title: 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+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+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+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+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.
authors: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors: Emily N J
authors: EN
authors: Ord
authors: Rachel
authors: R
authors: Shirley
authors: John D
authors: JD
authors: McClure
authors: Christopher
authors: C
authors: McCabe
authors: Eric J
authors: EJ
authors: Kremer
authors: I Mhairi
authors: IM
authors: Macrae
authors: Lorraine M
authors: LM
authors: Work
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000229:Dependovirus / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D002534:Hypoxia, Brain / Q000473:pathology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D000078787:Neuroglobin; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010991:Plethysmography; D051381:Rats; D011918:Rats, Inbred SHR; D060888:Real-Time Polymerase Chain Reaction; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D014161:Transduction, Genetic
chemical_list: D000873:Anthracenes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D018696:Neuroprotective Agents; D049452:Green Fluorescent Proteins; C432165:pyrazolanthrone; D005914:Globins; D048031:JNK Mitogen-Activated Protein Kinases
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