Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade. The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD+ and ATP, resulting in brain injury. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN), which is converted to NAD+ and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia. We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD+ and ATP levels in hippocampus were also measured. Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment. Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD+ and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD+. In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.

中文翻译：

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严重低血糖后给予烟酰胺单核苷酸可改善大鼠的神经元存活率和认知功能。

低血糖引起的脑损伤是糖尿病患者胰岛素治疗的潜在并发症。严重的低血糖会在易受伤害的神经元中引发一系列事件，即使在葡萄糖正常化后，这些事件也可能导致神经元死亡和认知障碍。氧化应激和聚（ADP-核糖）聚合酶-1 (PARP-1) 的激活是该级联反应中的关键事件。活性氧 (ROS) 的产生会诱导 DNA 损伤和随之而来的 PARP-1 激活，从而消耗 NAD+ 和 ATP，从而导致脑损伤。NAD+ 的关键前体之一是烟酰胺单核苷酸 (NMN)，它会转化为 NAD+ 并减少 ROS 的产生。在这里，我们研究了 NMN 是否可以减少严重低血糖后的脑损伤。我们使用胰岛素诱导的严重低血糖的大鼠模型并注射 NMN（500 mmg/kg，ip，1 周）严重低血糖 30 分钟后，在给予葡萄糖时。严重低血糖一周后，检查海马长时程增强 (LTP)，一种突触可塑性的电生理测定，并通过苏木精-伊红染色评估神经元损伤。还测量了海马中的 ROS 积累、PARP-1 激活、NAD+ 和 ATP 水平。在严重低血糖后 6 周使用 Morris 水迷宫评估认知功能。在严重低血糖后，添加 NMN 使神经元死亡减少了 83 ± 3% (P < 0.05)。海马 LTP 因严重低血糖而显着降低，但在 NMN 添加组中显示出恢复。NMN 治疗还减轻了严重低血糖引起的空间学习和记忆障碍。机械地，我们发现 NMN 给药减少了 ROS 积累，抑制了 PARP-1 激活，并恢复了海马中 NAD+ 和 ATP 的水平。所有这些保护作用都被 3-乙酰吡啶 (3-AP) 逆转，它会产生无活性的 NAD+。总之，严重低血糖后给予 NMN 可以改善严重低血糖引起的神经元损伤和认知障碍。这些结果表明，NMN 可能是预防低血糖引起的脑损伤的有前途的治疗药物。