Abstract
BackgroundBlood flow restoration with fibrinolysis and thrombectomy is recommended to limit injury in stroke patients with proximal artery occlusion. Angiotensin receptor blockers have been shown to be neuroprotective in models of permanent and temporary occlusion, but the benefits on expression of trophic factors have been seen only when the artery is reopened. It is possible that early artery opening with endovascular intervention may increase the likelihood of identifying an effective combination therapy for patients.MethodsNormotensive male Wistar rats were subjected to mechanical middle cerebral artery occlusion (either temporary or permanent), followed by randomization to receive candesartan (0.3 mg/kg IV) or saline. Functional outcome, infarct size, and biochemical changes were assessed 24 h after ischemia induction.ResultsLack of reperfusion blunted candesartan induced neuroprotection (p < 0.05) and reduced the improvement of functional outcome (p < 0.05). With reperfusion, candesartan increased mature BDNF expression in the contralateral hemisphere (p < 0.05) and activated prosurvival (Akt-GSK3-β) signaling (p < 0.05). Without reperfusion, candesartan significantly reduced VEGF expression and MMP activation and increased NOGO A expression, creating an environment hostile to recovery.ConclusionCandesartan induced pro-recovery effects are dependent on the presence of reperfusion.
Highlights
Blood flow restoration with fibrinolysis and thrombectomy is recommended to limit injury in stroke patients with proximal artery occlusion
A silicone coated filament was introduced into the internal carotid artery (ICA) through the external carotid artery (ECA) stub and was pushed all the way to block the origin of the middle cerebral artery (MCA)
To achieve this we used a dose of candesartan (0.3 mg/kg IV) that was demonstrated to have a minimal effect on blood pressure (BP) when administered at reperfusion [25]
Summary
Blood flow restoration with fibrinolysis and thrombectomy is recommended to limit injury in stroke patients with proximal artery occlusion. In the majority of cases, stroke results from a mechanical occlusion of one of the intracranial arteries [1] This results in reduced cerebral blood flow below a threshold necessary for neuronal function resulting in neurologic dysfunction [2, 3]. The only FDA approved drug for the acute management of stroke, alteplase, is intended to restore blood flow to the affected region [5]. In addition to restoring cerebral perfusion, opening an occluded artery is expected to theoretically improve drug delivery to the affected brain region. This might enhance the neuroprotective and prorecovery effects of pharmaceutical agents. It is still unknown whether opening occluded arteries would impact the neuroprotective and pro-recovery effects of pharmaceutical agents
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