Neuroprotection conferred by post-ischemia ethanol therapy in experimental stroke: an inhibitory effect on hyperglycolysis and NADPH oxidase activation.
Ethanol provides neuroprotection following ischemia/reperfusion. This study assessed ethanol's effect on hyperglycolysis and NADPH oxidase (NOX) activation. Adult, male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Three sets of experiments were conducted to determine ethanol's effect on (i) conferring neuroprotection by measuring infarct volume and neurological deficits 24 h post reperfusion; (ii) cerebral glucose metabolism and lactic acidosis by measuring brain and blood glucose concentrations and protein expression of glucose transporter 1 and 3 (GLUT1, GLUT3), phosphofructokinase (PFK), as well as lactic acidosis by measuring lactate dehydrogenase (LDH), and lactate; and (iii) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation by detecting enzymatic activity and subunit expression at 3 h after reperfusion. When administered upon reperfusion, ethanol (1.5 g/kg) reduced infarct volume by 40% (p < 0.01) and neurological deficits by 48% at 24 h post reperfusion while reducing (p < 0.01) elevations in glycolytic protein expression and lactate levels during early reperfusion (3 h). Ethanol increased the reductions in cerebral glucose concentration at 3 h post reperfusion by 64% (p < 0.01) while enhancing (p < 0.01) post stroke blood glucose concentration, suggesting a reduced cellular glucose uptake and utilization. Ethanol decreased (p < 0.01) stroke-induced NOX activation by reducing enzymatic activity and gp91(phox) expression by 45% and 38%, respectively. Post-ischemia ethanol treatment exerts neuroprotection through attenuation of hyperglycolysis and associated NOX activation. Because of the lack of associated hypoglycemia and selectivity toward decreasing cerebral metabolism, further investigation of ethanol's use as a post-stroke therapy, especially in the context of hyperglycemia, seems warranted.
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA.
Ryan
R
Kochanski
Changya
C
Peng
Tetsuhiro
T
Higashida
Xiaokun
X
Geng
Maik
M
Hüttemann
Murali
M
Guthikonda
Yuchuan
Y
Ding
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D002492:Central Nervous System Depressants / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D000431:Ethanol / Q000627:therapeutic use*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D018696:Neuroprotective Agents; D025221:Phosphofructokinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology
D001786:Blood Glucose; D002492:Central Nervous System Depressants; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D018696:Neuroprotective Agents; C495679:Slc2a1 protein, rat; C495690:Slc2a3 protein, rat; D019344:Lactic Acid; D000431:Ethanol; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D019255:NADPH Oxidases; D025221:Phosphofructokinases