title: Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl-2 expression after focal cerebral ischemia.
abstract: 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.
authors.affiliation: Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Servicio de Farmacología Clínica e Instituto de Gerontología, Hospital de La Princesa, 28029, Madrid, Spain. monica.sobrado@uam.es
authors.forename: M
authors.initials: M
authors.lastname: Sobrado
authors.forename: M G
authors.initials: MG
authors.lastname: López
authors.forename: F
authors.initials: F
authors.lastname: Carceller
authors.forename: A G
authors.initials: AG
authors.lastname: García
authors.forename: J M
authors.initials: JM
authors.lastname: Roda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology; D004359:Drug Therapy, Combination; D020287:In Situ Nick-End Labeling; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009553:Nimodipine / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D018697:Nootropic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D003566:Cytidine Diphosphate Choline; D009553:Nimodipine