Avoiding stroke during cerebral arterial occlusion by temporarily blocking neuronal functions in the rabbit

The temporary occlusion of cerebral vessels is being used with increased frequency in the surgical management of cerebral vascular disease, and this procedure places brain tissue at risk of infarction. Using a modified version of a well-established model of focal cerebral ischemia in the rabbit, we tested the protective effect of a combination of six agents; each agent was selected to temporarily block one or more neuronal functions, hence reducing their metabolic demands. The combination of six agents had been previously shown to protect neurological function against ischemia. Ten male adult New Zealand White rabbits were anesthetized with halothane, and physiological parameters were maintained within normal ranges. A branch of the left external carotid artery was catheterized and the vasculature supplying the left middle cerebral artery (MCA) territory was isolated. Mannitol was infused via the external carotid artery into the left internal carotid artery to open the blood-brain barrier in the territory of the MCA. This infusion was followed by either Ames' medium alone (control) or Ames' medium containing the combination of agents: tetrodotoxin (0.1 micromol/L), 2-amino-4-phosphonobutyric acid (20 mumol/L), 2-amino-5-phosphonovaleric acid (1 mmol/L), amiloride (1 mmol/L), magnesium (10 mmol/L), and lithium (10 mmol/L). Ischemia in the left MCA territory was then induced for 2 hours, followed by 4 hours of reperfusion. Animals pretreated with the combination of agents sustained infarctions that were markedly smaller (mean+/-SEM, 46+/-19.7 mm(3), n=5) than control animals (300+/-46.5 mm(3), n=5, P<.001). We conclude that the strategy of locally delivering a combination of agents designed to temporarily reduce neuronal metabolic demands by temporarily blocking several nonvital neuronal functions, can reduce the infarction induced by a focal reduction in cerebral blood flow in the rabbit.