Layer Nikolas, Brandes Janine, Lührs Philipp Justus, Wuttke Thomas V, Koch Henner
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Epilepsia. 2021 Nov;62(11):2790-2803. doi: 10.1111/epi.17066. Epub 2021 Sep 23.
Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role.
We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs.
We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBötC neurons.
Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies.
拉莫三嗪和其他钠通道阻滞剂是最常用的抗癫痫药物（AEDs）。由于其他钠通道阻滞剂，如利鲁唑，在缺氧时可严重改变呼吸节律的产生，我们想研究AEDs是否有类似作用。这在癫痫性猝死（SUDEP）的背景下尤为重要，SUDEP是难治性癫痫患者的主要死因。虽然其作用机制尚未完全明了，但全身强直阵挛性发作后的呼吸功能障碍似乎起主要作用。
我们使用了来自新生和幼年小鼠的包含前包钦格复合体（PreBötC）的横断脑干切片标本，在常氧和缺氧条件下，在有或没有AEDs存在的情况下，测量节律产生网络的群体活动以及细胞内活动。
我们发现应用钠通道阻滞剂（拉莫三嗪和卡马西平）可显著抑制喘息反应。相比之下，调节突触功能的AED左乙拉西坦的作用要小得多。拉莫三嗪对喘息的抑制伴随着PreBötC神经元中持续性钠电流（INap）的显著减少。令人惊讶的是，拉莫三嗪对持续性钠电流的抑制并不影响PreBötC起搏器神经元的电压依赖性爆发活动，但导致所有测量的PreBötC神经元中动作电位阈强度的缺氧依赖性偏移。
我们的结果有助于理解AEDs对中枢神经系统重要呼吸功能的影响。此外，我们的研究进一步深入了解了缺氧期间发生的钠依赖性变化以及细胞特性对前包钦格复合体中呼吸节律产生的贡献。这就提出了一个问题，即在极端缺氧的情况下，钠通道阻断性AEDs是否可能导致SUDEP，这是一个值得进一步研究的重要问题。
