Abstracts

This abstract has been invited to present during the Basic Science Poster Highlights poster session

Rationale: The MORTEMUS study reported that prior to SUDEP, patients experienced GTC seizure followed by repeated apnea. These events promoted hypoxic and hypercapnic (H-H) fluctuations in blood gases, an inability to autoresuscitate from which, resulted in a terminal apnea and death. The exact mechanisms underlying this autoresuscitation failure are unknown. H-H fluctuations in the blood activate the central serotonin-orexin chemosensing circuit that project to key brainstem respiratory and enable adaptive respiration until eupnea. Thus, central chemoreception dysfunction might be at the heart of autoresuscitation failure in SUDEP. We have previously reported that the Kv1.1 KO (KO) mice, a model of SUDEP, have increased seizures, apnea and chronic intermittent hypoxia; all indicative of progressively worsening blood gas instability as these mice approach death. We also reported a temporal increase in the orexin neurons in the KO mice as they approach death and blocking orexin receptors reduced apneas, and increased longevity in these mice. This suggests that increased orexinergic influence on impaired chemoresponse in this preclinical SUDEP model. We hypothesize that (a) as KO mice approach SUDEP, they have impaired chemoresponse to hypoxic and hypercapnic challenges, and (b) blocking orexin receptors will improve chemoresponses.

Methods: Separate cohorts of wildtype (WT) and KO mice at high-risk for SUDEP (high risk KO) were subjected to one of three gas challenges using the whole-body plethysmography. The blood gas challenges consisted of either (a) an intermittent hypoxia (94% N₂, 6% O₂) test, (b) a hypoxia-hypercapnia (85% N₂, 9% CO₂, 6% O₂) test, or (c) an anoxia (97% N₂, 3% CO₂) induced autoresuscitation test. For the anoxia autoresuscitation test, orexin receptors were blocked with TCS1102 (100 mg/kg, ip.) in a preliminary cohort of high-risk KO mice. Endpoints included survival, apnea, tidal volume, minute ventilation, peak expiratory flow and gasping.

Results: In response to intermittent hypoxia, and hypoxia-hypercapnia, chemoresponse in high-risk KO included higher tidal volume, peak expiratory flow and minute ventilation, compared to WT controls. When tested for anoxia-induced autoresuscitation, 8/9 older WT mice were able to autoresuscitate and survive. In contrast, 5/7 high-risk KO mice exhibited a deteriorating gasping response and failed to autoresuscitate. Specifically, in the KO mice that fail to autoresuscitate, minute ventilation was increased during anoxia, when compared to both WT and KO survivors. In a younger cohort, both WT and KO were able to autoresuscitate. Preliminary data suggest that acute blockade of orexin receptors enabled 5/6 high-risk Kcna1-null mice to successfully autoresuscitate and survive.

Conclusions: These data suggest that KO mice struggle to restore eupnea after gas challenges and that the autoresuscitation response progressively declines in KO mice. Thus impaired chemoresponse may be contributing to autoresuscitation failure in a preclinical SUDEP model. Blocking orexin receptors improved autoresuscitation in these mice.

Funding: NIH NINDS NS111389 R21 (KAS, TAS), NIH NINDS NS126418 R01 (KAS, TAS)