UNLOCKING BRAIN HEALING: HOW NR4A2 CALMS INFLAMMATION AFTER HEMORRHAGIC STROKE

• Dr. Sergio Moreno

  Division of Neurology, University of Toronto, Canada

  Author

• Dr. Ibrahim K. Idris

  Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

  Author

Intracerebral hemorrhage (ICH) is a severe type of stroke that often leaves patients with significant neurological challenges and cognitive difficulties. This damage largely stems from a destructive wave of inflammation that sweeps through the brain after the initial bleeding. At the heart of this inflammation are microglia, the brain's immune cells, which can either worsen the damage (M1 type) or help with healing (M2 type). Our study explores how a protein called NR4A2 might help reduce early brain injury after ICH. We hypothesized that NR4A2 could protect the brain by encouraging microglia to switch to their healing M2 form, specifically by calming down a major inflammatory pathway known as TLR4/TRAF6/NF-κB. Our findings, based on a simulated ICH in rats, suggest that boosting NR4A2 levels significantly shrinks the area of bleeding, reduces harm to brain cells, and improves overall neurological function. We found that NR4A2 indeed shifted microglia towards the M2 phenotype and put a brake on the TLR4, TRAF6, and NF-κB p65 activation. When we introduced a substance that activates TLR4, NR4A2's protective effects were diminished, confirming that this pathway is crucial. NR4A2 also helped to seal up the "blood-brain barrier," which protects the brain. These results point to NR4A2 as a vital protective factor in ICH, capable of reducing secondary brain injury by guiding microglial responses and shutting down key inflammatory signals. This makes NR4A2 a promising new target for treatment.

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