Neuronal Rho GTPase Rac1 elimination confers neuroprotection in a mouse model of permanent ischemic stroke

• Tipo: Artigo em Revista Científica Internacional
• Data: 2018

Autores

Karabiyik, C (Autor) Outra; Fernandes, R (Autor) Outra; Figueiredo, FR (Autor) Outra; Socodato, R (Autor) Outra; Brakebusch, C (Autor) Outra; Lambertsen, KL (Autor) Outra; Relvas, JB (Autor) ICBAS; Santos, SD (Autor) Outra

Revista

Título: Brain Pathology

Vol. 28

Páginas: 569-580

ISSN: 1015-6305

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 0 Citações

Scopus - 9 Citações

Outras Informações

ID Authenticus: P-00P-2HV

DOI: 10.1111/bpa.12562

Abstract (EN): The Rho GTPase Rac1 is a multifunctional protein involved in distinct pathways ranging from development to pathology. The aim of the present study was to unravel the contribution of neuronal Rac1 in regulating the response to brain injury induced by permanent focal cerebral ischemia (pMCAO). Our results show that pMCAO significantly increased total Rac1 levels in wild type mice, mainly through rising nuclear Rac1, while a reduction in Rac1 activation was observed. Such changes preceded cell death induced by excitotoxic stress. Pharmacological inhibition of Rac1 in primary neuronal cortical cells prevented the increase in oxidative stress induced after overactivation of glutamate receptors. However, this was not sufficient to prevent the associated neuronal cell death. In contrast, RNAi-mediated knock down of Rac1 in primary cortical neurons prevented cell death elicited by glutamate excitotoxicity and decreased the activity of NADPH oxidase. To test whether in vivo down regulation of neuronal Rac1 was neuroprotective after pMCAO, we used tamoxifen-inducible neuron-specific conditional Rac1-knockout mice. We observed a significant 50% decrease in brain infarct volume of knockout mice and a concomitant increase in HIF-1 expression compared to littermate control mice, demonstrating that ablation of Rac1 in neurons is neuroprotective. Transmission electron microscopy performed in the ischemic brain showed that lysosomes in the infarct of Rac1- knockout mice were preserved at similar levels to those of non-infarcted tissue, while littermate mice displayed a decrease in the number of lysosomes, further corroborating the notion that Rac1 ablation in neurons is neuroprotective. Our results demonstrate that Rac1 plays important roles in the ischemic pathological cascade and that modulation of its levels is of therapeutic interest.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12