Myelin Gene Regulation
Novel pharmacological drugs for preventing demyelination are needed for treating clinical disorders involving the demyelinating diseases of peripheral nerve. Currently, there is no effective therapy available for hereditary motor and sensory demyelinating neuropathies (e.g., HMSN Type I) and no effective treatment for Guillain-Barre syndrome. Most cells respond to stimuli via a cyclic nucleotide-dependent mechanism, which is regulated by the synthesizing enzymes, adenylyl cyclase and guanylyl cyclase (AC/GC), as well as a large family of phosphodiesterase (PDE) isotypes, which are responsible for opening up the ring structure and inactivating these cyclic nucleotides. Both the rise and fall of cyclic nucleotides are necessary for signaling. It is now apparent that the activation of PDEs is often the primary event that mediates the action of some hormones and external stimuli and, hence, provides the means of integration between the cyclic nucleotide and other signal transduction pathways.
Our data demonstrates that cyclic nucleotides are required for the maintenance of the myelin sheath rather than being involved in the induction of myelin gene expression in peripheral nerve. This is based on the observation that cAMP and cGMP decrease to 10% and 18%, respectively, of normal following both sciatic nerve crush or permanent transection injury and only begin to increase in the crushed nerve well after myelin gene induction. In addition, short or long term stimulation of cAMP in the transected nerve failed to induce myelin specific transcripts.
Recent data demonstrates that the decreased cyclic nucleotides after peripheral nerve injury are a consequence of inactivation of AC or GC and the activation of specific PDE isotypes. Based on these data, we hypothesize that specific PDE isotypes inactive peripheral nerve second messengers by stimuli that are dependent on the conversion of Schwann cells from a myelin-maintaining to a demyelinating phenotype. Inhibitors of these PDE isotypes are being used in conjunction with activators of AC or GC (forskolin and nitric oxide donors) to increase cyclic nucleotide levels in peripheral nerve to test whether the demyelination process can be inhibited by delaying or preventing the down-regulation of myelin specific transcripts and the induction of p75 NGF receptor - the characteristic response of Schwann cells to loss of axonal contact. By identifying PDE isozymes in peripheral nerve, determining their activity changes after injury, and using selective PDE isotype inhibitors and activators of AC/GC to modulate cyclic nucleotide levels, the role of cyclic nucleotides during the demyelination process will be determined. The pharmacological manipulation of this PDE switching off signal, therefore, may allow for novel therapeutic approaches for preventing demyelination in peripheral nerve.
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