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 [3]. 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 [3]. 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.

Public Health Relevance

These studies are designed to evaluate the role small molecules such as mGluR agonists play in demyelinating models of disease, such as MS, and the possibility that these agonists may prevent degenerative changes and/or enhance repair. An understanding of such interactions will provide insights to optimize maintenance and repair of OLGs that deteriorate in MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rbhs-Robert Wood Johnson Medical School
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Yu, Qili; Hui, Ryan; Park, Jiyoung et al. (2017) Strain differences in cuprizone induced demyelination. Cell Biosci 7:59
Huang, Yangyang; Dreyfus, Cheryl F (2016) The role of growth factors as a therapeutic approach to demyelinating disease. Exp Neurol 283:531-40
Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa et al. (2015) Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination. ASN Neuro 7:
Liu, Junli; Tian, Daishi; Murugan, Madhuvika et al. (2015) Microglial Hv1 proton channel promotes cuprizone-induced demyelination through oxidative damage. J Neurochem 135:347-56
Fulmer, Clifton G; VonDran, Melissa W; Stillman, Althea A et al. (2014) Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci 34:8186-96
Fulmer, Clifton G; Dreyfus, Cheryl F (2013) Culturing oligodendrocyte lineage cells from neonatal rats. Methods Mol Biol 1018:81-91
VonDran, Melissa W; Singh, Harmandeep; Honeywell, Jean Z et al. (2011) Levels of BDNF impact oligodendrocyte lineage cells following a cuprizone lesion. J Neurosci 31:14182-90
Vondran, Melissa W; Clinton-Luke, Patricia; Honeywell, Jean Z et al. (2010) BDNF+/- mice exhibit deficits in oligodendrocyte lineage cells of the basal forebrain. Glia 58:848-56
Van't Veer, Ashlee; Du, Yangzhou; Fischer, Tanya Z et al. (2009) Brain-derived neurotrophic factor effects on oligodendrocyte progenitors of the basal forebrain are mediated through trkB and the MAP kinase pathway. J Neurosci Res 87:69-78
Dai, Xudong; Lercher, Lauren D; Clinton, Patricia M et al. (2003) The trophic role of oligodendrocytes in the basal forebrain. J Neurosci 23:5846-53