title: Harpagoside attenuates MPTP/MPP⁺ induced dopaminergic neurodegeneration and movement disorder via elevating glial cell line-derived neurotrophic factor.
abstract: Parkinson's disease is a chronic neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. New therapeutic approaches aiming at delaying or reversing the neurodegenerative process are under active investigations. In this work, we found that harpagoside, an iridoid purified from the Chinese medicinal herb Scrophularia ningpoensis, could not only prevent but also rescue the dopaminergic neurodegeneration in MPTP/MPP(+) intoxication with promising efficacy. Firstly, in cultured mesencephalic neurons, harpagoside significantly attenuated the loss of TH-positive neuron numbers and the shortening of axonal length. Secondly, in a chronic MPTP mouse model, harpagoside dose-dependently improved the loco-motor ability (rotarod test), increased the TH-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) and increased the striatal DAT density ((125) I-FP-CIT autoradiography). Thirdly, harpagoside markedly elevated the GDNF mRNA and GDNF protein levels in MPTP/MPP(+) lesioned models. However, the protecting effect of harpagoside on the dopaminergic degeneration disappeared when the intrinsic GDNF action was blocked by either the Ret inhibitor PP1 or the neutralizing anti-GDNF antibody. Taken together, we conclude that harpagoside attenuates the dopaminergic neurodegeneration and movement disorder mainly through elevating glial cell line-derived neurotrophic factor.
authors.affiliation: Research Laboratory of Cell Regulation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Sun
authors.forename: Zhongkui
authors.initials: Z
authors.lastname: Xiong
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ya
authors.initials: Y
authors.lastname: Meng
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Xia
authors.forename: Jiamei
authors.initials: J
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Zunji
authors.initials: Z
authors.lastname: Ke
authors.forename: Zongqin
authors.initials: Z
authors.lastname: Xia
authors.forename: Yaer
authors.initials: Y
authors.lastname: Hu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism*; D006027:Glycosides / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011714:Pyrans / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000906:Antibodies; D050483:Dopamine Plasma Membrane Transport Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006027:Glycosides; D018696:Neuroprotective Agents; D011714:Pyrans; D012333:RNA, Messenger; C033249:harpagoside; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase