title: Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling.
abstract: The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.
authors: Department of Neurology, and Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors: Zhongfang
authors: Z
authors: Weng
authors: Armando P
authors: AP
authors: Signore
authors: Yanqin
authors: Y
authors: Gao
authors: Suping
authors: S
authors: Wang
authors: Feng
authors: F
authors: Zhang
authors: Teresa
authors: T
authors: Hastings
authors: Xiao-Ming
authors: XM
authors: Yin
authors: Jun
authors: J
authors: Chen
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D013565:Sympatholytics / Q000633:toxicity*
chemical_list: D002395:Catecholamines; D005419:Flavonoids; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D020738:Leptin; D018696:Neuroprotective Agents; D013565:Sympatholytics; D016627:Oxidopamine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one