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Biomed Pharmacother ; 176: 116778, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38788601

ABSTRACT

The incidence of cerebral infarction triggered by abnormal glucose tolerance has increased; however, the relationship between glucose concentration in the brain and the detailed mechanism of post ischemic cell death remains unclear. Nicotinamide phosphoribosyltransferase (NAMPT), an adipocytokine, is the rate-limiting enzyme for NAD+ synthesis in the salvage pathway. Although NAMPT activation prevents neuronal injury, the relationship between NAMPT activity, glucose metabolism disorders, and cerebral ischemia-induced neuronal cell death is unknown. In this study, we determined changes in NAMPT on cerebral ischemic injuries with diabetes using a db/db mouse model of type 2 diabetes and then identified the underlying mechanisms using Neuro2a cells. The expression of inflammatory cytokine mRNAs was increased in db/db and db/+ middle cerebral artery occlusion and reperfusion (MCAO/R) mice. Although NeuN-positive cells were decreased after MCAO/R, the number of NAMPT and NeuN double-positive cells in NeuN-positive neuronal cells increased in db/db MCAO/R mice. Next, the role of NAMPT in Neuro2a cells under conditions of high glucose (HGC) and oxygen-glucose deprivation (OGD), which mimics diabetes-complicated cerebral infarction, was examined. Treatment with P7C3-A20, a NAMPT activator, suppressed the decrease in cell viability caused by HGC/OGD; however, there were no significant differences in the levels of cleaved caspase-3 and Bax proteins. Moreover, increased FoxO3a and LC3-II levels after HGC/OGD were inhibited by P7C3-A20 treatment. Our findings indicate that NAMPT activation is associated with neuronal survival under ischemic conditions with abnormal glucose tolerance through the regulation of FoxO3a/LC3.


Subject(s)
Brain Ischemia , Cell Survival , Forkhead Box Protein O3 , Glucose , Neurons , Nicotinamide Phosphoribosyltransferase , Signal Transduction , Animals , Nicotinamide Phosphoribosyltransferase/metabolism , Forkhead Box Protein O3/metabolism , Glucose/metabolism , Glucose/deficiency , Neurons/metabolism , Neurons/pathology , Neurons/drug effects , Male , Mice , Cell Survival/drug effects , Signal Transduction/drug effects , Brain Ischemia/metabolism , Brain Ischemia/pathology , Cytokines/metabolism , Mice, Inbred C57BL , Infarction, Middle Cerebral Artery/pathology , Infarction, Middle Cerebral Artery/metabolism , Cell Line, Tumor , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/complications
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