Ginkgolide A improves the pleiotropic function and reinforces the neuroprotective effects by mesenchymal stem cell-derived exosomes in 6-OHDA-induced cell model of Parkinson’s disease

Parkinson’s disease (PD) is a common disorder attributed to the loss of midbrain dopamine (mDA) neurons and reduced dopamine secretion. Currently, the treatment regimes for PD comprise deep brain stimulations, however, it attenuates the PD progression marginally and does not improve neuronal cell death. We investigated the function of Ginkgolide A (GA) to reinforce Wharton’s Jelly-derived mesenchymal stem cells (WJMSCs) for treating the in vitro model of PD. GA enhanced the self-renewal, proliferation, and cell homing function of WJMSCs as assessed by MTT and transwell co-culture assay with a neuroblastoma cell line. GA pre-treated WJMSCs can restore 6-hydroxydopamine (6-OHDA)-induced cell death in a co-culture assay. Furthermore, exosomes isolated from GA pre-treated WJMSCs significantly rescued 6-OHDA-induced cell death as determined by MTT assay, flow cytometry, and TUNEL assay. Western blotting showed that apoptosis-related proteins were decreased following GA-WJMSCs exosomal treatment which further improved mitochondrial dysfunction. We further demonstrated that exosomes isolated from GA-WJMSCs could restore autophagy using immunofluorescence staining and immunoblotting assay. Finally, we used the alpha-synuclein recombinant protein and found that exosomes derived from GA-WJMSCs led to the reduced aggregation of alpha-synuclein compared to that in control. Our results suggested that GA could be a potential candidate for strengthening stem cell and exosome therapy for PD.

[1]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[2]  Y. Katakura,et al.  Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion , 2021, Nutrients.

[3]  B. Singh,et al.  Promising drug targets and associated therapeutic interventions in Parkinson’s disease , 2021, Neural regeneration research.

[4]  B. Singh,et al.  Mucuna pruriens in Parkinson’s and in some other diseases: recent advancement and future prospective , 2020, 3 Biotech.

[5]  F. Cao,et al.  Synergistic Effects of Ginkgolide B and Protocatechuic Acid on the Treatment of Parkinson’s Disease , 2020, Molecules.

[6]  Y. Tao,et al.  Exosomes: key players in cancer and potential therapeutic strategy , 2020, Signal Transduction and Targeted Therapy.

[7]  I. Shimomura,et al.  Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice , 2020, Molecular Therapy.

[8]  P. Ji,et al.  Ginkgolide B inhibits lung cancer cells promotion via beclin-1-dependent autophagy , 2020, BMC Complementary Medicine and Therapies.

[9]  S. An,et al.  Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy , 2020, Cell Death & Disease.

[10]  Jai-Sing Yang,et al.  Tetramethylpyrazine reverses high-glucose induced hypoxic effects by negatively regulating HIF-1α induced BNIP3 expression to ameliorate H9c2 cardiomyoblast apoptosis , 2020, Nutrition & Metabolism.

[11]  S. Rai,et al.  Advancement in the modelling and therapeutics of Parkinson’s disease , 2020, Journal of Chemical Neuroanatomy.

[12]  Zili Feng,et al.  The neuroprotective mechanisms of ginkgolides and bilobalide in cerebral ischemic injury: a literature review , 2019, Molecular Medicine.

[13]  F. Ye,et al.  Ginkgolide A protects adverse cardiac remodeling through enhancing antioxidation and nitric oxide utilization in mice with pressure overload. , 2019, Die Pharmazie.

[14]  Changqing Zhang,et al.  Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way , 2019, Journal of cellular and molecular medicine.

[15]  R. Giugno,et al.  Extracellular Vesicles Mediate Mesenchymal Stromal Cell-Dependent Regulation of B Cell PI3K-AKT Signaling Pathway and Actin Cytoskeleton , 2019, Front. Immunol..

[16]  Guan-Chiun Lee,et al.  Ginkgolide A Prevents the Amyloid-β-Induced Depolarization of Cortical Neurons. , 2018, Journal of agricultural and food chemistry.

[17]  J. Cho,et al.  Dysregulated autophagy contributes to caspase-dependent neuronal apoptosis , 2018, Cell Death & Disease.

[18]  J. Yu,et al.  Ginkgolide B promotes neuronal differentiation through the Wnt/β-catenin pathway in neural stem cells of the postnatal mammalian subventricular zone , 2018, Scientific Reports.

[19]  M. Simpson,et al.  Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice , 2018, PeerJ.

[20]  Muhammad Hassan,et al.  Ginkgolide B promotes the proliferation and differentiation of neural stem cells following cerebral ischemia/reperfusion injury, both in vivo and in vitro , 2018, Neural regeneration research.

[21]  Zhenzhong Wang,et al.  Diterpene ginkgolides protect against cerebral ischemia/reperfusion damage in rats by activating Nrf2 and CREB through PI3K/Akt signaling , 2018, Acta Pharmacologica Sinica.

[22]  H. Harn,et al.  Exosomes and Stem Cells in Degenerative Disease Diagnosis and Therapy , 2018, Cell transplantation.

[23]  Saheli Samanta,et al.  Exosomes: new molecular targets of diseases , 2017, Acta Pharmacologica Sinica.

[24]  Y. Bao,et al.  Ginkgolide A Ameliorates LPS-Induced Inflammatory Responses In Vitro and In Vivo , 2017, International journal of molecular sciences.

[25]  Z. Su,et al.  Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance , 2016, Journal of immunology research.

[26]  H. Tse,et al.  Mesenchymal stem cells and immunomodulation: current status and future prospects , 2016, Cell Death and Disease.

[27]  A. Strafella,et al.  Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment , 2015, The Lancet Neurology.

[28]  W. Kuo,et al.  ANG II promotes IGF-IIR expression and cardiomyocyte apoptosis by inhibiting HSF1 via JNK activation and SIRT1 degradation , 2014, Cell Death and Differentiation.

[29]  L. Bour,et al.  Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial , 2013, The Lancet Neurology.

[30]  Jian Pan,et al.  Effects of Ginkgolide A on Okadaic Acid-induced Tau Hyperphosphorylation and the PI3K-Akt Signaling Pathway in N2a Cells , 2012, Planta Medica.

[31]  W. Xue,et al.  The Role of SDF-1-CXCR4/CXCR7 Axis in the Therapeutic Effects of Hypoxia-Preconditioned Mesenchymal Stem Cells for Renal Ischemia/Reperfusion Injury , 2012, PloS one.

[32]  X. Zou,et al.  Ginkgolide B promotes proliferation and functional activities of bone marrow-derived endothelial progenitor cells: involvement of Akt/eNOS and MAPK/p38 signaling pathways. , 2011, European cells & materials.

[33]  John Hardy,et al.  Parkinson's disease , 2009, The Lancet.

[34]  A. Lumsden,et al.  Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries. , 2006, Journal of vascular surgery.

[35]  M. Breteler,et al.  Epidemiology of Parkinson's disease , 2006, The Lancet Neurology.

[36]  E Ray Dorsey,et al.  The Parkinson Pandemic-A Call to Action. , 2018, JAMA neurology.

[37]  E. Katunina,et al.  [Epidemiology of Parkinson's disease]. , 2013, Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova.

[38]  Shuwei Ma,et al.  Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats , 2011, Journal of Natural Medicines.