Journal
BRAIN RESEARCH
Volume 1184, Issue -, Pages 277-283Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2007.09.037
Keywords
apoptosis; acetylcholine receptor; inducing activity (ARIA); ErbB, excitotoxicity; glial growth factor (GGF); heregulin; inflammation; ischemia; Neu differentiation factor (NDF); stroke
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Funding
- NCRR NIH HHS [C06 RR07571] Funding Source: Medline
- NINDS NIH HHS [R01 NS056446, R01 NS056446-01S1, R01 NS056446-01, U54 NS034194, NS056446, R01 NS056446-02, R01 NS056446-02S1, NS34194, U54 NS034194-090010] Funding Source: Medline
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Neuregulin-1 (NRG-1) is a growth factor with potent neuroprotective capacity in ischemic stroke. We recently showed that NRG-1 reduced neuronal death following transient middle cerebral artery occlusion (tMCAO) by up to 90% with an extended therapeutic window. Here, we examined the neuroprotective potential of NRG-1 using a permanent MCAO ischemia (pMCAO) rat model. NRG-1 reduced infarction in pMCAO by 50% when administered prior to ischemia. We previously demonstrated using gene expression profiling that pMCAO was associated with an exaggerated excitotoxicity response compared to tMCAO. Therefore, we examined whether co-treatment with an inhibitor of excitotoxicity would augment the effect of NRG-1 following pMCAO. Both NRG-1 and the N-methyl-D-aspartate (NMDA) antagonist MK-801 similarly reduced infarct size following pMCAO. However, combination treatment with both NRG-1 and MK-801 resulted in greater neuroprotection than either compound alone, including a 75% reduction in cortical infarction compared to control. Consistent with these findings, NRG-1 reduced neuronal death using an in vitro ischemia model and this effect was augmented by MK-801. These results demonstrate the efficacy of NRG-1 in pMCAO rat focal ischemia model. Our findings further indicate the potential clinically relevance of NRG-1 alone or as a combination strategy for treating ischemic stroke. (c) 2007 Elsevier B.V. All rights reserved.
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