A novel synthetic chemical entity (UPEI-800) is neuroprotective in vitro and in an in vivo rat model of oxidative stress

作者：Saleh Tarek M^*; Saleh Monique C; Connell Barry J; Kucukkaya Inan; Abd El Aziz Alaa S

来源：CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2017, 44(10): 993-1000.

DOI：10.1111/1440-1681.12785

• APPC
• ischaemia-reperfusion injury
• lipoic acid
• mixed neuronal culture
• stroke

In this study, we tested a novel synthetic pyrazole-containing compound, 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (APPC), as an antioxidant in both in vitro and in vivo models of oxidative stress. In addition, the utility of covalently combining APPC with another well-established antioxidant, lipoic acid (LA), was also tested in both models. The in vitro results demonstrated that pretreatment with APPC in a mixed neuronal-glial culture exposed to oxygen-glucose deprivation (OGD) followed by reoxygenation-refeeding, resulted in significant neuroprotection at concentrations between 2.5 to 25mol/L. In contrast, LA was not neuroprotective following OGD alone or following reoxygenation-refeeding. However, the synthetic covalent combination of APPC with LA, named UPEI-800, resulted in significant neuroprotection at concentrations between 0.027 and 2.7mol/L (100-fold more potent than APPC alone), an effect shown to be correlated with increased cellular antioxidant capacity. Further, in an in vivo model of ischaemia-reperfusion injury following transient occlusion of the middle cerebral artery (tMCAO), both APPC (0.1 and 1.0mg/kg) and UPEI-800 (1x10(-3)mg/kg) provided significant neuroprotection. Consistent with the in vitro findings, the in vivo results following tMCAO also demonstrated a 100-fold increase in the potency of the covalently linked compound UPEI-800 compared to APPC alone.

• 出版日期2017-10