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David Della-Morte,1,2 Francesco Cacciatore,3 Elisa Salsano,4 Gilda Pirozzi,4 Maria Teresa Del Genio,4 Iole D'Antonio,4 Gaetano Gargiulo,5 Raffaele Palmirotta,2 Fiorella Guadagni,2 Tatjana Rundek,1 Pasquale Abete41Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA; 2Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele, Rome, Italy; 3Istituto Scientifico di Campoli/Telese, Fondazione Salvatore Maugeri, IRCCS, Benevento, Italy; 4Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II," Naples, Italy; 5AON, SS Antonio e Biagio e Cesare Arrigo, Struttura Complessa di Geriatria, Alessandria, ItalyAbstract: Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed.Keywords: ischemic preconditioning, stroke, transient cerebral ischemic attack, mortality, elderly

The object of this study was to assess the influence of oral contraceptives (OCs) on the risk of cerebral thromboembolic attacks (CTA) including thrombotic stroke and transitory cerebral ischemic attacks. A 5-year case-control study including all Danish hospitals was conducted. All women 15–44 years old suffering a first ever CTA during the period January 1, 1994 to December 31, 1998, were included. Controls were selected annually, 600 per year in 1994–1995, 1200 per year 1996–1998. Response rates for cases and controls were 88% and 90%, respectively. After exclusion of nonvalid diagnoses, pregnant women, and women with previous thrombotic diseases, 626 cases and 4054 controls were available for analysis.A multivariate matched analysis was performed. Controls were matched to cases within 1-year age bands. Adjustments were made for the following potential confounders: year, length of OC use, smoking, hypertension, migraine, family CTA, and years of schooling. There were 212 and 1208 current users of OCs among cases and controls, respectively.The risk of CTA among current users of OCs decreased significantly with decreasing estrogen dose (nonusers reference): OCs with 50 μg, 30–40 μg, 20 μg ethinyl estradiol (EE) and progestin-only pills implied adjusted odds ratios (ORs) (95% CI) of 4.5 (2.6–7.7), 1.6 (1.3–2.0), 1.7 (1.0–3.1), and 1.0 (0.3–3.0), respectively. Current users of OCs with second- (levonorgestrel or norgestimate) and third- (desogestrel or gestodene) generation progestins combined with 20–30 μg EE had ORs of CTA of 2.2 (1.6–3.0) and 1.4 (1.0–1.9), respectively. After correction for differences in estrogen dose, the third- to second-generation risk ratio was 0.6 (0.4–0.9; p = 0.01).In conclusion, high dose OCs and OCs with second-generation progestins were associated with the risk of CTA. The risk increased 2.5 times with estrogen dose increasing from 20 to 50 μg EE, and users of low-dose OCs with second-generation progestins had a 61% higher risk-association of CTA than users of OCs with third-generation progestins. [Copyright &y& Elsevier]