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.

中文翻译：

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抑制瞬时受体电位 M2 (TRPM2) 离子通道后幼年小鼠发生全脑缺血后的功能恢复

海马细胞死亡和认知功能障碍在所有年龄段（包括儿童）的全脑缺血后都很常见。大多数研究都集中在预防神经元死亡上。细胞死亡后神经元功能的恢复是一种替代方法（神经恢复）。我们之前将瞬时受体电位 M2 (TRPM2) 离子通道确定为成人 CA/CPR 小鼠模型中急性神经保护和延迟神经恢复的潜在靶标。幼年 (p20-25) 小鼠的心脏骤停/心肺复苏 (CA/CPR) 用于研究离子 TRPM2 通道在发育中的大脑中的神经保护和缺血诱导的突触功能障碍中的作用。我们的新型 TRPM2 抑制剂 tatM2NX，没有提供针对 CA1 锥体细胞死亡的保护，但减弱了两性的突触可塑性（长期可塑性（LTP））缺陷。进一步，CA/CPR 两周后体内给予 tatM2NX 可减少 LTP 损伤并恢复记忆功能。这些数据提供的证据表明，存活的海马网络的药理学突触恢复可以通过抑制 TRPM2 通道独立于神经保护发生，为改善脑缺血后儿童的认知恢复提供了一种新策略。重要的是，这些数据强调了适合年龄的模型在疾病研究中的重要性。