Faculty of Health Sciences, Aomori University of Health and Welfare, Aomori, Japan.
Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.
Front Neural Circuits. 2023 Mar 22;17:1006424. doi: 10.3389/fncir.2023.1006424. eCollection 2023.
Severe hypoxia induces seizures, which reduces ventilation and worsens the ictal state. It is a health threat to patients, particularly those with underlying hypoxic respiratory pathologies, which may be conducive to a sudden unexpected death in epilepsy (SUDEP). Recent studies provide evidence that brain microglia are involved with both respiratory and ictal processes. Here, we investigated the hypothesis that microglia could interact with hypoxia-induced seizures. To this end, we recorded electroencephalogram (EEG) and acute ventilatory responses to hypoxia (5% O in N) in conscious, spontaneously breathing adult mice. We compared control vehicle pre-treated animals with those pre-treated with minocycline, an inhibitory modulator of microglial activation. First, we histologically confirmed that hypoxia activates microglia and that pre-treatment with minocycline blocks hypoxia-induced microglial activation. Then, we analyzed the effects of minocycline pre-treatment on ventilatory responses to hypoxia by plethysmography. Minocycline alone failed to affect respiratory variables in room air or the initial respiratory augmentation in hypoxia. The comparative results showed that hypoxia caused seizures, which were accompanied by the late phase ventilatory suppression in all but one minocycline pre-treated mouse. Compared to the vehicle pre-treated, the minocycline pre-treated mice showed a delayed occurrence of seizures. Further, minocycline pre-treated mice tended to resist post-ictal respiratory arrest. These results suggest that microglia are conducive to seizure activity in severe hypoxia. Thus, inhibition of microglial activation may help suppress or prevent hypoxia-induced ictal episodes.
严重缺氧会引发癫痫发作，从而减少通气并使癫痫发作状态恶化。这对患者健康构成威胁，特别是那些患有潜在缺氧性呼吸道疾病的患者，这可能会导致癫痫猝死（SUDEP）。最近的研究表明，脑小胶质细胞与呼吸和癫痫发作过程都有关。在这里，我们研究了小胶质细胞是否可以与缺氧诱导的癫痫发作相互作用的假设。为此，我们记录了清醒、自主呼吸的成年小鼠的脑电图（EEG）和急性缺氧反应（5% O 在 N 中）。我们将用对照载体预处理的动物与用米诺环素预处理的动物进行了比较，米诺环素是小胶质细胞激活的抑制调节剂。首先，我们组织学地证实了缺氧激活了小胶质细胞，并且米诺环素预处理阻止了缺氧诱导的小胶质细胞激活。然后，我们通过体积描记法分析了米诺环素预处理对缺氧时通气反应的影响。米诺环素单独使用不会影响空气环境中的呼吸变量或缺氧时的初始呼吸增强。比较结果表明，缺氧会导致癫痫发作，除了一只用米诺环素预处理的小鼠外，所有小鼠都伴有后期通气抑制。与载体预处理相比，米诺环素预处理的小鼠癫痫发作发生延迟。此外，米诺环素预处理的小鼠倾向于抵抗癫痫后呼吸暂停。这些结果表明小胶质细胞有利于严重缺氧时的癫痫发作活动。因此，抑制小胶质细胞激活可能有助于抑制或预防缺氧引起的癫痫发作。
