title: FLZ protects dopaminergic neuron through activating protein kinase B/mammalian target of rapamycin pathway and inhibiting RTP801 expression in Parkinson's disease models.
abstract: The pathogenesis of Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in substantia nigra (SNpc). FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental Parkinson's disease (PD) models. However, it is still unclear whether FLZ protects against PD through regulating the function of dopaminergic system. In this study, we carried out a set of in vitro and in vivo experiments to address these questions. Oral administration of FLZ significantly improved motor dysfunction of mice challenged by MPTP. The beneficial effects of FLZ on motor behavior attributed to the elevation of dopamine level in striatum, tyrosine hydroxylase (TH)-positive cells, and TH activity in the middle brain of mouse. Mechanism study showed that treatment of FLZ increased the phosphorylation of activating protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Using LY294002 to block phosphoinositide 3-kinases (PI3K)/Akt signaling pathway prevented the phosphorylation of mTOR and attenuated the neuroprotection of FLZ in MN9D cells challenged by MPP(+). In addition, FLZ reduced the expression of RTP801, an important protein in PD, in mice and cells intoxicated by MPTP/MPP(+). Taken together, these results revealed a novel role that FLZ elevated TH expression and activity in dopaminergic neuron through activation of Akt/mTOR survival pathway and inhibition of RTP801 in MPTP/MPP(+)-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising anti-PD drug.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Bioactive Substance and Function of Natural Medicine, 1 Xian Nong Tan Street, Beijing, 100050, China.
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Bao
authors.forename: X-C
authors.initials: XC
authors.lastname: Kong
authors.forename: C
authors.initials: C
authors.lastname: Qian
authors.forename: D
authors.initials: D
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009069:Movement Disorders / Q000188:drug therapy / Q000503:physiopathology; D018696:Neuroprotective Agents; D051058:Oncogene Protein v-akt / Q000502:physiology; D010636:Phenols / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D044482:Benzeneacetamides; D002867:Chromones; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D009025:Morpholines; D018696:Neuroprotective Agents; D010636:Phenols; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D051844:alpha-Synuclein; C084439:squamosamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014446:Tyrosine 3-Monooxygenase; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D004298:Dopamine