The attenuation effect of potassium 2‐(1‐hydroxypentyl)‐benzoate in a mouse model of diabetes‐associated cognitive decline: The protein expression in the brain

Abstract

Aims dl‐PHPB (potassium 2‐(1‐hydroxypentyl)‐benzoate) has been shown to have neuroprotective effects against acute cerebral ischemia, vascular dementia, and Alzheimer's disease. The aim of this study was to investigate the effects of dl‐PHPB on memory deficits and preliminarily explore the underlying molecular mechanism. Methods Blood glucose and behavioral performance were evaluated in the KK‐Ay diabetic mouse model before and after dl‐PHPB administration. Two‐dimensional difference gel electrophoresis (2D‐DIGE)‐based proteomics was used to identify differentially expressed proteins in brain tissue. Western blotting was used to study the molecular mechanism of the related signaling pathways. Results Three‐month‐old KK‐Ay mice were given 150 mg/kg dl‐PHPB by oral gavage for 2 months, which produced no effect on the level of serum glucose. In the Morris water maze test, KK‐Ay mice treated with dl‐PHPB showed significant improvements in spatial learning and memory deficits compared with vehicle‐treated KK‐Ay mice. Additionally, we performed 2D‐DIGE to compare brain proteomes of 5‐month KK‐Ay mice treated with and without dl‐PHPB. We found 14 altered proteins in the cortex and 11 in the hippocampus; two of the 25 altered proteins and another four proteins that were identified in a previous study on KK‐Ay mice were then validated by western blot to further confirm whether dl‐PHPB can reverse the expression levels of these proteins. The phosphoinositide 3‐kinase/protein kinase B/glycogen synthase kinase‐3β (PI3K/Akt/GSK‐3β) signaling pathway was also changed in KK‐Ay mice and dl‐PHPB treatment could reverse it. Conclusions These results indicate that dl‐PHPB may play a potential role in diabetes‐associated cognitive impairment through PI3K/Akt/GSK‐3β signaling pathway and the differentially expressed proteins may become putative therapeutic targets.

PHPB Attenuated Cognitive Impairment in Type 2 Diabetic KK-Ay Mice by Modulating SIRT1/Insulin Signaling Pathway and Inhibiting Generation of AGEs

“…The excessive accumulation of AGEs downregulates PI3K/Akt/GSK-3β signaling pathway by inhibiting SIRT1 expression, promotes the astrocytic differentiation of cultured neurospheres by inhibiting neurogenesis through the Notch-Hes1 pathway, increases expression of inflammatory genes, and decreases learning and memory function [ 33 , 34 ]. Our previous research also proved that PHPB could significantly improve cognitive function in type 2 diabetic KK-Ay mice via elevation of neurotrophic factor and vesicular glutamate transporter 1 (vGLUT1), inhibition of neuroinflammatory, and modulation of PI3K/Akt/GSK-3β signaling pathway [ 14 ]. These results suggest that PHPB may be associated with the reduction of AGEs production in the treatment of DE.…”

“…Insulin signaling is known to be disrupted by AGEs via down-regulation of the SIRT1 protein [ 26 ]. Our previous results showed that PHPB could inhibit oxidative stress or inflammatory response and modulate PI3K/Akt signaling pathways [ 13 , 14 ]. Some studies have shown that increased activity of GSK-3β directly leads to hyperphosphorylation of tau, which contributes to the formation of NFTs that destabilize microtubule integrity [ 40 ].…”

“…Moreover, PHPB has been verified effective in the treatment of Alzheimer’s disease (AD) by attenuating amyloid and tau protein pathologies in APP/PS1 transgenic mice, promoting mitochondrial function, antioxidant, anti-neuroinflammation in chronic cerebral hypoperfused rats, β-amyloid protein 1–40 (Aβ 1-40 )-intracerebroventricular infused rats, APP/PS1-transgenic mice, and lipopolysaccharide-induced inflammatory mice [ 12 ]. Recently, our research also proved that PHPB could significantly improve cognitive function in type 2 diabetic KK-Ay mice via elevation of neurotrophic factor and vesicular glutamate transporter 1 (vGLUT1), inhibition of neuroinflammatory, and modulation of PI3K/Akt/GSK-3β signaling pathway [ 13 , 14 ]. However, the precise mechanism of PHPB in the treatment of DE is not fully understood.…”

Non-linear association between Mediterranean diet and depressive symptom in U.S. adults: A cross-sectional study

“…Furthermore, cognitive impairment is one key risk factor of depression (40). Cognitive impairment is also known to be a main complication of diabetes and PD (41,42). This may similarly explain the lack of a statistically significant association between aMED score and depressive symptom in patients suffering diabetes or PD.…”

Bioinformatics analysis of diagnostic biomarkers for Alzheimer's disease in peripheral blood based on sex differences and support vector machine algorithm

“…The downregulation of HINT1 has also been reported in diabetes and AD [ 60 , 61 ]. Yu W et al [ 62 ] found that potassium 2‐(1‐hydroxypentyl)‐benzoate can increase HINT1 expression levels, thus improving spatial learning and memory deficits in diabetic animals. Chen Q et al's study suggests that HINT1 may be associated with schizophrenia and the association is sex specific [ 63 ].…”