The neuroprotective effects and transdifferentiation of astrocytes into dopaminergic neurons of Ginkgolide K on Parkinson's disease mice

  • Qiang Miao
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China
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  • Zhi Chai
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China
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  • Li-Juan Song
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China

    Dept. of Neurology and Physiology, The First Clinical College, Shanxi Medical University, Taiyuan 030001, China
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  • Qing Wang
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China
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  • Guo-bin Song
    Affiliations
    Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Disease, Shanxi Datong University, Datong 037009, China
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  • Jing Wang
    Affiliations
    Dept. of Neurology and Physiology, The First Clinical College, Shanxi Medical University, Taiyuan 030001, China
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  • Jie-Zhong Yu
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China

    Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Disease, Shanxi Datong University, Datong 037009, China
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  • Bao-Guo Xiao
    Correspondence
    Corresponding author.
    Affiliations
    Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, China
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  • Cun-Gen Ma
    Correspondence
    Corresponding author at: The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China.
    Affiliations
    The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, Jinzhong 030619, China

    Institute of Brain Science, Shanxi Key Laboratory of Inflammatory Neurodegenerative Disease, Shanxi Datong University, Datong 037009, China
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      Highlights

      • GK protected dopaminergic neurons in MPTP mice, accompanied by anti-inflammation and immunomodulation.
      • GK up-regulated of neurotrophic factors and Wnt signal derived from astrocytes.
      • GK enhanced the transdifferentiation of astrocyte-to-neuron in MPTP mice.

      Abstract

      Parkinson's disease (PD) is a chronic and progressive movement disorder caused by the selective loss of midbrain dopaminergic neurons of unknown etiology. Up to now, although there is a great development on treatments of PD, cures with neuroprotective or nerve regenerative effects are underway for PD patients. Here we reported neuroprotective effects of Ginkgolide K (GK) when mice were upon acute MPTP exposure, in which GK ameliorated the gait dysfunction and dopaminergic neuron loss. GK exhibits its ability in immunomodulation, including switching microglia to M2 phenotype and decreasing the microglia-mediated inflammation, inhibiting peripheral CD4+IFN-γ+ and CD4+IL-17+ T cells and α-synuclein specific autoantibodies. The expression of neurotrophic factors BDNF, GDNF and NT-3 was promoted with a treatment of GK in MPTP mice brains. Notably, GK enhanced the expression of nestin in GFAP+ astrocytes followed by the transdifferentiation of astrocyte-to-neuron independent on the Wnt signaling although GK induced the expression of Wnt signaling on astrocytes. Based on these results, our work implicates a therapeutic potential of GK for protecting TH+ neurons by multiple and intercellular pathways to modify nerve regeneration in MPTP mice. However, its exactly cellular and molecular mechanisms need to be further explored and confirmed.

