The neuroprotective effect of the antioxidant flavonoid derivate di-tert-butylhydroxyphenyl is parallel to the preventive effect on post-ischemic Kir2.x impairment but not to post-ischemic endothelial dysfunction.
In the rat model of transient cerebral ischemia induced by intraluminal occlusion of the middle cerebral artery, we investigated the respective roles of ischemia and reperfusion in endothelium-dependent relaxation and smooth muscle relaxation related to the inward rectifier potassium current (Kir2.x), using the Halpern arteriography technique and/or patch-clamp technique. We first demonstrated that reperfusion is necessary to induce a significant impairment of smooth muscle Kir2.x, since ischemia alone has no effect on Kir2.x current density and function. In addition, we demonstrated that both ischemia and reperfusion are necessary for the occurrence of maximal post-ischemic endothelial dysfunction. The crucial role of reperfusion in post-ischemic vascular impairment prompted us to characterize the effect of a new antioxidant synthetic flavonoid derivate, 3'5'di- tert-butylhydroxyphenyl (dt-BC), on both neuronal and vascular injuries. Dt-BC (10 mg/kg) induced a neuroprotective effect as demonstrated by a significant decrease in infarct size, while there was no protective effect with the doses of 3 mg/kg and 30 mg/kg. Parallel to neuroprotection, dt-BC at a dose of 10 mg/kg, but not with doses of 3 mg/kg and 30 mg/kg, prevented post-ischemic impairment of smooth muscle Kir2.x current density and function, while dt-BC had no effect on the post-ischemic alteration of endothelial function whatever doses are used. These data demonstrate the potential of a new synthetic flavonoid derivate to induce neurovascular protection and support a possible relationship between vascular and neuronal protection via pharmacological modulation of oxidative stress.
Pétrault
Olivier
O
EA 1046-Laboratoire de Pharmacologie, Faculté de Médecine de l'Université de Lille 2, Centre Hospitalier, Universitaire de Lille, 1 place de Verdun, 59045 Lille Cedex, France.
Bastide
Michèle
M
Cotelle
Nicole
N
Gelé
Patrick
P
Gautier
Sophie
S
Laprais
Maud
M
Vamecq
Joseph
J
Duriez
Patrick
P
Bordet
Régis
R
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D005419:Flavonoids; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying; C500667:di-tert-butylhydroxyphenyl