Stobadine-induced hastening of sensorimotor recovery after focal ischemia/reperfusion is associated with cerebrovascular protection.
In a model of 1 hour-intraluminal occlusion of rat middle cerebral artery (MCA), we investigated the spontaneous recovery of vascular functions and functional deficit together with ischemia volume evolution at 24 h, 3 days and 7 days of reperfusion. Infarct cerebral volumes and edema were quantified with histological methods. Endothelium-dependent and smooth muscle potassium inward rectifier current (Kir2.x)-dependent relaxing responses of MCA were tested using Halpern arteriograph and Kir2.x current density evaluated on MCA myocytes with whole-cell patch-clamp technique. Sensorimotor recovery was estimated according to performances obtained with adhesive removal test and prehensile traction test. A time-dependent improvement of smooth muscle K(+)-dependent vasorelaxation and Kir2.x current density is observed at 7 days of reperfusion while endothelium-dependent relaxation is still impaired. In parallel a significant reduction of functional deficit is observed at 7 days of reperfusion together with a time-matched reduction of striatal infarct and edema volumes. Administration of an antioxidant agent, stobadine, at time of reperfusion and 5 h later allowed: (i) a neuroprotective effect with a significant reduction of infarct size compared to vehicle-treated rats; (ii) a prevention of endothelial-dependent relaxation and Kir2.x current density reductions of MCA ipsilateral to occlusion; (iii) a hastening of the functional recovery. The beneficial effect of stobadine underlines a link between vascular protection, neuronal protection and sensorimotor recovery that could become a promising pharmacological target in the treatment of cerebral ischemia.
Plaisier
F
F
EA1046-Département de Pharmacologie, Institut de Médecine Prédictive et de Recherche Thérapeutique, Faculté de Médecine-Université de Lille 2, Centre Hospitalier et Universitaire, 1, Place de Verdun, 59045 Lille Cedex, France.
Bastide
M
M
Ouk
T
T
Pétrault
O
O
Laprais
M
M
Stolc
S
S
Bordet
R
R
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D000975:Antioxidants; D002243:Carbolines; D024661:Potassium Channels, Inwardly Rectifying; D000109:Acetylcholine; C100106:dicarbine