      Keywords

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      References

        • Akhtar R.S.
        • Licata J.P.
        • Luk K.C.
        • Shaw L.M.
        • Trojanowski J.Q.
        • Lee V.M.
        Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.
        J. Neurochem. 2018; 145: 489-503https://doi.org/10.1111/jnc.14330
        • Aryal S.
        • Skinner T.
        • Bridges B.
        • Weber J.T.
        The pathology of Parkinson's disease and potential benefit of dietary polyphenols.
        Molecules. 2020; 25: E4382https://doi.org/10.3390/molecules25194382
        • Benner E.J.
        • Banerjee R.
        • Reynolds A.D.
        • Sherman S.
        • Pisarev V.M.
        • Tsiperson V.
        • Nemachek C.
        • Ciborowski P.
        • Przedborski S.
        • Mosley R.L.
        • Gendelman H.E.
        Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.
        PLoS One. 2008; 3e1376https://doi.org/10.1371/journal.pone.0001376
        • Bok E.
        • Chung Y.C.
        • Kim K.S.
        • Baik H.H.
        • Shin W.H.
        • Jin B.K.
        Modulation of M1/M2 polarization by capsaicin contributes to the survival of dopaminergic neurons in the lipopolysaccharide-lesioned substantia nigra in vivo.
        Exp. Mol. Med. 2018; 50: 76https://doi.org/10.1038/s12276-018-0111-4
        • Brochard V.
        • Combadière B.
        • Prigent A.
        • Laouar Y.
        • Perrin A.
        • Beray-Berthat V.
        • Bonduelle O.
        • Alvarez-Fischer D.
        • Callebert J.
        • Launay J.M.
        • Duyckaerts C.
        • Flavell R.A.
        • Hirsch E.C.
        • Hunot S.
        Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease.
        J. Clin. Invest. 2009; 119: 182-192https://doi.org/10.1172/JCI36470
        • Charvin D.
        • Medori R.
        • Hauser R.A.
        • Rascol O.
        Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.
        Nat. Rev. Drug Discov. 2018; 17: 804-822https://doi.org/10.1038/nrd.2018.136
        • Chen J.
        • Cao X.
        • Xu Y.
        • Sun S.
        Experimental study of serum substantia nigra neuron autoantibody and its effect in Parkinson disease patients.
        J. Tongji Med. Univ. 2001; 21: 280-282https://doi.org/10.1007/BF02886556
        • Chen M.
        • Zou W.Y.
        • Chen M.M.
        • Cao L.
        • Ding J.H.
        • Xiao W.
        • Hu G.
        Ginkgolide K promotes angiogenesis in a middle cerebral artery occlusion mouse model via activating JAK2/STAT3 pathway.
        Eur. J. Pharmacol. 2018; 833: 221-229https://doi.org/10.1016/j.ejphar.2018.06.012
        • Chen S.
        • Zhang J.
        • Yu W.B.
        • Zhuang J.C.
        • Xiao W.
        • Wu Z.Y.
        • Xiao B.G.
        Eomesodermin in CD4+ T cells is essential for Ginkgolide K ameliorating disease progression in experimental autoimmune encephalomyelitis.
        Int. J. Biol. Sci. 2021; 17: 50-61https://doi.org/10.7150/ijbs.50041
        • Chmielarz P.
        • Saarma M.
        Neurotrophic factors for disease-modifying treatments of Parkinson's disease: gaps between basic science and clinical studies.
        Pharmacol. Rep. 2020; 72: 1195-1217https://doi.org/10.1007/s43440-020-00120-3
        • Churchill M.J.
        • Pflibsen L.
        • Sconce M.D.
        • Moore C.
        • Kim K.
        • Meshul C.K.
        Exercise in an animal model of Parkinson's disease: motor recovery but not restoration of the nigrostriatal pathway.
        Neuroscience. 2017; 359: 224-247https://doi.org/10.1016/j.neuroscience
        • García-Domínguez I.
        • Veselá K.
        • García-Revilla J.
        • Carrillo-Jiménez A.
        • Roca-Ceballos M.A.
        • Santiago M.
        • de Pablos R.M.
        • Venero J.L.
        Peripheral inflammation enhances microglia response and nigral dopaminergic cell death in an in vivo MPTP model of Parkinson's disease.
        Front. Cell. Neurosci. 2018; 12: 398https://doi.org/10.3389/fncel.2018.00398
