The Effect of a Nerve Growth Factor Mimetic in Demyelination and Remyelination

[unreadable] DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic, unpredictable neurological disease of the central nervous system (CNS) and may be caused by more than one factor, such as genetic predisposition, gender, environmental factors, and exposure to seemingly innocuous viruses. Pharmacologic therapies targeting CNS demyelinating diseases such as MS have been sparse and mostly act by broad-spectrum immune suppression of which the mechanisms of actions are not completely understood. Recent studies have brought small molecule mimetics (SMMs) that emulate functional protein ligand-receptor interactions to the fore in potential therapeutic development. Our laboratory will use an SMM of nerve growth factor (NGF), namely C31 or LM11A-31, as a therapeutic agent to alter CNS demyelination and/or remyelination. NGF is well known for its trophic role in neuronal and glial cell survival and differentiation in the CNS via tyrosine receptor kinase A (TrkA). However, NGF, unlike other neurotrophins, also has the ability to induce apoptosis in its precursor form, proNGF, through the p75 neurotrophin receptor (p75NTR). C31, which is comprised of residues of the 2-loop 1 domain of NGF, interacts with p75NTR. Previous studies show NGF Loop 1 mimetics provide in vitro protection against neuronal cell death via p75NTR-dependent signaling and also afforded protection of mature oligodendrocytes (OLs) from cell death in the presence of proNGF, presumably by initiating pro-survival signaling. To further study the effect of C31 in vivo, our laboratory will use the cuprizone intoxication model in which changes in cellular populations and myelination are both reproducible and predictable in the corpus callosum of a C57BL/6 mouse. Although p75NTR is mainly expressed during early neuronal development, we have preliminary data that re-expression of p75NTR can be detected by immunohistochemistry in the demyelinating corpus callosum. Using our cuprizone intoxication model of demyelination and remyelination, we hypothesize that C31 protects OLs in vivo. We predict this may prevent or delay demyelination or increase the rate of remyelination. The specific aims of this proposal are designed to demonstrate the effects of C31 on the cellular, molecular, and morphologic profiles during demyelination/remyelination, and to eventually link the expression profile of p75NTR to the mechanism of C31 action. If administration of C31 hinders disease progression, then this may provide insights to feasibility and mechanism of SMM with potential therapeutic ramifications for demyelinating diseases. This proposal explores the feasibility of a potential novel therapeutic compound, C31 that mimics a fragment of nerve growth factor, to ameliorate central nervous system demyelination. C31 has been shown to protect oligodendrocytes in vitro and examination of its function in vivo is warranted. If this proposal provides evidence that C31 ameliorates CNS pathology, then there is a potential to move C31 towards clinical considerations for the eventual application to human diseases such as multiple sclerosis. [unreadable] [unreadable] [unreadable]