中国神经再生研究(英文版) ›› 2017, Vol. 12 ›› Issue (11): 1791-1794.doi: 10.4103/1673-5374.219033

• 综述:神经损伤修复保护与再生 • 上一篇    下一篇

ΔN-Bcl-xL,神经保护的治疗靶标

  

  • 收稿日期:2017-11-04 出版日期:2017-11-15 发布日期:2017-11-15

ΔN-Bcl-xL, a therapeutic target for neuroprotection

Han-A Park1, 2, Elizabeth A. Jonas2   

  1. 1 Department of Human Nutrition and Hospitality Management, College of Human Environmental Science, The University of Alabama,Tuscaloosa, AL, USA
    2 Department of Internal Medicine, Section of Endocrinology, Yale University, New Haven, CT, USA
  • Received:2017-11-04 Online:2017-11-15 Published:2017-11-15
  • Contact: Han-A Park,hpark36@ches.ua.edu.

Abstract:

 

The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-BclxL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-xL by glutamate, overexpression of ΔN-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-xL is a central target for interventions.

Key words: B-cell lymphoma-extra large, ΔN-Bcl-xL, mitochondria, ABT-737