Synaptic Mitochondria Sustain More Damage than Non-Synaptic Mitochondria after Traumatic Brain Injury and Are Protected by Cyclosporine A
Synaptic Mitochondria Sustain More Damage than Non-Synaptic Mitochondria after Traumatic Brain Injury and Are Protected by Cyclosporine A
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DOI：
10.1089/neu.2016.4628
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发表时间：
2017-04-01
影响因子：
4.2
通讯作者：
Hall, Edward D.
中科院分区：
文献类型：
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作者：
Kulbe, Jacqueline R.;Hill, Rachel L.;Hall, Edward D.
目前，尚无美国食品药品监督管理局 (FDA) 批准的药物疗法用于治疗创伤性脑损伤 (TBI) 患者。作为继发性损伤级联的中心介质，线粒体是预防 TBI 后细胞死亡和功能障碍的有希望的治疗靶点。最有前途和广泛研究的线粒体靶向 TBI 疗法之一是通过 FDA 批准的药物环孢菌素 A (CsA) 抑制线粒体通透性转换孔 (mPTP)。许多研究评估了 CsA 对 TBI 后脑线粒体总量的影响；然而，尚无研究调查 CsA 对分离的突触和非突触线粒体的影响。突触线粒体被认为对于正常的神经传递和突触可塑性至关重要，其功能障碍与神经变性有关。突触和非突触线粒体具有异质性特征，但它们的异质性可以在总线粒体（突触和非突触）制剂中被掩盖。因此，有必要在两个人群中评估线粒体靶向药物疗法（例如 CsA）。这是第一项研究 CsA 对实验性 TBI 后分离的突触和非突触线粒体的影响的研究。我们得出的结论是，严重控制性皮质冲击损伤（CCI）后 24 小时，突触线粒体比非突触线粒体遭受更多损伤，损伤后 15 分钟腹腔内给予 CsA（20 mg/kg）可改善突触和非突触呼吸，在受损更严重的突触群体中观察到显着改善。因此，CsA 仍然是治疗 TBI 患者的有前途的神经保护候选药物。
Currently, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of those with traumatic brain injury (TBI). As central mediators of the secondary injury cascade, mitochondria are promising therapeutic targets for prevention of cellular death and dysfunction after TBI. One of the most promising and extensively studied mitochondrial targeted TBI therapies is inhibition of the mitochondrial permeability transition pore (mPTP) by the FDA-approved drug, cyclosporine A (CsA). A number of studies have evaluated the effects of CsA on total brain mitochondria after TBI; however, no study has investigated the effects of CsA on isolated synaptic and non-synaptic mitochondria. Synaptic mitochondria are considered essential for proper neurotransmission and synaptic plasticity, and their dysfunction has been implicated in neurodegeneration. Synaptic and non-synaptic mitochondria have heterogeneous characteristics, but their heterogeneity can be masked in total mitochondrial (synaptic and non-synaptic) preparations. Therefore, it is essential that mitochondria targeted pharmacotherapies, such as CsA, be evaluated in both populations. This is the first study to examine the effects of CsA on isolated synaptic and non-synaptic mitochondria after experimental TBI. We conclude that synaptic mitochondria sustain more damage than non-synaptic mitochondria 24 h after severe controlled cortical impact injury (CCI), and that intraperitoneal administration of CsA (20 mg/kg) 15 min after injury improves synaptic and non-synaptic respiration, with a significant improvement being seen in the more severely impaired synaptic population. As such, CsA remains a promising neuroprotective candidate for the treatment of those with TBI.