title: Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke.
abstract: CDP-choline has shown neuroprotective effects in cerebral ischemia. In humans, although a recent trial International Citicoline Trial on Acute Stroke (ICTUS) has shown that global recovery is similar in CDP-choline and placebo groups, CDP-choline was shown to be more beneficial in some patients, such as those with moderate stroke severity and not treated with t-PA. Several mechanisms have been proposed to explain the beneficial actions of CDP-choline. We have now studied the participation of Sirtuin1 (SIRT1) in the neuroprotective actions of CDP-choline. Fischer rats and Sirt1⁻/⁻ mice were subjected to permanent focal ischemia. CDP-choline (0.2 or 2 g/kg), sirtinol (a SIRT1 inhibitor; 10 mg/kg), and resveratrol (a SIRT1 activator; 2.5 mg/kg) were administered intraperitoneally. Brains were removed 24 and 48 h after ischemia for western blot analysis and infarct volume determination. Treatment with CDP-choline increased SIRT1 protein levels in brain concomitantly to neuroprotection. Treatment with sirtinol blocked the reduction in infarct volume caused by CDP-choline, whereas resveratrol elicited a strong synergistic neuroprotective effect with CDP-choline. CDP-choline failed to reduce infarct volume in Sirt1⁻/⁻ mice. Our present results demonstrate a robust effect of CDP-choline like SIRT1 activator by up-regulating its expression. Our findings suggest that therapeutic strategies to activate SIRT1 may be useful in the treatment of stroke. Sirtuin 1 (SIRT1) is implicated in a wide range of cellular functions. Regarding stroke, there is no direct evidence. We have demonstrated that citicoline increases SIRT1 protein levels in brain concomitantly to neuroprotection. Citicoline fails to reduce infarct volume in Sirt1⁻/⁻ mice. Our findings suggest that therapeutic strategies acting on SIRT1 may be useful in the treatment of stroke.
authors.affiliation: Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, Madrid, Spain.
authors.forename: Olivia
authors.initials: O
authors.lastname: Hurtado
authors.forename: Macarena
authors.initials: M
authors.lastname: Hernández-Jiménez
authors.forename: Juan G
authors.initials: JG
authors.lastname: Zarruk
authors.forename: María I
authors.initials: MI
authors.lastname: Cuartero
authors.forename: Iván
authors.initials: I
authors.lastname: Ballesteros
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Camarero
authors.forename: Ana
authors.initials: A
authors.lastname: Moraga
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Pradillo
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D004357:Drug Synergism; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013267:Stilbenes / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D009284:Naphthols; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D013267:Stilbenes; C439060:sirtinol; D003566:Cytidine Diphosphate Choline; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: CDP-choline; SIRT1; citicoline; neuroprotection; stroke