        • Geldenhuys W.J.
        • Guseman T.L.
        • Pienaar I.S.
        • Dluzen D.E.
        • Young J.W.
        A novel biomechanical analysis of gait changes in the MPTP mouse model of Parkinson's disease.
        PeerJ. 2015; 3e1175https://doi.org/10.7717/peerj.1175
        • Horvath I.
        • Iashchishyn I.A.
        • Forsgren L.
        • Morozova-Roche L.A.
        Immunochemical detection of α-synuclein autoantibodies in Parkinson's disease: correlation between plasma and cerebrospinal fluid levels.
        ACS Chem. Neurosci. 2017; 8: 1170-1176https://doi.org/10.1021/acschemneuro.7b00063
        • Huang Y.
        • Yun W.
        • Zhang M.
        • Luo W.
        • Zhou X.
        Serum concentration and clinical significance of brain-derived neurotrophic factor in patients with Parkinson's disease or essential tremor.
        J. Int. Med. Res. 2018; 46: 1477-1485https://doi.org/10.1177/0300060517748843
        • Iba M.
        • Kim C.
        • Sallin M.
        • Kwon S.
        • Verma A.
        • Overk C.
        • Rissman R.A.
        • Sen R.
        • Sen J.M.
        • Masliah E.
        Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models.
        J. Neuroinflammation. 2020; 17: 214https://doi.org/10.1186/s12974-020-01888-0
        • Lee E.
        • Eo J.C.
        • Lee C.
        • Yu J.W.
        Distinct features of brain-resident macrophages: microglia and non-parenchymal brain macrophages.
        Mol. Cell. 2021; 44: 281-291https://doi.org/10.14348/molcells.2021.0060
        • L'Episcopo F.
        • Tirolo C.
        • Testa N.
        • Caniglia S.
        • Morale M.C.
        • Cossetti C.
        • D'Adamo P.
        • Zardini E.
        • Andreoni L.
        • Ihekwaba A.E.
        • Serra P.A.
        • Franciotta D.
        • Martino G.
        • Pluchino S.
        • Marchetti B.
        Reactive astrocytes and Wnt/β-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
        Neurobiol. Dis. 2011; 41: 508-527https://doi.org/10.1016/j.nbd.2010.10.023
        • L'episcopo F.
        • Serapide M.F.
        • Tirolo C.
        • Testa N.
        • Caniglia S.
        • Morale M.C.
        • Pluchino S.
        • Marchetti B.
        A Wnt1 regulated Frizzled-1/β-catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection.
        Mol. Neurodegener. 2011; 6: 49https://doi.org/10.1186/1750-1326-6-49
        • L'Episcopo F.
        • Tirolo C.
        • Serapide M.F.
        • Caniglia S.
        • Testa N.
        • Leggio L.
        • Vivarelli S.
        • Iraci N.
        • Pluchino S.
        • Marchetti B.
        Microglia polarization, gene-environment interactions and Wnt/β-catenin signaling: emerging roles of glia-neuron and glia-stem/neuroprogenitorcrosstalk for dopaminergic neurorestoration in aged parkinsonian brain.
        Front. Aging Neurosci. 2018; 10: 12https://doi.org/10.3389/fnagi.2018.00012
        • Li H.
        • Yahaya B.H.
        • Ng W.H.
        • Yusoff N.M.
        • Lin J.
        Conditioned medium of human menstrual blood-derived endometrial stem cells protects against MPP+-induced cytotoxicity in vitro.
        Front. Mol. Neurosci. 2019; 12: 80https://doi.org/10.3389/fnmol.2019.00080
        • Liu Q.
        • Li X.
        • Li L.
        • Xu Z.
        • Zhou J.
        • Xiao W.
        Ginkgolide K protects SH-SY5Y cells against oxygen-glucose deprivation-induced injury by inhibiting the p38 and JNK signaling pathways.
        Mol. Med. Rep. 2018; 18: 3185-3192https://doi.org/10.3892/mmr.2018.9305
        • Liu Z.
        • Qiu A.W.
        • Huang Y.
        • Yang Y.
        • Chen J.N.
        • Gu T.T.
        • Cao B.B.
        • Qiu Y.H.
        • Peng Y.P.
        IL-17A exacerbates neuroinflammation and neurodegeneration by activating microglia in rodent models of Parkinson's disease.
        Brain Behav. Immun. 2019; 81: 630-645https://doi.org/10.1016/j.bbi.2019.07.026
        • Liu X.G.
        • Lu X.
        • Gao W.
