摘要
OBJECTIVE Nicotinamide phos⁃phoribosyltransferase(NAMPT)is the key enzyme for the synthesis of nicotinamide ade⁃nine dinucleotide(NAD)in the salvaging pathway.NAD is an essential co-enzyme of multiple enzymes involved in cell metabolism and important enzymes such as sirtuins.The level of both NAMPT and NAD decreases upon aging,which may cause neuronal degeneration.However,the roles of NAMPT and NAD in Par⁃kinson disease(PD)remain unknown.This study was to explore the roles of NAMPT and NAD decline in the pathogenesis of PD in mice.METOHDS Floxed nampt gene C57BL/6J mice,including Namptwt/wt,Namptflox/wt and Namptflox/flox,were used.The rAAV-hSyn-Cre-WPRE pA or rAAV-TH-Cre-WPRE pA adeno-associated virus(AAV)was used to conditioning knockout nampt gene in neurons or dopaminergic neurons,respectively.At 2,4,6,and 8 weeks after AAV injection,the motor deficits of mice were evaluat⁃ed.Immunofluorescence and immunohistochem⁃istry were used to evaluate the neuronal injury.Transmission electron microscope was used to evaluate the axonal degeneration.RESULTS The knockout of nampt gene induced dopaminer⁃gic neuron loss in substantia nigra at 4 weeks but not 2 weeks after AAV injection.At 8 weeks after AAV injection,the Namptflox/flox mice showed a significantly decrease in motor activity in an open-field than Namptwt/wt and Namptflox/wt mice.And some Namptflox/flox mice showed spin behav⁃ior at 6-8 weeks after AAV injection.The dopa⁃minergic neurons in substantia nigra and ventral tegmental area are more susceptible to the knockout of nampt gene than the non-dopaminer⁃gic neurons.Transmission electron microscope examine showed degenerative changes of the myelin in striatum at 4 weeks after AAV injection for the Namptflox/flox mice.The orally supplementary of NAD precursor,nicotinamide ribose,improved the motor activity and decreased neuronal injury for the nampt gene knockout mice.CONCLU⁃SION Decline of NAMPT and NAD in dopaminer⁃gic neurons is a risk for developing PD,and NAD precursors might be a new strategy for treatment of PD.
出处
《中国药理学与毒理学杂志》
CAS
北大核心
2021年第9期652-653,共2页
Chinese Journal of Pharmacology and Toxicology
