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Am J Physiol Heart Circ Physiol 286: H2442-H2451, 2004; doi:10.1152/ajpheart.01169.2003
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Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

Ikuyo Kusaka,1 Gen Kusaka,1 Changman Zhou,1 Mami Ishikawa,2 Anil Nanda,1 D. Neil Granger,2 John H. Zhang,1,2,3 and Jiping Tang2

1Neurosurgery, 2Molecular and Cellular Physiology, and 3Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

Submitted 16 December 2003 ; accepted in final form 12 February 2004

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT1-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT1-R antagonist candesartan (0.5 mg·kg–1·day–1) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats (n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91phox and p22phox mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91phox and p22phox mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91phox and p22phox, decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT1-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.

angiotensin type 1 receptor antagonist


Address for reprint requests and other correspondence: J. Tang, Dept. of Molecular and Cellular Physiology, Louisiana State Univ. Health Sciences Center, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130-3932 (E-mail: jtang{at}lsuhsc.edu).




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