        • Li P.
        • Yang H.
        Structure, synthesis, biosynthesis, and activity of the characteristic compounds from Ginkgo biloba L.
        Nat. Prod. Rep. 2021; https://doi.org/10.1039/d1np00026h
        • LorigadosPedre L.
        • Pavón Fuentes N.
        • Alvarez González L.
        • McRae A.
        • Serrano Sánchez T.
        • Blanco Lescano L.
        • Macías González R.
        Nerve growth factor levels in Parkinson disease and experimental parkinsonian rats.
        Brain Res. 2002; 952: 122-127https://doi.org/10.1016/s0006-8993(02)03222-5
        • Ma S.W.
        • Yin H.F.
        • Chen L.Y.
        • Liu H.X.
        • Zhao M.
        • Zhang X.T.
        Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats.
        J. Nat. Med. 2012; 66: 25-31https://doi.org/10.1007/s11418-011-0545-7
        • Marchetti B.
        Wnt/β-catenin signaling pathway governs a full program for dopaminergic neuron survival, neurorescue and regeneration in the MPTP mouse model of Parkinson's disease.
        Int. J. Mol. Sci. 2018; 19: 3743https://doi.org/10.3390/ijms19123743
        • Marchetti B.
        Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease.
        Redox Biol. 2020; 36101664https://doi.org/10.1016/j.redox.2020.101664
        • McCarthy K.D.
        • de Vellis J.
        Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
        J. Cell Biol. 1980; 85: 890-902https://doi.org/10.1083/jcb.85.3.890
        • McFarthing K.
        • Buff S.
        • Rafaloff G.
        • Dominey T.
        • Wyse R.K.
        • Stott S.R.W.
        Parkinson's disease drug therapies in the clinical trial pipeline: 2020.
        J. Parkinsons Dis. 2020; 10: 757-774https://doi.org/10.3233/JPD-202128
        • Mesman S.
        • Smidt M.P.
        Acquisition of the midbrain dopaminergic neuronal identity.
        Int. J. Mol. Sci. 2020; 21: 4638https://doi.org/10.3390/ijms21134638
        • Niu W.Z.
        • Zang T.
        • Zou Y.H.
        • Fang S.H.
        • Smith D.K.
        • Bachoo R.
        • Zhang C.L.
        In vivo reprogramming of astrocytes to neuroblasts in the adult brain.
        Nat. Cell Biol. 2013; 15: 1164-1175https://doi.org/10.1038/ncb2843
        • Orihuela R.
        • McPherson C.A.
        • Harry G.J.
        Microglial M1/M2 polarization and metabolic states.
        Br. J. Pharmacol. 2016; 173: 649-665https://doi.org/10.1111/bph.13139
        • Pöyhönen S.
        • Er S.
        • Domanskyi A.
        • Airavaara M.
        Effects of neurotrophic factors in glial cells in the central nervous system: expression and properties in neurodegeneration and injury.
        Front. Physiol. 2019; 10: 486https://doi.org/10.3389/fphys.2019.00486
        • Qian H.
        • Kang X.
        • Hu J.
        • Zhang D.
        • Liang Z.
        • Meng F.
        • Zhang X.
        • Xue Y.
        • Maimon R.
        • Dowdy S.F.
        • Devaraj N.K.
        • Zhou Z.
        • Mobley W.C.
        • Cleveland D.W.
        • Fu X.D.
        Reversing a model of Parkinson's disease with in situ converted nigral neurons.
        Nature. 2020; 582: 550-556https://doi.org/10.1038/s41586-020-2388-4
        • Qin Y.
        • Qiu J.R.
        • Wang P.
        • Liu J.
        • Zhao Y.
        • Jiang F.
        • Lou H.Y.
        Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson's disease.
        Brain Behav. Immun. 2020; 8 (S0889-1591(20)30760-1)https://doi.org/10.1016/j.bbi.2020.10.010
        • Ransohoff R.M.
        A polarizing question: do M1 and M2 microglia exist?.
        Nat. Neurosci. 2016; 19: 987-991https://doi.org/10.1038/nn.4338
        • Salari S.
        • Bagheri M.
        In vivo, in vitro and pharmacologic models of Parkinson's disease.
        Physiol. Res. 2019; 68: 17-24https://doi.org/10.33549/physiolres.933895
        • Serapide M.F.
        • L'Episcopo F.
        • Tirolo C.
        • Testa N.
        • Caniglia S.
        • Giachino C.
        • Marchetti B.
