Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
Brain Health Institute, Rutgers University, Piscataway, New Jersey, USA.
Epilepsia. 2024 Sep;65(9):2798-2811. doi: 10.1111/epi.18055. Epub 2024 Jul 17.
Respiratory arrest plays an important role in sudden unexpected death in epilepsy (SUDEP). Adenosine is of interest in SUDEP pathophysiology due to its influence on seizures and breathing. The objective of this investigation was to examine the role of adenosine in seizure severity, seizure-induced respiratory disruption, and seizure-induced death using mouse models. Understanding adenosinergic contributions to seizure cessation and seizure-induced death may provide insights into how SUDEP can be prevented while avoiding increased seizure severity.
Our approach was to examine: (1) seizure severity and seizure-induced death after 15 mA electroshock seizures and during repeated pentylenetetrazol (PTZ) administration in wild-type mice (Adk ) and transgenic mice with reduced adenosine metabolism (Adk ); (2) the postictal hypercapnic ventilatory response (HCVR) in wild-type mice (the postictal HCVR could not be examined in Adk mice due to their high mortality rate); and (3) the effects of adenosinergic drugs on seizure severity and seizure-induced death following maximal electroshock (MES).
Adk mice were more vulnerable to seizure-induced death in the 15 mA electroshock and repeated PTZ models. Despite increased mortality, Adk mice had comparable seizure severity in the PTZ model and reduced seizure severity in the 15 mA electroshock model. Breathing and HCVR were suppressed by 15 mA electroshock seizures in wild-type mice. Pharmacological inhibition of adenosine metabolism decreased MES seizure severity but did not increase mortality. A selective and nonselective adenosine receptor antagonists increased seizure-induced death following MES.
Adenosine has opposing effects on seizure severity and seizure-induced death. On the one hand, our seizure severity data highlight the importance of adenosine in seizure suppression. On the other hand, our mortality data indicate that excessive extracellular adenosine signaling can increase the risk of seizure-induced respiratory arrest.
呼吸暂停在癫痫猝死（SUDEP）中起着重要作用。由于腺苷对癫痫发作和呼吸的影响，它在 SUDEP 病理生理学中引起了关注。本研究的目的是使用小鼠模型检查腺苷在癫痫发作严重程度、癫痫发作引起的呼吸中断和癫痫发作引起的死亡中的作用。了解腺苷能对癫痫发作停止和癫痫发作引起的死亡的贡献可能有助于了解如何预防 SUDEP，同时避免癫痫发作严重程度增加。
我们的方法是检查：（1）在 15mA 电休克发作后和反复戊四氮（PTZ）给药期间，野生型小鼠（Adk ）和腺苷代谢减少的转基因小鼠（Adk ）的癫痫发作严重程度和癫痫发作引起的死亡；（2）野生型小鼠的 postictal 高碳酸血症通气反应（HCVR）（由于其高死亡率，无法在 Adk 小鼠中检查 postictal HCVR）；（3）腺苷能药物对最大电休克（MES）后癫痫发作严重程度和癫痫发作引起的死亡的影响。
Adk 小鼠在 15mA 电休克和重复 PTZ 模型中更容易发生癫痫发作引起的死亡。尽管死亡率增加，但 Adk 小鼠在 PTZ 模型中的癫痫发作严重程度相当，在 15mA 电休克模型中的癫痫发作严重程度降低。呼吸和 HCVR 被野生型小鼠的 15mA 电休克发作抑制。腺苷代谢的药理学抑制降低了 MES 癫痫发作的严重程度，但没有增加死亡率。选择性和非选择性腺苷受体拮抗剂增加了 MES 后癫痫发作引起的死亡。
腺苷对癫痫发作严重程度和癫痫发作引起的死亡有相反的影响。一方面，我们的癫痫发作严重程度数据强调了腺苷在癫痫发作抑制中的重要性。另一方面，我们的死亡率数据表明，细胞外腺苷信号过度增强会增加癫痫发作引起的呼吸暂停的风险。
