An additional or alternative explanation to explain the lack of phenotype in SkgxTgLYPW mice is that after the threshold of signaling inhibition necessary to trigger thymic signaling anomalies has been trespassed, quantitative reductions in signaling are required in order to see further decreases of selection and an increase in severity of arthritis. Since no studies to date have uncovered profound effects of LYP-W620 on thymic selection, an alternative explanation is that TCR signaling in thymocytes might be controlled by multiple redundant phosphatases. LYP-dependent effects might not be detectable in the presence of a dominant regulator such as CD45, which plays a major role in both positive and negative regulation of TCR signaling in double positive and single positive thymocytes. Throughout its Albaspidin-AA protracted course, alternating deficits of axonal 20S-Notoginsenoside-R2 functions associated with demyelination deteriorates into conduction failure and progressive axonal degeneration, culminating in partial or complete sensory and motor incapacitation. Functional and developmental studies have indicated essential roles for myelin in the rapid conduction of action potentials along thick myelinated axons. Enveloping neurites in a highly compartmented manner, myelin provides an effective shield essential for saltatory propagation of action potentials. There is considerable but conflicting evidence suggesting a stabilizing influence of voltage-activated KV1 currents on the excitability and conductivity of central and peripheral axons. Mediated through channels produced by tetramerization of KV1.1 with 1.2 a subunits, and normally concentrated at the juxta-paranodes, KV1 channels spread to internodes and nodal segments upon demyelination, causing impedance mismatch and disruption of action potential conduction. Accordingly, indiscriminate pharmacological inhibition of K + currents has been shown to restore the electrogenic functions of demyelinated axons, a mechanism that is implicated in some of the ameliorative influence of 4-aminopyridine and its analogues in MS patients. However, emerging evidence from animal studies suggests that the beneficial effects of therapeuticallyrelevant concentrations of 4-AP on axonal physiology are due to its action as a synaptic transmission enhancer. Indeed, low mM concentrations of 4-AP and 3,4-di-aminopyridine greatly facilitate neurotransmission at both excitatory and inhibitory synapses in the central and peripheral nervous systems. Of note, several studies also assigned therapeutic effects of 4-AP to its inhibition of immune cell proliferation. Inevitably, such broad-spectrum effects hampers the utilisation of 4-AP for discriminatory restoration of the functionality of demyelinated axons without off target effects. A prevalence of optic neuropathies with functional disruptions during early MS kindled our interest in analysing the importance of KV1 currents in regulating electrophysiological properties of the optic nerve in a cuprizone-induced model of demyelination. The pervasive correlation between inflammatory optic neuropathies and symptoms of clinical MS, manifested by disruptions of visual functions, renders the ON an attractive experimental model. Being an anatomical extension of the forebrain, ON share key features of central myelinated tracts under healthy and disease conditions. Thus, along with the demonstration of myelin loss and a decrease in the axon diameter, our data also provide important insights into demyelination-related changes in the molecular composition of KV1 channels in central axons, which could be of potential relevance to MS and other disease associated with the loss of myelin.