        Boosting antioxidant self-defenses by grafting astrocytes rejuvenates the aged microenvironment and mitigates nigrostriatal toxicity in Parkinsonian brain via an Nrf2-driven Wnt/β-Catenin prosurvivalaxis.
        Front. Aging Neurosci. 2020; 12: 24https://doi.org/10.3389/fnagi.2020.00024
        • Sidorova Y.A.
        • Volcho K.P.
        • Salakhutdinov N.F.
        Neuroregeneration in Parkinson's disease: from proteins to small molecules.
        Curr. Neuropharmacol. 2019; 17: 268-287https://doi.org/10.2174/1570159X16666180905094123
        • Storelli E.
        • Cassina N.
        • Rasini E.
        • Marino F.
        • Cosentino M.
        Do Th17 lymphocytes and IL-17 contribute to Parkinson's disease? A systematic review of available evidence.
        Front. Neurol. 2019; 10: 13https://doi.org/10.3389/fneur.2019.00013
        • Sulzer D.
        • Alcalay R.N.
        • Garretti F.
        • Cote L.
        • Kanter E.
        • Agin-Liebes J.
        • Liong C.
        • McMurtrey C.
        • Hildebrand W.H.
        • Mao X.
        • Dawson V.L.
        • Dawson T.M.
        • Oseroff C.
        • Pham J.
        • Sidney J.
        • Dillon M.B.
        • Carpenter C.
        • Weiskopf D.
        • Phillips E.
        • Mallal S.
        • Peters B.
        • Frazier A.
        • LindestamArlehamn C.S.
        • Sette A.
        T cells from patients with Parkinson's disease recognize α-synuclein peptides.
        Nature. 2017; 546: 656-661https://doi.org/10.1038/nature22815
        • Sun S.H.
        • Zhu X.J.
        • Huang H.
        • Guo W.
        • Tang T.
        • Xie B.H.
        • Xu X.F.
        • Zhang Z.Y.
        • Shen Y.
        • Dai Z.M.
        • Qiu Z.M.
        WNT signaling represses astrogliogenesis via Ngn2-dependent direct suppression of astrocyte gene expression.
        Glia. 2019; 67: 1333-1343https://doi.org/10.1002/glia.23608
        • Tan E.K.
        • Chao Y.X.
        • West A.
        • Chan L.L.
        • Poewe W.
        • Jankovic J.
        Parkinson disease and the immune system - associations, mechanisms and therapeutics.
        Nat. Rev. Neurol. 2020; 16: 303-318https://doi.org/10.1038/s41582-020-0344-4
        • Tao X.Q.
        • Cao Z.Y.
        • Cao L.
        • Xiao W.
        Effects of ginkgolide K on platelet aggregation activity and neuroprotection.
        Zhongguo Zhong Yao Za Zhi. 2017; 42: 4727-4732https://doi.org/10.19540/j.cnki.cjcmm.2017.0208
        • Wang K.L.
        • Li Z.Q.
        • Cao Z.Y.
        • Ke Z.P.
        • Cao L.
        • Wang Z.Z.
        • Xiao W.
        Effects of ginkgolide A, B and K on platelet aggregation.
        Zhongguo Zhong Yao Za Zhi. 2017; 42: 4722-4726https://doi.org/10.19540/j.cnki.cjcmm.2017.0207
        • Xu J.
        • Wang K.L.
        • Cao Z.Y.
        • Cao L.
        • Wang Z.Z.
        • Xiao W.
        Antagonistic effect of ginkgolide homologues on PAF-induced platelet aggregation and neuroprotective effect.
        Zhongguo Zhong Yao Za Zhi. 2017; 42: 4716-4721https://doi.org/10.19540/j.cnki.cjcmm.2017.0206
        • Yu W.B.
        • Chen S.
        • Cao L.
        • Tang J.
        • Xiao W.
        • Xiao B.G.
        Ginkgolide K promotes the clearance of A53T mutation alpha-synuclein in SH-SY5Y cells.
        Cell Biol. Toxicol. 2018; 34: 291-303https://doi.org/10.1007/s10565-017-9419-4
        • Yu W.B.
        • Wang Q.
        • Chen S.
        • Cao L.
        • Tang J.
        • Ma C.G.
        • Xiao W.
        • Xiao B.G.
        The therapeutic potential of ginkgolide K in experimental autoimmune encephalomyelitis via peripheral immunomodulation.
        Int. Immunopharmacol. 2019; 70: 284-294https://doi.org/10.1016/j.intimp.2019.02.035
        • Zhao Y.F.
        • Zhang Q.
        • Xi J.Y.
        • Xiao B.G.
        • Li Y.H.
        • Ma C.G.
        Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/β-catenin dependent pathways in a mice model of Parkinson's disease.
        Int. J. Clin. Exp. Pathol. 2015; 8: 2354-2364