Diabetes mellitus (DM) has been recognized as an increased risk factor for
cognitive impairment, known as
diabetic encephalopathy (DE).
Hyperglycemia and
insulin resistance are the main initiators of DE, which is related to the accumulation of
advanced glycation end products (AGEs).
Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a derivative of
3-n-butylphthalide (dl-NBP), has emerged various properties including improved mitochondrial function,
antioxidant, anti-
neuroinflammation, and
neuroprotective effects. The present study aimed to investigate the
neuroprotective effect of PHPB against AGEs accumulation in type 2 diabetic KK-Ay mice model with DE and further explore the underlying mechanisms. The results showed that PHPB markedly ameliorated the spatial learning ability of KK-Ay mice in the Morris water maze and decreased AD-like pathologic changes (Tau hyperphosphorylation) in the cortex. Furthermore, we found that PHPB treatment significantly reduced AGEs generation via up-regulation of glyoxalase-1 (GLO1)
protein and enhancement of
methylglyoxal (MG) trapping, while there was no obvious difference in levels of
glucose in plasma or brain, contents of total
cholesterol (TC),
triglycerides (TG), and plasma
insulin. Also, PHPB treatment improved the
insulin signaling pathway by increasing sirtuin1 (
SIRT1) deacetylase activity and attenuated oxidative stress evidenced by elevating
glucose-6-phosphate dehydrogenase (G-6-PD)
protein expression, promoting the production of
reduced glutathione (GSH) and reduced
nicotinamide adenine dinucleotide phosphate (
NADPH), restoring mitochondrial membrane potential, increasing
adenosine triphosphate (
ATP) generation, and reducing
malondialdehyde (MDA) levels in the brain. Taken together, PHPB exhibited a beneficial effect on DE, which involved modulating the
SIRT1/
insulin signaling pathway and reducing oxidative stress by inhibiting the generation of AGEs.