Ever since the pathology of multiple sclerosis (MS) was described, it has been debated whether immune-mediated myelin damage is a primary or secondary event to axon degeneration. Traditionally the ...disease is considered to ensue as a consequence of demyelination followed by neuronal loss. Recent in vivo findings, however, demonstrate axons to be the primary target of the disease process. Animal models of MS are greatly instrumental in studying the pathogenesis of the disease and understanding the sequence of events that take place in neurodegenerative disorders.
Tumor-necrosis-factor-alpha (TNF-alpha) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal ...culture model. In accordance with our previous findings, TNF-alpha decreased outward potassium currents in RGCs. Antagonism of the TNF-alpha-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-alpha-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-alpha-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.
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