摘要
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, △N-Bcl-xL. Accumulation of △N-Bcl-xL is associated with mitochon- drial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of △N-Bcl- xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor △BT- 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 △BT-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 △N-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of △N-Bcl-xL by glutamate, overexpression of △N-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for △N-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 △N-Bcl-xL is a central target for interventions.
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, △N-Bcl-xL. Accumulation of △N-Bcl-xL is associated with mitochon- drial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of △N-Bcl- xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor △BT- 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 △BT-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 △N-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of △N-Bcl-xL by glutamate, overexpression of △N-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for △N-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 △N-Bcl-xL is a central target for interventions.
