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Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With no Alteration in Insulin Sensitivity
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posted on 2020-04-28, 21:30 authored by Ada AdminAda Admin, Kewarin Jinawong, Nattayaporn Apaijai, Supawit Wongsuchai, Wasana Pratchayasakul, Nipon Chattipakorn, Siriporn C ChattipakornPrevious
studies show that 12-week
of high-fat diet (HFD) consumption
caused not only prediabetes, but also cognitive decline
and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor,
showed beneficial effects in brain against stroke. However, the comparative effects of
nec-1 and metformin on cognition and brain
pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated
cognitive decline and brain pathologies in prediabetic rats. Rats
(n=32) were fed
with either normal diet (ND) or high-fat
diet (HFD) for 20 weeks. At week 13, ND-fed
rats were given a vehicle (n=8) and HFD-fed rats were randomly assigned into 3 subgroups (n=8/subgroup) with vehicle, nec-1 or metformin for 8 weeks. Metabolic parameters, cognitive function,
brain insulin receptor function, synaptic plasticity, dendritic spine density,
microglial morphology, brain mitochondrial function, Alzheimer’s
protein, and cell death were determined. HFD-fed
rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1
and metformin equally improved cognitive function, synaptic plasticity,
dendritic spine density, microglial morphology, brain mitochondrial function, reduced
hyperphosphorylated-tau and necroptosis in HFD-fed rats. Interestingly
metformin, but not nec-1, improved brain insulin
sensitivity in those rats. In conclusion, necroptosis inhibition
directly improved cognition in prediabetic rats without alteration in insulin sensitivity.