In Multiple Sclerosis (MS) the oligodendrocyte (a cell that produces an insulating myelin sheath around axons) becomes dysfunctional and dies, resulting in demyelination. Many groups are searching for molecules that can reverse this destruction. Studies completed during the tenure of our previous grant revealed that BDNF is one molecule that enhanced recovery from one type of demyelination that is elicited by the agent, cuprizone [1, 2]. Moreover, BDNF was found localized to cells in the lesion site. To examine how we might enhance BDNF synthesis and release from these cellular sources and potentially enhance recovery from a lesion, in our recent studies we examined effects of a number of transmitter systems affiliated with the lesion site. In particular, our experiments revealed that metabotropic glutamate receptors (mGluRs) play protective roles under demyelination conditions . This observation is consistent with those of others looking at other degenerative conditions [4,5]. Moreover, these mGluRs are upregulated in a number of brain diseases, including MS, suggesting that their importance may be accentuated under conditions of injury [6-9]. In our studies we report that BDNF is released after treatment with a metabotropic agonist, ACPD, and elicits increases in myelin proteins. ACPD does so by interacting with mGluRs on astrocytes (ASTs) in the lesion site . New results suggest further that BDNF and MBP elevations result from peripheral, as well as brain injections of the Group I mGluR agonist relative of ACPD, CHPG. In addition, recent data suggest that peripheral injections of CHPG ameliorate clinical signs of EAE, a second demyelinating model of MS. These new data raise the exciting possibility that mGluR agonists can reverse demyelinating deficits through the mediation of AST-derived BDNF. The agonists can be applied peripherally to elicit this reversal. Our proposed work is designed to test this possibility. First, since ACPD can be relatively general in its actions, we will continue to identify the specific receptors that best elicit increases in BDNF and myelin traits upon injection. Second, we will identify the cellular roles of CHPG in the demyelination lesion site that promote oligodendrocyte maturation. Third we will identify roles of CHPG that prevent progression of the EAE model that is affiliated with an immune response as well as a demyelinating phenotype.
|Effective start/end date||6/1/98 → 8/31/20|
- National Institutes of Health (NIH)