4.6 Article

CHPG enhances BDNF and myelination in cuprizone-treated mice through astrocytic metabotropic glutamate receptor 5

Journal

GLIA
Volume 69, Issue 8, Pages 1950-1965

Publisher

WILEY
DOI: 10.1002/glia.24003

Keywords

astrocytes; BDNF; CHPG; cuprizone; metabotropic glutamate receptors; myelin; oligodendrocytes

Categories

Funding

  1. National Institute of Environmental Health Sciences [NIH T32 ES007148]
  2. National Institute of Neurological Disorders and Stroke [NIH F31 NS098642, RO1 NS036647]
  3. National Multiple Sclerosis Society [RG 4257B4/]
  4. Rutgers School of Graduate Studies Acceleration and Completion Fellowship

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The study suggests that the mGluR agonist CHPG may be a potential therapeutic strategy for demyelinating diseases by enhancing the release of BDNF from astrocytes.
It is well recognized that astrocytes can produce factors known to affect the myelination process. One such factor, brain-derived neurotrophic factor (BDNF), can enhance the differentiation of oligodendrocyte lineage cells following a demyelinating lesion. Our previous work indicated that enhancing astrocyte-derived BDNF via injection of a general agonist of Group I/II metabotropic glutamate receptors (mGluRs) into the lesion increased myelin proteins in the cuprizone model of demyelination after 4 hr. To determine if this observation has potential therapeutic significance, we now use a more specific mGluR agonist, 2-chloro-5-hydroxyphenylglycine (CHPG), which binds to mGluR5, to examine effects on myelination through the clinically relevant approach of a peripheral injection. In initial studies, intraperitoneal injection of CHPG resulted in an increase in myelin proteins within the lesioned corpus callosum. These effects were blocked when either BDNF or the CHPG receptor, mGluR5, was deleted from glial fibrillary acidic protein (GFAP)+ astrocytes or when the BDNF receptor, tropomyosin receptor kinase B (TrkB), was deleted from proteolipid protein (PLP)+ oligodendrocytes. Moreover, injection of CHPG over 2 weeks not only elevated BDNF and myelin proteins, but also enhanced myelination and reversed behavioral deficits. Interestingly, effects on myelin and myelin proteins were not seen in the control animals, indicating that a lesion is critical in eliciting effects. Taken together, the data suggest that the mGluR agonist CHPG may be a potential therapeutic strategy for treating demyelinating diseases and that it works by enhancing the release of BDNF from astrocytes.

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