title: NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53.
abstract: To evaluate the contribution of NF-kappaB and the NF-kappaB target gene p53 to nigral dopaminergic neuron degeneration in rodent models of Parkinson's disease, time-course of dopaminergic neuron loss as well as changes in the expression of some NF-kappaB-regulated proapoptotic proteins were assayed after unilateral infusion of 6-hydroxydopamine into rat medial forebrain bundle. Substantial loss of tyrosine hydroxylase immunoreactivity in nigral was observed 24 h after 6-hydroxydopamine treatment. The degenerative processes began 12 h after 6-hydroxydopamine administration as evidenced by a positive silver staining. Apoptotic death of dopaminergic neurons was suggested by the appearance of TUNEL-positive nuclei in substantia nigra and internucleosomal DNA fragmentation as detected by agarose gel electrophoresis. NF-kappaB activation in dopaminergic neurons as revealed by immunohistochemistry and electrophoresis mobility shift assay, began at 12 h after 6-hydroxydopamine administration. Levels of c-Myc and p53 immunoreactivities increased after 6-hydroxydopamine treatment, mainly in dopaminergic neurons as indicated by co-localization with tyrosine hydroxylase immunoreactivity. Blockade of NF-kappaB nuclear translocation with recombinant cell-permeable peptide NF-kappaB SN50 inhibited NF-kappaB nuclear translocation and p53 induction. SN50 and the p53 antagonist pifithrin-alpha significantly reduced nigral dopaminergic neuron degeneration. These results suggest that NF-kappaB activation contributes, at least in part, to oxidative stress-induced degeneration of dopaminergic neurons through a NF-kappaB-dependent p53-signaling pathway.
authors: Department of Pharmacology, Soochow University School of Medicine, Suzhou-Singapore Industrial Park, Suzhou 215123, China.
authors: Zhong-Qin
authors: ZQ
authors: Liang
authors: Yun-Lin
authors: YL
authors: Li
authors: Xi-Lin
authors: XL
authors: Zhao
authors: Rong
authors: R
authors: Han
authors: Xiao-Xia
authors: XX
authors: Wang
authors: Yumei
authors: Y
authors: Wang
authors: Thomas N
authors: TN
authors: Chase
authors: M Catherine
authors: MC
authors: Bennett
authors: Zheng-Hong
authors: ZH
authors: Qin
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013565:Sympatholytics; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D016328:NF-kappa B; D009498:Neurotoxins; D010455:Peptides; C118258:SN50 peptide; D013565:Sympatholytics; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D016627:Oxidopamine; C121565:pifithrin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine