Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.
It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischaemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery.
Early MEK1/2 inhibition improves long-term functional outcome, promotes recovery processes after stroke and most importantly provides a realistic time window for therapy.
Objectives A growing body of evidence shows that leptin acts as a proinflammatory cytokine in autoimmune disorders and is related to multiple sclerosis (MS) pathogenesis. The present study was an analysis of serum leptin levels among healthy volunteers and patients with different subtypes of MS, opticospinal MS (OSMS) and neuromyelitis optica (NMO). Methods Leptin concentrations in the sera of 121 healthy volunteers and 201 patients with different subtypes of MS, as well as in 27 NMO and 27 OSMS, were measured. Results Significant differences in leptin serum levels were observed between healthy volunteers, and MS, OSMS and NMO patients (P < 0.001). Furthermore, leptin serum concentration was in correlation with expanded disability status scale (EDSS) in primary progressive MS and secondary progressive MS groups. Interestingly, while the female-to-male ratio of leptin was approximately 2 in each group, the NMO female patients showed sevenfold higher levels of leptin than males. Conclusion The present results show that leptin concentration is important in the pathogenesis of different neuroinflammatory diseases of the central nervous system, in particular NMO. (Clin. Exp. Neuroimmunol.
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