Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Abstract

We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/ reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO þ control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO þ Ngb-expressing CAV-2, CAVNgb; tMCAO þ SP600125; tMCAO þ CAVNgb þ SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression þ SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb þ SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb þ SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.

CAV-2—why a canine virus is a neurobiologist's best friend

“…In another line of therapy, a CAV-2 vector expressing neuroglobin, in combination with a c-Jun N-terminal kinase inhibitor, protects against oxidative stress and neuronal apoptosis induced by stroke in hypertensive rats [50]. In this study a direct comparison of CAV-2 vector biodistribution in the rat brain also showed that CAV-2 vectors significantly outperform HIV-1 vectors.…”

Intravenous Treatment With Coenzyme Q10 Improves Neurological Outcome and Reduces Infarct Volume After Transient Focal Brain Ischemia in Rats

“…Excitotoxicity, inflammation, oxidative stress, necrosis, and apoptosis have been identified as key contributory pathways underlying lesion progression after ischemia. 4 Dissolving the clot allows the restoration of normal blood flow to the affected part of the brain. However, reperfusion can also cause tissue damage.…”

Sevoflurane Postconditioning Increases the Activities of Antioxidant Enzymes and Improves Spatial Learning and Memory after Cardiac Arrest in Rats

“…Oxidative stress induced by reperfusion after CA leads to the exhaustion of cerebral antioxi- dant reserves and causes severe oxidative damage. Moreover, it has been reported that oxidative stress-induced lipid peroxidation alters the antioxidant defense system and plays an important role in the neurological damage occurring after cerebral ischemia (22,23). Surplus amount of ROS generation is thought to be the key module of neuronal damage in the brain.…”