Potassium-Hydroxypentyl Benzoate

The treatment of acute ischemic stroke (AIS) remains a tough challenge in clinic. Here, we report the anti-AIS activity of R- and S-FMPB generated from hybridization of ring-opened R- and S-3-N-butylphthalide (R- and S-NBP) derivatives (R- and S-APB) with 4-fluro-edaravone (4-F-Eda), respectively. S-FMPB (10 mg/kg, iv) significantly improved the neurological score and alleviated cerebral infarction and edema of rats suffered from transient middle cerebral artery occlusion (tMCAO), superior to RS- and R-FMPB, as well as better than RS-FMPB by oral administration in previous studies. Importantly, S-FMPB is more active not only than the equimolar S-APB and 4-F-Eda alone or in combination but also than the clinical drugs NBP and edaravone (Eda) in combination at the equimolar doses. Furthermore, S-FMPB showed relative stability in plasma or liver microsome of rats but could be converted into two active metabolites (S-NBP and 4-F-Eda) in rats with good pharmacokinetic properties in terms of longer half-life period (t_1/2) and mean residence time (MRT) as well as larger area under the concentration-time curve (AUC) of S-NBP than those from S-NBP and 4-F-Eda single or in combination by iv administration, suggesting that S-NBP and 4-F-Eda may synergistically play the anti-AIS activity. Our findings suggest that S-FMPB may be used as a potential anti-AIS agent to further study.

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.

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.

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.

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.