△N-Bcl-xL, a therapeutic target for neuroprotection

Han-A Park; Elizabeth A.Jonas

doi:10.4103/1673-5374.219033

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 mitochondrial 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 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 △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.