title: Ischemic brain injury: New insights on the protective role of melatonin.
abstract: Stroke represents one of the most common causes of brain's vulnerability for many millions of people worldwide. The plethora of physiopathological events associated with brain ischemia are regulate through multiple signaling pathways leading to the activation of oxidative stress process, Ca2+dyshomeostasis, mitochondrial dysfunction, proinflammatory mediators, excitotoxicity and/or programmed neuronal cell death. Understanding this cascade of molecular events is mandatory in order to develop new therapeutic strategies for stroke. In this review article, we have highlighted the pleiotropic effects of melatonin to counteract the multiple processes of the ischemic cascade. Additionally, experimental evidence supports its actions to ameliorate ischemic long-term behavioural and neuronal deficits, preserving the functional integrity of the blood-brain barrier, inducing neurogenesis and cell proliferation through receptor-dependent mechanism, as well as improving synaptic transmission. Consequently, the synthesis of melatonin derivatives designed as new multitarget-directed products has focused a great interest in this area. This latter has been reinforced by the low cost of melatonin and its reduced toxicity. Furthermore, its spectrum of usages seems to be wide and with the potential for improving human health. Nevertheless, the molecular and cellular mechanisms underlying melatonin´s actions need to be further exploration and accordingly, new clinical studies should be conducted in human patients with ischemic brain pathologies.
authors.affiliation: Department of Toxicology & Pharmacology, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Ramos
authors.affiliation: Paediatric Unit, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Patiño
authors.affiliation: Department of Cellular and Structural Biology. University of Texas Health Science Center at San Antonio, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Department of Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, Vigo, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Gil-Martín
authors.affiliation: Medicinal Chemistry Laboratory, Institute of General Organic Chemistry (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain; Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain; Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Cristobal
authors.initials: C
authors.lastname: de Los Rios
authors.affiliation: Department of Toxicology & Pharmacology, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain. Electronic address: manarome@ucm.es.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.affiliation: Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, 28006 Madrid, Spain; Instituto de I+D del Medicamento Teófilo Hernando (ITH), Facultad de Medicina, Universidad Autónoma de Madrid, Spain. Electronic address: javier.egea@inv.uam.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000378:metabolism* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use; D018384:Oxidative Stress / Q000502:physiology*; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D008550:Melatonin; D002118:Calcium
keywords: Brain ischemia; Free radicals; Melatonin; Neuroprotection