Disruption of adenosine metabolism increases risk of seizure-induced death despite decreased seizure severity

Objective: 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.

Methods: 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).

Results: 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. A₁ selective and nonselective adenosine receptor antagonists increased seizure-induced death following MES.

Significance: 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.