Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic-ischemic encephalopathy.
Targeting the mitochondrial permeability transition pore for neuroprotection in a piglet model of neonatal hypoxic-ischemic encephalopathy.
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靶向线粒体通透性转换孔对新生儿缺氧缺血性脑病仔猪模型的神经保护作用。
DOI：
10.1002/jnr.24821
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发表时间：
2021-06
影响因子：
4.2
通讯作者：
Martin LJ
中科院分区：
文献类型：
--
作者：
Chen MW;Santos P;Kulikowicz E;Koehler RC;Lee JK;Martin LJ
新生儿缺氧缺血性脑病（HIE）导致显着的发病率，尽管治疗低温。线粒体功能障碍可能驱动神经元细胞死亡的机制，从而使线粒体成为神经保护的主要靶点。线粒体通透性转换孔（mPTP）是线粒体内的一个这样的靶标。在成年动物模型中，mPTP抑制具有神经保护作用。然而，在新生儿神经系统疾病模型中mPTP抑制的证据不太确定。我们测试了mPTP小分子抑制剂GNX-4728的治疗效果，并在新生仔猪缺氧缺血性脑损伤模型中检查了用于药物靶向的脑mPTP蛋白的发育存在。将雄性新生仔猪随机分配至缺氧-缺血（HI）或用GNX-4728（15 mg/kg，IV）或媒介物（盐水/环糊精/DMSO，IV）的假手术。在心动过缓停搏复苏后5分钟内给予GNX-4728单次给药。使用苏木精和伊红染色对壳核和躯体感觉皮层中的正常、缺血和损伤的神经元进行计数。在单独的新生和幼年猪，蛋白质印迹法的壳核蛋白质富集馏分用于评估线粒体的完整性和mPTP蛋白的存在。我们发现，单剂量的GNX-4728不能保护壳核和皮质神经元在HI后免于细胞死亡。然而，线粒体基质完整性的损失发生在HI后6小时内，虽然mPTP成分存在于新生儿脑中，但其水平与成熟的青少年脑相比显着不同。因此，新生儿脑mPTP可能不是基于成人线粒体开发的当前神经治疗药物的良好靶点。
Neonatal hypoxic-ischemic encephalopathy (HIE) causes significant morbidity despite treatment with therapeutic hypothermia. Mitochondrial dysfunction may drive the mechanisms underlying neuronal cell death, thereby making mitochondria prime targets for neuroprotection. The mitochondrial permeability transition pore (mPTP) is one such target within mitochondria. In adult animal models, mPTP inhibition is neuroprotective. However, evidence for mPTP inhibition in neonatal models of neurologic disease is less certain. We tested the therapeutic efficacy of the mPTP small molecule inhibitor GNX-4728 and examined the developmental presence of brain mPTP proteins for drug targeting in a neonatal piglet model of hypoxic-ischemic brain injury. Male neonatal piglets were randomized to hypoxia-ischemia (HI) or sham procedure with GNX-4728 (15 mg/kg, IV) or vehicle (saline/cyclodextrin/DMSO, IV). GNX-4728 was administered as a single dose within 5 min after resuscitation from bradycardic arrest. Normal, ischemic, and injured neurons were counted in putamen and somatosensory cortex using hematoxylin and eosin staining. In separate neonatal and juvenile pigs, western blots of putamen mitochondrial-enriched fractions were used to evaluate mitochondrial integrity and the presence of mPTP proteins. We found that a single dose of GNX-4728 did not protect putamen and cortical neurons from cell death after HI. However, loss of mitochondrial matrix integrity occurred within 6h after HI, and while mPTP components are present in the neonatal brain their levels were significantly different compared to that of a mature juvenile brain. Thus, the neonatal brain mPTP may not be a good target for current neurotherapeutic drugs that are developed based on adult mitochondria.
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影响因子：
5.7
作者：
Lee JK;Yang ZJ;Wang B;Larson AC;Jamrogowicz JL;Kulikowicz E;Kibler KK;Mytar JO;Carter EL;Burman HT;Brady KM;Smielewski P;Czosnyka M;Koehler RC;Shaffner DH
通讯作者：
Shaffner DH
影响因子：
2.1
作者：
Fatemi A;Wilson MA;Johnston MV
通讯作者：
Johnston MV
影响因子：
1.5
作者：
Martin LJ
通讯作者：
Martin LJ
DOI：
10.3390/ph3040839
发表时间：
2010
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Martin LJ
通讯作者：
Martin LJ
影响因子：
7.3
作者：
Fancelli, Daniele;Abate, Agnese;Plyte, Simon
通讯作者：
Plyte, Simon