Functional Restoration following Global Cerebral Ischemia in Juvenile Mice following Inhibition of Transient Receptor Potential M2 (TRPM2) Ion Channels.
Functional Restoration following Global Cerebral Ischemia in Juvenile Mice following Inhibition of Transient Receptor Potential M2 (TRPM2) Ion Channels.
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DOI：
10.1155/2021/8774663
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发表时间：
2021
影响因子：
3.1
通讯作者：
Herson PS
中科院分区：
文献类型：
--
作者：
Dietz RM;Orfila JE;Chalmers N;Minjarez C;Vigil J;Deng G;Quillinan N;Herson PS
全脑缺血后海马细胞死亡和认知功能障碍在包括儿童在内的所有年龄段都很常见。大多数研究都集中在预防神经元死亡。细胞死亡后神经元功能的恢复是另一种方法（神经恢复）。我们以前确定瞬时受体电位M2（TRPM 2）离子通道作为一个潜在的目标，急性神经保护和延迟神经恢复在成年CA/CPR小鼠模型。在幼年（p20-25）小鼠中使用心脏骤停/心肺复苏（CA/CPR）来研究离子TRPM 2通道在发育中的脑中的神经保护和缺血诱导的突触功能障碍中的作用。我们的新TRPM 2抑制剂，tatM 2NX，并没有赋予对CA 1锥体细胞死亡的保护，但衰减突触可塑性（长期可塑性（LTP））在两种性别的缺陷。此外，在CA/CPR后两周体内施用tatM 2NX减少了LTP损伤并恢复了记忆功能。这些数据提供的证据表明，通过抑制TRPM 2通道，存活海马网络的药理学突触恢复可以独立于神经保护作用而发生，为改善脑缺血后儿童的认知恢复提供了一种新的策略。重要的是，这些数据强调了年龄合适的模型在疾病研究中的重要性。
Hippocampal cell death and cognitive dysfunction are common following global cerebral ischemia across all ages, including children. Most research has focused on preventing neuronal death. Restoration of neuronal function after cell death is an alternative approach (neurorestoration). We previously identified transient receptor potential M2 (TRPM2) ion channels as a potential target for acute neuroprotection and delayed neurorestoration in an adult CA/CPR mouse model. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in juvenile (p20-25) mice was used to investigate the role of ion TRPM2 channels in neuroprotection and ischemia-induced synaptic dysfunction in the developing brain. Our novel TRPM2 inhibitor, tatM2NX, did not confer protection against CA1 pyramidal cell death but attenuated synaptic plasticity (long-term plasticity (LTP)) deficits in both sexes. Further, in vivo administration of tatM2NX two weeks after CA/CPR reduced LTP impairments and restored memory function. These data provide evidence that pharmacological synaptic restoration of the surviving hippocampal network can occur independent of neuroprotection via inhibition of TRPM2 channels, providing a novel strategy to improve cognitive recovery in children following cerebral ischemia. Importantly, these data underscore the importance of age-appropriate models in disease research.