Abstracts

Rationale: Adenosinergic activities are suggested to participate in SUDEP pathophysiology; this study aimed to evaluate the adenosine hypothesis of SUDEP and specifically the role of adenosine A_2A receptor (A_2AR) in the development of a clinically relevant SUDEP mouse model.

Methods: Using a combined paradigm of intrahippocampal and intraperitoneal administration of kainic acid (KA), we developed a boosted-KA model of SUDEP in genetically modified adenosine kinase (ADK) knockdown (Adk^+/-) mice, which has reduced ADK in the brain. Seizure activity was monitored using video-EEG methods, and in vivo recording of local field potential was used to evaluate neuronal activity within the nucleus tractus solitarius (NTS).

Results: Our boosted-KA model of SUDEP was characterized by a delayed, postictal sudden death in epileptic mice. We demonstrated a higher incidence of SUDEP in Adk^+/- mice (34.8%) vs. WTs (8.0%), and the ADK inhibitor, 5-ITU, further increased SUDEP in Adk^+/- mice (46.7%). We revealed that NTS expression of ADK was significantly increased in epileptic WTs, but not in epileptic Adk^+/- mutants, while A_2AR expression in NTS was increased in epileptic (WT and Adk^+/-) mice vs non-epileptic controls. The A_2AR antagonist, SCH58261, drastically reduced SUDEP events in both Adk^+/- and WT mice. Further, we revealed NTS gamma oscillations were suppressed during KA-induced seizures, which were partially restored by SCH58261 pretreatment, accompanied by increased theta and beta oscillations in the NTS.

Conclusions: Together, we revealed a crucial role for NTS A_2AR in SUDEP pathophysiology suggesting A_2AR as a potential therapeutic target for SUDEP risk prevention.

Funding: Please list any funding that was received in support of this abstract.: The research was supported by grants from the Good Samaritan Foundation of Legacy Health.