Normobaric Hyperoxia Extends Neuro- and Vaso-Protection of N-Acetylcysteine in Transient Focal Ischemia

Abstract

N-acetylcysteine (NAC), a precursor of glutathione that reduces reperfusion-induced injury, has been shown protection when it was administered pre-ischemia. However, less is known about the effect when it was given post-ischemia and there is no positive result associated with anti-oxidant in clinical trials. This study investigated the neuro- and vaso-protection of post-ischemia NAC administration as well as combining NAC with normobaric hyperoxia (NBO). Male Sprague-Dawley rats were exposed to NBO or normoxia during 2-h occlusion of the middle cerebral artery, followed by 48-h reperfusion. NAC or vehicle was intraperitoneally administered to rats immediately before reperfusion onset. NAC and NBO treatments produced 1.2 and 30 % reduction of infarction volume, respectively, and combination treatment showed greater reduction (59.8 %) as well as more decrease of hemispheric swelling volume. Of note, combination therapy showed improved neurological assessment and motor function which were sustained for 7 days after reperfusion. We also determined that the combination therapy showed greater inhibitory effects on tight junction protein degradation accompanied by Evan's blue extravasation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) induction, and poly ADP-ribose polymerase (PARP)-1 activation in ischemic brain tissue. Our results showed that although post-ischemia NAC administration had limited protection, combination treatment of NAC plus NBO effectively prevented blood-brain barrier (BBB) damage and significantly improved the outcome of brain injury, providing new evidence to support the concept that "cocktail" treatment targeting different stages provides better neuro- and vaso-protection than current individual treatment that has all failed in their clinical trials.

The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels

“…In addition, expression level of TRPM2 and TRPV1 in the brain were decreased by experimental brain injury13. As a result, ADPR production in the brains of cerebral ischemia-induced rats increased16. Prevention of apoptotic cascades through inhibition of the TRPM2 and TRPV1 in the hippocampal (HIPPO) and DRG neurons of rats were more recently reported517.…”

Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice

“…BBB damage was determined by assessing the extravasation of EB (Sigma). Twenty‐four hours after LPS treatment, EB (2% wt/vol in sterile PBS) was administered (3 mL kg −1 ) through the tail vein, and 20 min later, mice were transcardially perfused with ice‐cold PBS and then the brain was quickly taken out and BBB disruption was quantitatively assessed by measuring EB contents as we have reported (Liu et al ., ). In brief, the brain tissue was harvested as described above and homogenized in 50% wt/vol trichloroacetic acid (Sigma).…”

The decrease in hippocampal transient receptor potential M2 (TRPM2) channel and muscarinic acetylcholine receptor 1 (CHRM1) is associated with memory loss in a surgical menopause rat model

“…Oxidative stress induced by cerebral ischemia-reperfusion injury is considered to be the main event leading to neuronal death [27]. As a result of cerebral ischemia, ADPR production in-creases in the rat brain [28]. Activation of the enzyme ADPR pyrophosphatase by some stimulants such as ADPR and oxidative stress triggers the TRPM2 channel [29].…”