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Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke
Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke
- Source :
- Neurochemistry international. 127
- Publication Year :
- 2018
-
Abstract
- Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. BET proteins (BRD2, BRD3, BRD4, and BRDT) have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. BRD2/4 are of particularly interest to stroke-induced neuroinflammation that contributes to delayed cell death as they are required for NF-κB-dependent gene transcription. We hypothesized that targeting BET proteins for degradation with dBET1, a proteolysis targeting chimera (PROTAC) that combines the highly selective BET inhibitor JQ1 and a ligand for cereblon E3 ubiquitin ligase, will reduce brain injury in ischemic stroke. Male aged mice (18–20 months old) were subjected to permanent occlusion of the middle cerebral artery and received either vehicle or dBET1 (10 mg/kg; i.p.) at various times after stroke. Neurobehavioral tests were performed before (baseline) and at 24 and 48 h after stroke induction. Infarct volume was quantified at 48 h. Data showed that BET degradation significantly reduced infarct volume in permanent focal cerebral ischemia in aged mice, and this was associated with reduced brain levels of pro-inflammatory mediators including TNF-α, CXCL1, CXCL10, CCL2, and matrix metalloproteinase-9. Treatment with dBET1 significantly reduced blood-brain barrier damage and infiltration of neutrophils into the ischemic brain. Importantly, treatment with the BET degrader dBET1 resulted in a significant improvement in stroke-induced neurological deficits. Collectively, these data indicate that BET proteins are a novel target for neuroprotection in ischemic stroke.
- Subjects :
- 0301 basic medicine
Male
BRD4
Aging
Ischemia
Nerve Tissue Proteins
Receptors, Cell Surface
Pharmacology
Neuroprotection
Chromatin remodeling
Brain Ischemia
BET inhibitor
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
medicine
Histone acetyltransferase activity
Animals
Transcription factor
Neuroinflammation
business.industry
Cell Biology
medicine.disease
Mice, Inbred C57BL
Stroke
Disease Models, Animal
Protein Transport
030104 developmental biology
Neuroprotective Agents
Brain Injuries
business
030217 neurology & neurosurgery
Transcription Factors
Subjects
Details
- ISSN :
- 18729754
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Neurochemistry international
- Accession number :
- edsair.doi.dedup.....9ddecf265677495777bf9edc5f82a964