PGJ(2) provides prolonged CNS stroke protection by reducing white matter edema.

Abstract

Few clinically effective approaches reduce CNS-white matter injury. After early in-vivo white matter infarct, NFκB-driven pro-inflammatory signals can amplify a relatively small amount of vascular damage, resulting in progressive endothelial dysfunction to create a severe ischemic lesion. This process can be minimized by 15-deoxy-Δ(12,14)-prostaglandin J2 (PGJ(2)), an analog of the metabolically active PGD(2) metabolite. We evaluated PGJ(2)'s effects and mechanisms using rodent anterior ischemic optic neuropathy (rAION); an in vivo white matter ischemia model. PGJ(2) administration systemically administered either acutely or 5 hours post-insult results in significant neuroprotection, with stereologic evaluation showing improved neuronal survival 30 days post-infarct. Quantitative capillary vascular analysis reveals that PGJ(2) improves perfusion at 1 day post-infarct by reducing tissue edema. Our results suggest that PGJ(2) acts by reducing NFκB signaling through preventing p65 nuclear localization and inhibiting inflammatory gene expression. Importantly, PGJ(2) showed no in vivo toxicity structurally as measured by optic nerve (ON) myelin thickness, functionally by ON-compound action potentials, on a cellular basis by oligodendrocyte precursor survival or changes in ON-myelin gene expression. PGJ(2) may be a clinically useful neuroprotective agent for ON and other CNS infarcts involving white matter, with mechanisms of action enabling effective treatment beyond the currently considered maximal time for intervention.

• Authors: James D Nicholson, Adam C Puche, Yan Guo, Daniel Weinreich, Bernard J Slater, Steven L Bernstein
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e50021 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23284631 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Neuroprotective Agents
• 9-deoxy-delta-9-prostaglandin D2
• Prostaglandin D2

Topics

• Animals
• Brain (drug effects, pathology, physiopathology)
• Capillaries (drug effects, physiopathology)
• Cerebral Infarction (complications)
• Edema (complications, drug therapy)
• Male
• NF-kappa B (metabolism)
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Optic Nerve (drug effects, pathology, physiopathology)
• Optic Neuropathy, Ischemic (complications, drug therapy)
• Prostaglandin D2 (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Stroke (complications, drug therapy, pathology, physiopathology)
• Time Factors