The high morbidity, high socioeconomic costs and lack of specific treatments are key factors that define the relevance of brain pathology for human health and the importance of research on neuronal protective agents. Epidemiological studies have shown beneficial effects of flavonoids on arteriosclerosis-related pathology in general and neurodegeneration in particular. Flavonoids can protect the brain by their ability to modulate intracellular signals promoting cellular survival. Quercetin and structurally related flavonoids (myricetin, fisetin, luteolin) showed a marked cytoprotective capacity in in vitro experimental conditions in models of predominantly apoptotic death such as that induced by medium concentrations (200 µM) of H 2 O 2 added to PC12 cells in culture. Nevertheless, quercetin did not protect substantia nigra neurons in vivo from an oxidative insult (6-hydroxydopamine), probably due to difficulties in crossing the blood-brain barrier. On the other hand, treatment of permanent focal ischemia with a lecithin/quercetin preparation decreased lesion volume, showing that preparations that help to cross the blood-brain barrier may be critical for the expression of the effects of flavonoids on the brain. The hypothesis is advanced that a group of quercetin-related flavonoids could become lead molecules for the development of neuroprotective compounds with multitarget anti-ischemic effects. Key words
Brain vascular pathology and oxidative stressIt is known that brain pathology in the form of cerebrovascular and neurodegenerative disease is a leading cause of death all over the world, with an incidence of about 2/1000 and an 8% total death rate (1-3). Moreover, stroke and dementia are a source of high individual and family suffering mainly because of the lack of efficient therapeutic alternatives. The latter motivates research efforts to identify the mechanisms of neuronal death and to discover new compounds to control them.Neuronal death in stroke is a complex event involving failure of metabolic processes, excitotoxicity, loss of calcium homeostasis and oxidative stress, among other factors (4). During ischemic stroke, a decrease in metabolic energy in the form of ATP affecting membrane ionic pumps leads to an increase in intracellular Ca 2+ and Na + concentrations and to increased glutamate
Flavonoids are an important group of recognized antioxidants ubiquitous in fruits, vegetables and herbs. There are epidemiological evidences for the stroke-protecting capacity of flavonoids and while the neuroprotective power of complex extracts rich in flavonoids like those of Ginkgo biloba, green tea or lyophilized red wine have been demonstrated in several studies, neuroprotection by individual flavonoids has been poorly studied in vivo. The neuroprotective capacity of individual flavonoids was studied in PC12 cells in culture and in a model of permanent focal ischemia (permanent Middle Cerebral Artery Occlusion - pMCAO). In the in vivo experiments, flavonoids were administered in lecithin preparations to facilitate the crossing of the blood brain barrier. The simultaneous incubation of PC12 cells with 200 micro M hydrogen peroxide (H2O2) and different flavonoids for 30 min resulted in a conspicuous profile: quercetin, fisetin, luteolin and myricetin significantly increased cell survival while catechin, kaempherol and taxifolin did not. Quercetin was detected in brain tissue 30 min and 1 h after intraperitoneal administration. When one of the protective flavonoids (quercetin) and one of those that failed to increase PC12 cell survival (catechin) were assessed for their protective capacity in the pMCAO model, administered i.p. 30 min after vessel occlusion, quercetin significantly decreased the brain ischemic lesion while catechin did not. It is concluded that when administered in liposomal preparations, flavonoids structurally related to quercetin could become leads for the development of a new generation of molecules to be clinically effective in human brain ischemia.
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