RESUMO
Statins may act on inflammatory responses, decreasing oxidative stress and also reducing brain inflammation in several brain disorders. Epileptogenesis is a process in which a healthy brain becomes abnormal and predisposed to generating spontaneous seizures. We previously reported that lovastatin could prevent neuroinflammation in pilocarpine-induced status epilepticus (SE). In this context, this study investigated the long-lasting effects of lovastatin on mRNA expression of proinflammatory cytokines (interleukin-1ß, tumor necrosis factor α, interleukin-6) and the antiinflammatory cytokine IL-10 in the hippocampus during epileptogenesis by immunohistochemistry and real time polymerase chain reaction (RT-PCR) during the latent and chronic phases in the epilepsy model induced by pilocarpine in rats. For these purposes, four groups of rats were employed: saline (CONTROL), lovastatin (LOVA), pilocarpine (PILO), and pilocarpine plus lovastatin (PILO+LOVA). After pilocarpine injection (350mg/kg, i.p.), the rats were treated with 20mg/kg of lovastatin via an esophagic probe 2h after SE onset. All surviving rats were continuously treated during 15days, twice/day. The pilocarpine plus lovastatin group showed a significant decrease in the levels of IL-1ß, TNF-α, and IL-6 during the latent phase and a decreased expression of IL-1ß and TNF-α in the chronic phase when compared with the PILO group. Moreover, lovastatin treatment also induced an increased expression of the antiinflammatory cytokine, IL-10, in the PILO+LOVA group when compared with the PILO group in the chronic phase. Thus, our data suggest that lovastin may reduce excitotoxicity during epileptogenesis induced by pilocarpine by increasing the synthesis of IL-10 and decreasing proinflammatory cytokines in the hippocampus.
Assuntos
Anticolesterolemiantes/farmacologia , Citocinas/metabolismo , Epilepsia/patologia , Hipocampo/metabolismo , Lovastatina/farmacologia , Animais , Anticolesterolemiantes/uso terapêutico , Citocinas/genética , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Lovastatina/uso terapêutico , Masculino , Agonistas Muscarínicos/toxicidade , Pilocarpina/toxicidade , RNA Mensageiro/metabolismo , Ratos , Ratos WistarRESUMO
We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Epilepsia do Lobo Temporal/fisiopatologia , Peptidil Dipeptidase A/fisiologia , Alelos , Animais , Lobectomia Temporal Anterior , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Genótipo , Humanos , Mutação INDEL , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologiaRESUMO
Extracellular matrix proteoglycans (PGs) and glycosaminoglycans (GAGs) play a crucial role in cell differentiation and synaptogenesis by modulating neurite outgrowth. The chondroitin sulfate (CS)-rich PG, the receptor protein tyrosine phosphatase zeta/beta (RPTP zeta/beta), has been related to neural morphogenesis and axon guidance. Hippocampal sclerosis is the most frequent pathologic finding in patients with intractable mesial temporal lobe epilepsy (MTLE), which is associated with neuron loss, reactive gliosis, and mossy fiber sprouting. In the present study, we investigated the concentration of CS, heparan sulfate (HS) and hyaluronic acid (HA) in the hippocampus and temporal neocortex as well as RPTP zeta/beta expression in the hippocampus of patients with MTLE. Compared to autopsy control tissue, epileptic hippocampi showed a significantly increased concentration of CS (224%; p=0.0109) and HA (146%; p=0.039). HS was instead similar to control values. No differences were found in the concentration of CS, HS, or HA in the temporal neocortex of epileptic patients when compared to control values. In contrast, RPTP zeta/beta immunoreactivity was induced in astrocytes of the inner molecular layer of the dentate gyrus of the sclerotic hippocampus. Because matrix compounds have been associated with tissue injury and repair, the present findings suggest that changes in PGs and GAGs might be related to damage-induced gliosis and neuronal reorganization in the hippocampus of MTLE patients.
Assuntos
Epilepsia do Lobo Temporal/metabolismo , Glicosaminoglicanos/metabolismo , Hipocampo/metabolismo , Proteoglicanas/biossíntese , Adulto , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Sulfatos de Condroitina/metabolismo , Epilepsia do Lobo Temporal/patologia , Heparitina Sulfato/metabolismo , Hipocampo/patologia , Humanos , Ácido Hialurônico/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Proteínas Tirosina Fosfatases/biossíntese , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores , EscleroseRESUMO
PURPOSE: This work studied the profile of glycosaminoglycans (GAGs) in the hippocampus, cortex, and cerebrospinal fluid of patients with temporal lobe epilepsy (TLE). METHODS: The GAGs were analyzed by agarose gel electrophoresis, enzymatic degradation, and enzyme-linked immunosorbent assay (ELISA). RESULTS: The hippocampus of TLE patients showed increased levels of chondroitin sulfate and hyaluronic acid against normal levels of these GAGs in the neocortex and cerebrospinal fluid (CSF). CONCLUSIONS: These results suggest that these matrix components could be involved in the pathophysiology of TLE.