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Vascular smooth muscle cells potassium channels implication in cerebral ischemia/reperfusion and brain plasticity

Canaux potassiques du muscle lisse vasculaire au cours du processus d'ischémie reperfusion : cibles pharmacologiques potentielles de la plasticité cérébrale?

Abstract : Stroke is the third leading cause of mortality and the first cause of handicap in industrialized countries. It induces several important functional alterations on neuro-glio-vascular tissue with dramatic consequences on the well-being of the patients in terms of cognitive and motor functional disability. The objective of this work is to highlight modifications of the Kir and Kv vascular potassium conductances, using model of focal cerebral ischemia by middle cerebral artery occlusion in the rats. During the post-ischemic period (7 days), ionic plasticity was studied by electrophysiological techniques (patch-clamp) and by sensorimotor deficit evaluation, representative of disability observed among patients following stroke. Beneficial effects of two pharmacological neuroprotective treatments in acute phase were evaluated, by administration of Stobadine, an antioxidant agent, and Fenofibrate, an agonist of PPAR alpha receptors.
Vascular smooth muscle Kir2.x current alteration and its associated potassium-dependent relaxation as well as endothelium-dependent relaxation have been confirmed. It is highlighted for the first time the alteration of one another potassium conductance, voltage-dependant, implying Kv channels. During the extended post-ischemic period to 7 days, a total, spontaneous and progressive recovery from the Kir2.x current density and its associated vasorelaxation were obtained. On the other hand, there was no endothelium-dependent recovery at the 7 days of reperfusion. With regard to the sensorimotor deficits observed at 24 hours and evaluated by the adhesive removal test and the prehensile traction test, a significant and progressive but partial recovery of sensorimotor status is observed.
Administration of Stobadine (1h and 6h after ischemia) prevents endothelium-dependant relaxation and current density Kir2.x alterations since 24 hours of reperfusion without modifying kinetics of potassium-dependent relaxation recovery. On the other hand, this treatment induces a significant reduction in the cerebral lesions and hastens the motor and sensorimotor functional recovery during the 7 days of reperfusion. Moreover, following the administration of Fenofibrate (twice daily treatment for 3 days), a significant reduction of the cerebral infarct volume and a hastening of motor functions were observed at 3 days of reperfusion, and these observations are in parallel to the two studied mechanisms of vasorelaxation recovery.
Effects of ischemia reperfusion on potassium current Kv was evaluated at 24 hours of reperfusion in a specific study of the cGMP/PKG pathway modulation. Regulation of Kv current appears to be ineffective in normal conditions and would be effective only in pathological situation. Reduction of Kv observed after ischemia reperfusion is potentiated when this pathway is activated. Usage of modulators (NO donors, protein kinase G activators, phosphodiesterase inhibitors) confirmed negative implication of the cGMP-dependent effect on Kv current density.
Our work shows on one hand a reduction of the Kv current at the same time as the current density Kir2.x alteration at 24 hours of reperfusion. They could participate in the pathological mechanisms by inducing cerebral blood flow alteration in response to the neuronal demand and takes part in the extension of the cerebral lesions. In addition, ionic plasticity taking place in post-ischemic period could be hastened by pharmacological treatments with parallel neuroprotective effect and improvement of the functional deficit. In conclusion, usage of treatments aimed to protect and hasten the ionic plasticity in the vascular compartment following ischemia reperfusion could be considered as a potential target in neuroprotection concept.