BackgroundTo evaluate the role of NADPH oxidase-mediated reactive oxygen species (ROS) production in multiple sclerosis pathogenesis, we examined the effects of apocynin, an NADPH oxidase assembly inhibitor, on experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced by immunization with myelin oligodendrocyte glycoprotein (MOG (35-55)) in C57BL/6 female mice. Three weeks after initial immunization, the mice were analyzed for demyelination, immune cell infiltration, and ROS production. Apocynin (30 mg/kg) was given orally once daily for the entire experimental course or after the typical onset of clinical symptom (15 days after first MOG injection).ResultsClinical signs of EAE first appeared on day 11 and reached a peak level on day 19 after the initial immunization. The daily clinical symptoms of EAE mice were profoundly reduced by apocynin. The apocynin-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination, reduced infiltration by encephalitogenic immune cells including CD4, CD8, CD20, and F4/80-positive cells. Apocynin reduced MOG-induced pro-inflammatory cytokines in cultured microglia. Apocynin also remarkably inhibited EAE-associated ROS production and blood–brain barrier (BBB) disruption. Furthermore, the present study found that post-treatment with apocynin also reduced the clinical course of EAE and spinal cord demyelination.ConclusionsThese results demonstrate that apocynin inhibits the clinical features and neuropathological changes associated with EAE. Therefore, the present study suggests that inhibition of NADPH oxidase activation by apocynin may have a high therapeutic potential for treatment of multiple sclerosis pathogenesis.
Global cerebral ischemia (GCI) is the leading cause of a poor prognosis even after successful resuscitation from cardiac arrest. Therapeutic induction of hypothermia (TH) is the only proven therapy-and current standard care-for GCI after cardiac arrest; however, its application has been significantly limited owing to technical difficulties. Mesenchymal stem cells (MSCs) are known to suppress neuronal death after cerebral ischemia. The prevention of blood-brain barrier (BBB) disruption has not been suggested as a mechanism of MSC treatment but has for TH. We evaluated the therapeutic effect of MSC administration on BBB disruption and neutrophil infiltration after GCI. To evaluate the therapeutic effects of MSC treatment, rats were subjected to 7 minutes of transient GCI and treated with MSCs immediately after reperfusion. Hippocampal neuronal death was evaluated at 7 days after ischemia using Fluoro-Jade B (FJB). BBB disruption, endothelial damage, and neutrophil infiltration were evaluated at 7 days after ischemia by immunostaining for IgG leakage, Rat endothelial antigen-1, and myeloperoxidase (MPO). Rats treated with MSCs showed a significantly reduced FJB+ neuron count compared with the control group. They also showed reduced IgG leakage, endothelial damage, and MPO+ cell counts. The present study demonstrated that administration of MSCs after transient GCI provides a dramatic protective effect against hippocampal neuronal death. We hypothesized that the neuroprotective effects of MSC treatment might be associated with the prevention of BBB disruption and endothelial damage and a decrease in neutrophil infiltration.
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