Related Experiment Video
Updated: May 24, 2026
A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury
Kimberly R Byrnes1, David J Loane, Bogdan A Stoica
1Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
Background:
Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors in vitro, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.
Methods:
One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.
Results:
Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field ex vivo diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.
Conclusion:
Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.
Insights
Delayed treatment with CHPG significantly improved functional recovery and limited lesion progression after traumatic brain injury. This suggests CHPG may be a viable therapeutic for reducing chronic neuroinflammation and neurodegeneration post-TBI.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Traumatic brain injury (TBI) triggers biochemical cascades leading to secondary neurodegeneration.
- Chronic microglial activation and associated tissue loss can persist for years after TBI.
- Metabotropic glutamate receptor 5 (mGluR5) activation by CHPG reduces microglial activation and pro-inflammatory factors in vitro.
Purpose of the Study:
- To investigate if delayed CHPG administration can mitigate chronic neuroinflammation and neurodegeneration following experimental TBI in mice.
- To assess the therapeutic potential of targeting mGluR5 for TBI recovery.
Main Methods:
- Mice with TBI received a single intracerebroventricular dose of CHPG or vehicle one month post-injury.
- Treatment groups included CHPG alone and CHPG with an mGluR5 antagonist.
- Evaluated lesion volume, white matter integrity, and neurological recovery over three months.
Main Results:
- Delayed CHPG treatment reduced reactive microglia expressing NADPH oxidase.
- CHPG administration decreased hippocampal neuronal loss and limited lesion progression.
- Significant improvements in motor and cognitive recovery were observed in CHPG-treated mice.
Conclusions:
- A single, delayed dose of CHPG significantly enhances functional recovery after experimental TBI.
- CHPG treatment effectively limits lesion progression and associated neurodegeneration.
- The therapeutic effects are likely mediated by mGluR5 receptor modulation of neuroinflammation.
