Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression.
Neuregulins are a family of growth factors with potent neuroprotective properties. We recently demonstrated that neuregulin-1 blocked delayed neuronal death following focal ischemic stroke in the rat. Focal ischemia results in the release of pro-inflammatory cytokines that produce profound changes in gene expression and contribute to cell death associated with stroke. Inflammatory and stress mediators are involved in the pathogenesis of focal ischemic brain damage. We examined whether neuregulin-1 can influence inflammatory and stress gene expression in the rat brain following transient middle cerebral artery occlusion (MCAO). In this study, we compared gene expression profiles in animals treated with neuregulin-1beta (NRG-1) or vehicle followed by MCAO. We used the Affymetrix GeneChip system to analyze gene expression in focal ischemia of the rat brain. Several inflammatory and stress genes were significantly induced following MCAO compared to sham controls including heat shock protein-70 (HSP70), interleukin-1beta, and macrophage chemotattractant protein-1 (JE/MCP-1). Treatment with NRG-1 attenuated the expression of many of these genes by 50% or more. In vitro studies demonstrated that NRG-1 suppressed inflammatory gene expression in activated macrophages. NRG-1 also prevented neuronal death induced by oxygen-glucose deprivation in a rat neuroblastoma cell line, suggesting that NRG-1 may have both direct and indirect neuroprotective capacity. These results demonstrate that NRG-1 can regulate inflammatory and stress gene expression and may give new insight to the molecular mechanisms involved in the neuroprotective role of neuregulins in stroke.
Xu
Zhenfeng
Z
Department of Anatomy and Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, SW; MRC 222, Atlanta, GA 30310, USA.
Ford
Gregory D
GD
Croslan
DaJoie R
DR
Jiang
Ju
J
Gates
Alicia
A
Allen
Robert
R
Ford
Byron D
BD
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D015870:Gene Expression; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D007249:Inflammation / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008959:Models, Neurological; D020890:Neuregulin-1 / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000235:genetics
D020890:Neuregulin-1; D018696:Neuroprotective Agents; D012333:RNA, Messenger