A novel nitronyl nitroxide radical HPN-C6 attenuates brain damage in an acute hypobaric hypoxia mouse model through inhibition of the oxidative stress

Abstract

Hypobaric hypoxia (HH) results in the increased formation of ROS and induces a wide range of deleterious effects on the brain. Nitronyl nitroxide radicals are a kind of stable organic nitroxide radicals with a good ability to scavenge ROS. Herein, a series of new nitronyl nitroxide radicals was synthesized according to the previous method. Among them, a compound with six carbon atoms alkyl chain (HPN-C₆) was screened for estimating the protective effect against HH-induced brain injury in the acute HH mouse model. The results showed that HPN-C₆ ameliorated oxidative stress by decreasing the activity of LDH and the content of H₂O₂, NO, and MDA, increasing the activities of SOD, CAT and GSH-PX in the brain tissue of HH injured mice. Moreover, HPN-C₆ exhibited an anti-inflammatory effect by reducing the level of IL-1β, TNF-α, and IL-6 in the brains of mice after HH exposure through regulating the P38 MAPK signaling pathway. In addition, HPN-C₆ exhibited the protection effect by inhibiting the release of mitochondrial cytochrome C, locking the activation of caspase-3, and downregulating the expression of Bax and upregulating the expression of Bcl-2. HPN-C₆ pretreatment could inhibit the caspase-dependent mitochondria apoptosis pathway. These findings indicate that HPN-C₆ is a potential therapeutic agent to prevent brain damage induced by HH.

Keywords: Brain damage; Hypobaric hypoxia; Nitronyl nitroxide radicals; Oxidative stress.