RESUMO
Brain ischemia is associated with detrimental changes in energy production and utilization. Therefore, we hypothesized that leptin, an adipokynin hormone protecting against severe energy depletion, would reduce infarct volume and improve functional outcome after stroke. Male Sabra mice underwent permanent middle cerebral artery occlusion (PMCAO) by photothrombosis. Following initial dose-response and time-window experiments animals were treated with vehicle or leptin, were examined daily by a neurological severity score (NSS) and were sacrificed 72 hours after stroke. Infarct volume was determined and the expression of key genes involved in neuroprotection and survival including the cannabinoid receptors CB1, CB2 and TRPV1, SIRT-1, leptin receptor and Bcl-2 was quantified in the cortex. A separate group of mice were examined with the neurological severity scale 1, 24 and 48 hours and 1, 2 and 3 weeks after stroke, and were killed 3 weeks post stroke to examine metabolic status in the peri-infarct area. Leptin given at a dose of 1mg/kg intra-peritoneally 30 minutes after PMCAO significantly improved neurological disability and reduced infarct volume. Leptin treatment led to increased expression of CB2 receptor, TRPV1, SIRT-1 and leptin receptor and reduced expression of CB1 receptor. There was also a non-significant increase in Bcl-2 gene expression following leptin administration. These results suggest that leptin may be used for attenuating ischemic injury after stroke via induction of an anti-apoptotic state.
Assuntos
Infarto Encefálico/tratamento farmacológico , Leptina/uso terapêutico , Receptor CB2 de Canabinoide/metabolismo , Receptores para Leptina/metabolismo , Sirtuína 1/metabolismo , Canais de Cátion TRPV/metabolismo , Regulação para Cima/efeitos dos fármacos , Análise de Variância , Animais , Infarto Encefálico/etiologia , Avaliação da Deficiência , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/etiologia , Leptina/farmacologia , Masculino , Camundongos , Receptor CB2 de Canabinoide/genética , Receptores para Leptina/genética , Sirtuína 1/genética , Canais de Cátion TRPV/genética , Fatores de TempoRESUMO
Stem cells have been proposed as a new form of cell-based therapy in a variety of disorders, including acute and degenerative brain diseases. Endogenous neural stem cells (eNSC) reside in the subventricular zone and in the subgranular zone of the hippocampus. eNSC are capable of self-renewal and differentiation into functional glia and neurons. Unfortunately, spontaneous brain regeneration is inefficient for clinically significant improvement following brain injury. However, eNSC responses may be augmented considerably by perturbing the pathways governing cell proliferation, migration and differentiation by application of exogenous growth factors. Importantly, current evidence suggests that such perturbations may lead to better functional outcome after stroke. This article summarizes the progress made in this field.
