RESUMO
Changes of neurosteroids may be involved in the pathophysiology of multiple sclerosis (MS). The present study investigated whether changes of neurosteroidogenesis also occurred in the grey and white matter regions of the brain in mice subjected to cuprizone-induced demyelination. Accordingly, we compared the expression of neurosteroidogenic proteins, including steroidogenic acute regulatory protein (StAR), voltage-dependent anion channel (VDAC) and 18 kDa translocator protein (TSPO), as well as neurosteroidogenic enzymes, including the side chain cleavage enzyme (P450scc), 3ß-hydroxysteroid dehydrogenase/isomerase and 5α-reductase (5α-R), during the demyelination and remyelination periods. Using immunohistochemistry and a quantitative polymerase chain reaction, we demonstrated a decreased expression of StAR, P450scc and 5α-R with respect to an increase astrocytic and microglial reaction and elevated levels of tumor necrosis factor (TNF)α during the cuprizone demyelination period in the hippocampus, cortex and corpus callosum. These parameters, as well as the glial reaction, were normalised after 2 weeks of spontaneous remyelination in regions containing grey matter. Conversely, persistent elevated levels of TNFα and low levels of StAR and P450scc were observed during remyelination in corpus callosum white matter. We conclude that neurosteroidogenesis/myelination status and glial reactivity are inversely related in the hippocampus and neocortex. Establishing a cause and effect relationship for the measured variables remains a future challenge for understanding the pathophysiology of MS.
Assuntos
Encéfalo/enzimologia , Encéfalo/metabolismo , Bainha de Mielina/enzimologia , Bainha de Mielina/metabolismo , Remielinização , 3-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Colestenona 5 alfa-Redutase/metabolismo , Cuprizona/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/enzimologia , Esclerose Múltipla/metabolismo , Bainha de Mielina/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/enzimologia , Neuroglia/metabolismo , Fosfoproteínas/metabolismo , Receptores de GABA/metabolismo , Remielinização/efeitos dos fármacos , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task.