לוח שנה משולב

17-β estradiol (E2) has been implicated to be neuroprotective, yet the mechanisms underlying E2-mediated protection against stroke remains unclear. The purpose of the current study was to elucidate the role of E2 in NADPH oxidase (NOX2) activation during ischemia/reperfusion induction of superoxide in the hippocampus CA1 region following global cerebral ischemia (GCI) and to explore the regulation of downstream proapoptotic factors by E2. Using a 4-vessel occlusion model to induce GCI, we showed that neuronal NOX2 localizes to the membrane and that NADPH oxidase activity and superoxide production were rapidly and markedly attenuated by E2 following reperfusion. Inhibition of NADPH oxidase activation via icv administration of a NOX2 competitive inhibitor, gp91ds-tat, strongly attenuated superoxide production and was neuroprotective. The increase of neuronal NADPH oxidase and superoxide following cerebral ischemia was shown to require Rac1 activation, as administration of a Rac1 inhibitor (NSC23766) significantly attenuated NADPH oxidase activation and superoxide production following stroke. NSC23766 treatment was also neuroprotective and improved spatial learning and memory. Interestingly, treatment with the competitive NOX2 inhibitor (Gp91ds-tat), but not the scrambled tat peptide control, attenuated acetylation of downstream p53 and reduced levels of the P53 transcriptional target and apoptotic factor, PUMA. Taken as a whole, our studies reveal a novel, membrane-mediated antioxidant mechanism of E2-induced neuroprotection via reduction of neuronal NOX2 activation, superoxide production and neuronal cell death in the hippocampus CA1 following cerebral ischemia.

I will report on work with Vivien Lecomte, Stewart Barnes, and Thierry Giamarchi. In it, we study in a rather general framework how domain walls move in a periodic potential when they are coupled to an internal degree of freedom. This problem can be analyzed in the presence of (thermal) noise. The behavior is not only different from the case without this additional degree of freedom, but also, the speed with which the front advances ceases to be a monotone function of the driving force.