Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity.
p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-α) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure.
Department of Neurological Surgery, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH, USA.|Medical Faculty, Kunming University of Science and Technology, Kunming, Yunnan, China.
Tao
T
Lu
Department of Neurological Surgery, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH, USA.
Paul P
PP
Kim
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute of Aging, Baltimore, USA.
Nigel H
NH
Greig
Department of Neurological Surgery, Case Western Reserve University, 2109 Adelbert Rd, Cleveland, OH, USA. yxl710@case.edu.
Yu
http://orcid.org/0000-0002-7939-5505
Y
Luo
D000818:Animals; D052160:Benzothiazoles / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005334:Fever / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D052160:Benzothiazoles; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C493215:Slc6a3 protein, mouse; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D014050:Toluene; D008694:Methamphetamine; C121565:pifithrin; D014446:Tyrosine 3-Monooxygenase; D020741:rho GTP-Binding Proteins
Dopaminergic neurons; Methamphetamine; Neurotoxicity; p53