), a chronic and progressive neurodegenerative disease, is multifactorial but not fully unknown. Until now, no drug has been proven to have neuroprotective or neuroregenerative effects in patients with PD. Objectives: To observe the therapeutic potential of Bilobalide (BB), a constituent of ginkgo biloba, in MPTP-induced PD model, and explore its possible mechanisms of action. Material and Methods: Mice were randomly divided into three groups: healthy group, MPTP group and MPTP + BB group. PD-related phenotypes were induced by intraperitoneal injection of MPTP into male C57BL/6 mice, and BB (40 mg/kg/day) was intraperitoneally given for 7 consecutive days at the end of modeling. The injection of saline was set up as the control in a similar manner. Results: BB induced M2 polarization of microglia, accompanied by inhibition of neuroinflammation in the brain. Simultaneously, BB promoted the expression of BDNF in astrocytes and neurons, and expression of GDNF in neurons. Most interestingly, BB enhanced the formation of GFAP⁺ astrocytes expressing nestin, Brn2 and Ki67, as well as the transformation of GFAP⁺ astrocytes expressing tyrosine hydroxylase around subventricular zone, providing experimental evidence that BB could promote the conversion of astrocytes into TH⁺ dopamine neurons in vivo and in vitro. Conclusions: These results suggest the natural product BB may utilize multiple pathways to modify degenerative process of TH⁺ neurons, revealing an exciting opportunity for novel neuroprotective therapeutics. However, its multi-target and important mechanisms need to be further explored.

Graphical Abstract

Keywords:

• Bilobalide
• MPTP-PD model
• neuroregeneration
• astrocytes

Authors’ contribution

CG and BG designed the experimental process, checked all experimental data and revised the manuscript. LJ and RX are involved in the establishment of animal model, intervention of drug and the writing of the manuscript. JW, QM, ZB and QX carried out Western blot. YH, JJ, JA and JZ carried out immunohistopathology and immunohistochemistry. QW carried out q-PCR, prepared and identified Bilobalide used in this experiment. All authors read and approved the final manuscript.

Conflict of interest

None of the authors has any potential financial and non-financial conflict of interest related to this manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Data availability statement

The datasets used or analyzed during the current study are available from the first authors and corresponding authors on reasonable request.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (81473577); Open Project of The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University (2019004); Open Project of Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Shanxi Datong University (KF-2019002); Leading Team of Medical Science and Technology, Shanxi Province (2020TD05); Funds for construction of key disciplines from Shanxi University of Chinese Medicine and Young Scientists Cultivation Project of Shanxi University of Chinese Medicine (2021PY-QN-09).