Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia.
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.
Li
Yonggang
Y
Department of Anatomy and Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Xu
Zhenfeng
Z
Ford
Gregory D
GD
Croslan
Dajoie R
DR
Cairobe
Tariq
T
Li
Zhenzhong
Z
Ford
Byron D
BD
D000818:Animals; D020520:Brain Infarction / Q000209:etiology* / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia; D008297:Male; D020890:Neuregulin-1 / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts
D020890:Neuregulin-1; D018696:Neuroprotective Agents; D013778:Tetrazolium Salts; D016291:Dizocilpine Maleate; C009591:triphenyltetrazolium; D005947:Glucose