The effects of the metabotropic glutamate receptor, CHPG, in mouse models of demyelination
Creators: name: Planas Fontánez, Talia Marel
Publisher: name: No Publisher Supplied
Year: 2022

description: A central question in the development of treatments for demyelinating diseases is how to reverse the decreases in myelin to enhance remyelination. Over the past years, the Dreyfus laboratory has investigated novel therapeutic agents that can enhance endogenous brain derived neurotrophic factor (BDNF) expression and signaling to promote repair in demyelinating lesions. Previous studies, using the cuprizone model, have demonstrated that Group I metabotropic glutamate receptor (mGluR) agonist 1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) and the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) elevate synthesis and release of BDNF from astrocytes and increase myelin protein levels in the lesion site. These effects are blocked after deletion of astrocyte-derived BDNF, deletion of the mGluR5 from astrocytes or deletion of the tropomyosin receptor kinase B from oligodendrocyte cells, the BDNF receptor. More interesting, the data showed that CHPG impacts myelination and enhances motor function in cuprizone-lesioned mice. These observations support my hypothesis that CHPG stimulates mGluR5 to enhance BDNF signaling in activated astrocytes leading to a reversal in myelin protein deficits and enhancement of behavioral functions in mouse models of demyelination. To determine whether the mGluR5 agonist CHPG imparts a protective role in an inflammatory based demyelination model, I used the experimental autoimmune encephalomyelitis (EAE) mouse model. A significant decrease in EAE progression is found with treatment of CHPG (20 mg/kg, i.p., every other day). The reduction in clinical scores is accompanied by an increase in BDNF and myelin proteins in the lumbar spinal cord. An upregulation in the expression of mGluR5 on astrocytes is identified in the lesion site. Effects of CHPG on clinical scores, as well as on BDNF and myelin protein levels are blocked when mGluR5 is deleted from astrocytes. These results indicate that CHPG stimulates mGluR5 on astrocytes to reverse clinical signs in the EAE mouse model. To further investigate the effects of CHPG in another model of demyelinating injury, I used the triple transgenic Alzheimer’s Disease (3xTg-AD) model. Initial examination of the basal forebrain (BF) from 12-month-old 3xTg-AD mice demonstrate a significant decrease in BDNF and myelin proteins compared to age-matched controls. Peripheral injections of CHPG (40 mg/kg, 3x, 1week) to 12-month-old 3xTg-AD male mice results in an increase of BDNF and myelin protein expression in the BF and hippocampus. However, no effects on BDNF or myelin proteins are found when female 12-month-old 3xTg-AD mice are treated. Furthermore, memory and learning deficits are detected in 6-month-old 3xTg-AD mice. These deficits are reversed by CHPG and are accompanied by BDNF, and myelin protein increases in the BF. The studies suggest that CHPG may have a protective effect on demyelination in multiple models of neurodegeneration. In conclusion, these studies fill gaps in the fields of glial cells and demyelinating diseases of the central nervous system and advance our understanding of the use of metabotropic agonists as a potential therapeutic approach to reverse demyelinating events.