Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase BCL-2 expression after focal cerebral ischemia

• Published in: Neuroscience Vol. 118; no. 1; pp. 107 - 113
• Main Authors: SOBRADO, M, LOPEZ, M. G, CARCELLER, F, GARCIA, A. G, RODA, J. M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.04.2003
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Infarction - drug therapy; Cerebral Infarction - physiopathology; Cerebral Infarction - prevention & control; citicoline; Cytidine Diphosphate Choline - pharmacology; Drug Therapy, Combination; In Situ Nick-End Labeling; Male; Medical sciences; Nerve Degeneration - drug therapy; Nerve Degeneration - physiopathology; Nerve Degeneration - prevention & control; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuropharmacology; Neuroprotective agent; Nimodipine - pharmacology; Nootropic Agents - pharmacology; Nootropic Agents - therapeutic use; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Treatment Outcome; Up-Regulation - drug effects; Up-Regulation - physiology; Nervous system diseases; Citicoline; Rat; Rodentia; Cardiovascular disease; Neuroprotective agent; ischemia-reperfusion; Cerebral disorder; Vascular disease; Vertebrata; Experimental disease; Mammalia; TUNEL; Ischemia; Nimodipine; Animal; neuroprotection; Central nervous system disease; rats; Cerebrovascular disease; Apoptosis; Brain (vertebrata)
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/s0306-4522(02)00912-0

Cerebral ischemia triggers a multitude of pathophysiological and biochemical events that separately affect the evolution of focal ischemia and, therefore, stroke treatment should logically employ all known neuroprotective agents. We hypothesized that a treatment combining nimodipine and citicoline might have a potential neuroprotective effect. To assess this idea, Sprague-Dawley rats underwent transient bilateral common carotid artery ligation with simultaneous middle cerebral artery occlusion for 60 min. Four treatment groups were established. Animals received either: a) saline (control group); b) intracarotid nimodipine infusion during 30 min in the ischemia-reperfusion (nimodipine group); c) i.p. postischemic citicoline injections once daily for 7 days (citicoline group); or d) intracarotid nimodipine bolus during ischemia-reperfusion plus i.p. postichemic citicoline injections (combination group). They were killed after either 7 or 3 days after reperfusion. In the first case, the volume of the infarcted tissue was studied by a stereological procedure and in the second case, in situ end-labeling of nuclear DNA fragmentation (TUNEL) and Bcl-2 expression were employed to determine the level of apoptosis. The infarct volume was significantly reduced in both the nimodipine and the citicoline treatment groups after 7 days of reperfusion; combination of both drugs produced an additive effect. After 3 days of reperfusion, the number of Bcl-2-positive neurons was significantly increased while that of TUNEL-positive cells significantly decreased at the infarct border in the combined-treatment animals. Our findings demonstrate a neuroprotective effect from an acute single dose of nimodipine during ischemia-reperfusion and prolonged post-ischemic treatment with citicoline in a model of focal cerebral ischemia. These results suggest that a possible mechanism of neuroprotective action would be mediated by increased Bcl-2 expression and decreased apoptosis within the boundary zone of the infarct together with neutralization of the ischemia-reperfusion injury.