Ischemic Brain Injury Caused by Interrupted Versus Uninterrupted Occlusion in Hypotensive Rats with Subarachnoid Hemorrhage: Neuroprotective Effects of Citicoline

Abstract

This study investigated the neuroprotection provided by cytidine 5'-diphosphocholine (citicoline) during interrupted and uninterrupted occlusion of the basilar artery after subarachnoid hemorrhage (SAH) in 121 hypotensive rats. Animals were anesthetized and the basilar artery was exposed through a transclival approach. Baseline local cerebral blood flow (LCBF) values were recorded, and then the basilar artery was punctured, causing SAH. Blood was drawn to induce hypotension [60–70 mmHg mean arterial blood pressure (MABP)]. Control rats received intraperitoneal (i.p.) injections of 0.5 ml saline immediately after SAH before hypotension induction and after 60 min of occlusion. Experimental rats received 400-mg/kg citicoline i.p. at the same time points. Control group I and treatment group III were subjected to 60 min of interrupted occlusion (5 min of reperfusion after each 10 min of occlusion). Control group II and treatment group IV were subjected to 60 min of uninterrupted occlusion. MABP and LCBF were recorded every 5 minutes. Brain edema was evaluated in seven rats from each group at 24 hours after ischemic injury. At 3 days after occlusion, another set of 28 rats was killed and coronal brain slices were stained to assess infarct volume. The groups' physiological and edema findings were similar. In all groups, LCBF fell immediately after SAH and remained below baseline throughout the experiment. In the citicoline-treated rats, arterial pressure increased significantly after 30–40 min of occlusion, and brain slices showed significantly smaller infarct volumes compared to control slices (p < 0.05). Mortality was significantly lower in the citicoline-treated animals (p < 0.001). The results suggest that citicoline provides significant neuroprotection during cerebral ischemia, and that it significantly reduces mortality. Part of the neuroprotective effect may be mediated by recovery of arterial pressure.