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.

The role of adenosine in alcohol-induced respiratory suppression.

Alcohol-related poisoning is the foremost cause of death resulting from excessive acute alcohol consumption. Respiratory failure is crucial to the pathophysiology of fatal alcohol poisoning. Alcohol increases accumulation of extracellular adenosine. Adenosine suppresses breathing. The goal of this investigation was to test the hypothesis that adenosine signaling contributes to alcohol-induced respiratory suppression. In the first experiment, the breathing of mice was monitored following an injection of the non-selective adenosine receptor antagonist caffeine (40 mg/kg), alcohol (5 g/kg), or alcohol and caffeine combined. Caffeine reduced alcohol-induced respiratory suppression suggesting that adenosine contributes to the effects of alcohol on breathing. The second experiment utilized the same experimental design, but with the blood brain barrier impermeant non-selective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT, 60 mg/kg) instead of caffeine. 8-SPT did not reduce alcohol-induced respiratory suppression suggesting that adenosine is contributing to alcohol-induced respiratory suppression in the central nervous system. The third and fourth experiments used the same experimental design as the first, but with the selective A1 receptor antagonist DPCPX (1 mg/kg) and the selective A2A receptor antagonist istradefylline (3.3 mg/kg). Istradefylline, but not DPCPX, reduced alcohol-induced respiratory suppression indicating an A2A receptor mediated effect. In the fifth experiment, alcohol-induced respiratory suppression was evaluated in Adk+/- mice which have impaired adenosine metabolism. Alcohol-induced respiratory suppression was exacerbated in Adk+/- mice. These findings indicate that adenosinergic signaling contributes to alcohol-induced respiratory suppression. Improving our understanding of how alcohol affects breathing may lead to better treatment strategies and better outcomes for patients with severe alcohol poisoning.