RESUMO
Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It's signals are mediated by SHIP (Src homology 2-containing inositol 5' phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation. Intravenous immunoglobulin (IVIG) is a FDA-approved drug containing IgG. We hypothesized that IVIG will attenuate the ICH-induced mast cell activation via FcγRIIB/SHIP1 pathway, resulting in a decrease of brain inflammation, protection of the blood-brain-barrier, and improvement of neurological functions after ICH. To prove this hypothesis we employed the ICH collagenase mouse model. We demonstrated that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activation. Mast cell deactivation resulted in reduced inflammation, consequently attenuating brain edema and improving of neurological functions after ICH. Furthermore using siRNA-induced in vivo knockdown approach we demonstrated that beneficial effects of IVIG were mediated, at least partly, via SHIP1/PIP3 pathway. We conclude that IVIG treatment represents a promising therapeutic approach potentially able to decrease mortality and morbidity after ICH in experimental models.
Assuntos
Hemorragia Cerebral/tratamento farmacológico , Colagenases/genética , Inflamação/tratamento farmacológico , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Receptores de IgG/genética , Administração Intravenosa , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cálcio/metabolismo , Hemorragia Cerebral/genética , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/patologia , Colagenases/imunologia , Modelos Animais de Doenças , Humanos , Imunoglobulina G/administração & dosagem , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Fosfatos de Fosfatidilinositol/metabolismo , RNA Interferente Pequeno/genética , Receptores de IgG/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Hemorrhagic transformation (HT) is a common and natural complication after acute ischemic stroke. The only FDA-approved treatment so far for acute ischemic stroke is rapid reperfusion with recombinant tissue plasminogen activator (rtPA). Although it has been shown to exaggerate the risk and severity of HT and to be associated with increased morbidity and mortality. OBJECTIVE: The aim of this review is to discuss the multifactorial pathophysiology of hemorrhagic transformation, promising interventional targets, and pharmacological treatment options. RESULTS AND CONCLUSION: Understanding HT is essential to restore cerebral blood flow to ischemic brain by reperfusion therapy without causing this complication and additional brain injury. Therefore methods for the prevention and treatment of HT are needed. Although experimental studies showed promising results, clinical translation remains unsatisfactory to date.