Notoginsenoside R1, a novel natural PPARγ agonist, attenuates cognitive deficits in a mouse model of diabetic Alzheimer’s disease through enhancing GLUT4-dependent neuronal glucose uptake

Abstract

Our previous studies demonstrated the potential of Notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng, in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid-β (Aβ)-induced neuronal damage. However, the impact of NGR1 on cognitive dysfunction in a diabetic Alzheimer’s disease (AD) mouse model remains unclear. In this investigation, we identified NGR1 as a novel PPARγ agonist through a dual-luciferase reporter assay system. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2-deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, intragastric administration of NGR1 (40 mg/kg/day) for 16 weeks notably mitigated cognitive deficits in APP/PS1xdb/db mice. This treatment correlated with reduced blood glucose levels, lowered serum HbA1c, and decreased serum insulin levels, coupled with enhanced glucose tolerance and insulin sensitivity. Additionally, NGR1 treatment ameliorated Aβ burden, suppressed microglia-induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by ¹⁸F-FDG PET scans. NGR1 treatment could upregulate PPARγ and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS-1 at Ser616 in the hippocampus of APP/PS1xdb/db mice. Crucially, the protective effects of NGR1 were abolished by co-administration with a selective PPARγ inhibitor GW9662. In conclusion, NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPARγ/Akt/GLUT4 signaling pathways in APP/PS1xdb/db mice, positioning it as a promising candidate for diabetic AD treatment.