RESUMO
Many studies have shown that chronic inflammation occurs in the brain of patients with Alzheimer's disease (AD). It is well known that long-term administration of non-steroidal anti-inflammatory drugs (NSAIDs) can alleviate the cognitive decline of AD patient and elderly. Several inflammatory cytokines produced in the metabolism of arachidonic acid (AA) are closely related to inflammatory diseases. Lipoxygenases (LOXs) and cyclooxygenases (COXs) play a crucial role in the AA network, the products eicosanoids have an important impact on the progression of AD. Although there are many arguments and conflicting evidence, currently LOXs and COXs are still the hot topics in the research on AD pathogenesis and drug development. Here, we review the progress in research on COXs and LOXs, including their actions on CNS and their association with AD, and explore the feasibility of LOXs and COXs as targets for the drugs to prevent and/or treat AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Anti-Inflamatórios não Esteroides , Inibidores de Ciclo-Oxigenase/uso terapêutico , Inibidores de Lipoxigenase/uso terapêutico , Lipoxigenases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácido Araquidônico/metabolismo , Encéfalo/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Prostaglandina H2/metabolismoRESUMO
Oxidative stress and neuroinflammation are highly relevant to the pathological processes of various neurodegenerative diseases including Alzheimer's disease (AD). (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), a novel 5-lipoxygenase inhibitor, was isolated from the whole plant of Incarvillea mairei var granditlora (Wehrhahn) Grierson. In this study, we investigated the protective effect of HOEC on hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) -induced cytotoxicity and neuroinflammation in vitro and in vivo. MTT assay, LDH release assay, morphological observation and Hoechst 33342/PI dual staining followed by EIA, immunofluorescence staining and Western Blotting analysis were performed to elucidate the neuroprotective effect of HOEC. Treatment with HOEC at various concentrations prior to H2O2 exposure significantly enhanced cell viability, decreased LDH release, prevented cell morphologic changes and apoptosis. Instead of PGE2 reduction, HOEC markedly inhibited the production of LTB4 and suppressed the macrophage-mediated neurotoxicity. Western blotting and immunofluorescence staining showed that HOEC inhibited H2O2-induced p38 phosphorylation and NF-κB activation. Neuroprotective effect of HOEC was abolished by a p38 inhibitor. Further in vivo studies of LPS-induced neuroinflammation confirmed the anti-inflammatory effects of HOEC. These findings that HOEC protects SH-SY5Y cells from H2O2 and LPS-induced injury via arachidonic acid network modulation followed by p38 MAPK and NF-κB signaling, might make HOEC be considered as a therapeutic candidate for prevention and treatment of neurodegenerative diseases involving oxidative stress or/and inflammation.
Assuntos
Ácido Araquidônico/metabolismo , Ácidos Cafeicos/farmacologia , Cicloexanonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Ácidos Cafeicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cicloexanonas/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Peróxido de Hidrogênio/toxicidade , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos ICR , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Distribuição AleatóriaRESUMO
Cognitive deficits in AD correlate with progressive synaptic dysfunction and loss. The Rho family of small GTPases, including Rho, Rac, and Cdc42, has a central role in cellular motility and cytokinesis. Acetylcholinesterase inhibitor has been found to protect cells against a broad range of reagents-induced injuries. Present studies examined if the effect of HupA on neurite outgrowth in Aß-treated neuronal cells executed via regulating Rho-GTPase mediated axon guidance relative gene expression. Affymetrix cDNA microarray assay followed by real-time RT-PCR and Western Blotting analysis were used to elucidate and analyze the signaling pathway involved in Aß and HupA's effects. The effects of Aß and HupA on the neurite outgrowth were further confirmed via immunofluorescence staining. Aß up-regulated the mRNA expressions of NFAT5, LIMK1, EPHA1, NTN4 and RAC2 markedly in SH-SY5Y cells. Co-incubation of Aß and HupA reversed or decreased the changes of NFAT5, NTN4, RAC2, CDC42 and SEMA4F. HupA treated alone increased NFAT5, LIMK1, NTN4 significantly. Following qRT-PCR validation showed that the correlation of the gene expression ratio between microarray and qRT-PCR is significant. Western blot result showed that the change of CDC42 protein is consistent with the mRNA level while RAC2 is not. The morphological results confirmed that HupA improved, or partly reversed, the Aß-induced damage of neurite outgrowth. The protective effect of HupA from Aß induced morphological injury might be correlative to, at least partially, regulating the network of neurite outgrowth related genes.