RESUMO
The use of intravenous tissue plasminogen activator (tPA) in the treatment of ischemic stroke is limited by its propensity to exacerbate brain edema and hemorrhage. The mechanisms underlying these deleterious effects of tPA remain incompletely understood. The purpose of this study was to delineate a pathway of tPA-mediated complement cascade activation in stroke and to determine whether complement inhibition ameliorates the adverse effects of post-ischemic tPA administration. We found that tPA promotes C3 cleavage both in vitro and in ischemic brain through a plasmin-mediated extrinsic pathway. Using cell culture models, we then showed that the C3a-receptor is strongly expressed on ischemic endothelium and that exogenous C3a dramatically enhances endothelial cell permeability. Next, we assessed the effect of tPA administration on brain edema and hemorrhage in a transient model of focal cerebral ischemia in C57BL/6 mice. We found that intravenous tPA exacerbates brain edema and hemorrhage in stroke, and that these effects are abrogated by a small-molecule antagonist of the C3a receptor. These findings establish for the first time that intravenous tPA dramatically upregulates complement cascade activation in ischemic brain and that pharmacologic complement inhibition protects against the adverse effects of tPA-mediated thrombolysis in stroke.
Assuntos
Acidente Vascular Cerebral/metabolismo , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Compostos Benzidrílicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Complemento C3/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fibrinolisina/farmacologia , Hemoglobinas/metabolismo , Hemorragia/metabolismo , Humanos , Imuno-Histoquímica , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson's disease and Huntington's disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans.
