Authors :
XiaoXia Xu, PhD – Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine
Qing Xu, MD – Zhejiang University School of Medicine
LeYuan Gu, MD – Zhejiang University School of Medicine
YaXuan Wu, BS – the Fourth Clinical School of Medicine, Zhejiang Chinese Medical University
Yue Yang, PhD – Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine
ZhuoYue Zhang, BS – Zhejiang University School of Medicine
ZiWen Zhang, BS – the Fourth Clinical School of Medicine, Zhejiang Chinese Medical University
XuanYi Di, BS – the Fourth Clinical School of Medicine, Zhejiang Chinese Medical University
Presenting Author: HongHai Zhang, MD – Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine
Rationale:
1. Unmet Clinical Need
Sudden unexpected death in epilepsy (SUDEP) claims ~1 in 1,000 epilepsy patients annually, with seizure-induced respiratory arrest (S-IRA) as the dominant mechanism. Despite three decades of research, no clinically approved SUDEP-preventive therapy exists. Current strategies (e.g., nocturnal monitoring) are impractical for widespread use, creating an urgent need for mechanistic-driven interventions.
2. Pioneering Findings
We present three transformative discoveries with first-in-field evidence:
- Synergistic neuroprotection: Co-activation of 5-HT and NE systems reduces SUDEP incidence , demonstrating supra-additive effects.
- Circuit-level resolution: Identifiedthe dorsal raphe nucleus (DR) - locus coeruleus (LC) - pre-Bötzinger complex (PBC) pathway as the essential neural substrate using optogenetic techniques.
- Therapeutic targets: Localized 5-HT2A and NE α-1 receptors in PBC as non-redundant gatekeepers of respiratory protection (antagonism abolishes efficacy).
3. Clinical Translation Potential
With its unique integration of circuit neuroscience and translational pharmacology, this work promises to redefine clinical approaches to SUDEP prevention.
Methods:
Using the SUDEP-prone DBA/1 mouse model, we employed integrated approaches: pharmacological interventions (5-hydroxytryptophan, atomoxetine, venlafaxine), in vivo calcium imaging, and optogenetics. Targeted microinjections of receptor antagonists (ketanserin: 5-HT2A; prazosin: NE α-1) into the pre-Bötzinger complex (PBC) assessed local receptor contributions.
Results:
We demonstrate, for the first time, a robust synergistic interaction between 5-HT and NE in mitigating S-IRA and preventing SUDEP. Co-elevation of 5-HT and NE levels significantly reduced SUDEP incidence, with synergy confirmed pharmacologically. The serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine enhanced this cooperative protection. Crucially, we identified the dorsal raphe nucleus (DR) - locus coeruleus (LC) - pre-Bötzinger complex (PBC) pathway as the essential neural substrate mediating this effect. Antagonism of either 5-HT2A or NE α-1 receptors specifically within the PBC abolished the protective effects of 5-HT and NE elevation, pinpointing these receptors as pivotal mediators in this key respiratory center.Conclusions:
This study establishes the DR-LC-PBC pathway as a critical network for the synergistic protective action of 5-HT and NE against S-IRA and SUDEP. We identify 5-HT2A and NE α-1 receptors within the PBC as key therapeutic targets. These findings provide a mechanistic foundation for developing novel SUDEP prevention strategies, particularly those enhancing combined 5-HT/NE signaling, such as SNRIs.
Funding:
The work was supported by the National Natural Science Foundation of China (Grant no.: 81771403 and 81974205), the Natural Science Foundation of Zhejiang Province (LZ20H090001, LZ25H090003 and LQN25H090016), and the Program of New Century 131 outstanding young talent plan top-level of Hang Zhou .