5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest

Epilepsia. 2016 Aug;57(8):1228-35. doi: 10.1111/epi.13430. Epub 2016 Jun 15.


Objective: The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure-induced respiratory arrest (S-IRA) evoked by acoustic stimulation, followed by cardiac arrhythmia and death. Defects in serotonergic neurotransmission may contribute to S-IRA. The tryptophan hydroxylase-2 (TPH2) enzyme converts L-tryptophan to 5-hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis; and DBA/1 mice have a polymorphism that decreases TPH2 activity. We, therefore, hypothesized that supplementation with 5-HTP may bypass TPH2 and suppress S-IRA in DBA/1 mice.

Methods: TPH2 expression was examined by Western blot in the brainstem of DBA/1 and C57BL/6J mice both with and without acoustic stimulation. Changes in breathing and cardiac electrical activity in DBA/1 and C57BL/6J mice that incurred sudden death during generalized seizures evoked by pentylenetetrazole (PTZ) were studied by plethysmography and electrocardiography. The effect of 5-HTP administration on seizure-induced mortality evoked by acoustic stimulation or by PTZ was investigated in DBA/1 mice.

Results: Repetitive acoustic stimulation resulted in reduced TPH2 protein in the brainstem of DBA/1 mice as compared with C57BL/6J mice. S-IRA evoked by acoustic stimulation in DBA/1 mice was significantly reduced by 5-HTP. Following S-IRA, cardiac electrical activity could be detected for minutes before terminal asystole and death in both DBA/1 and C57BL/6J mice after PTZ treatment. The incidence of S-IRA by PTZ administration was greater in DBA/1 than in C57BL/6J mice, and administration of 5-HTP also significantly reduced S-IRA by PTZ in DBA/1 mice.

Significance: Our data suggest that S-IRA is the primary event leading to death incurred in most DBA/1 and some C57BL/6J mice during PTZ-evoked seizures. Suppression of S-IRA by 5-HTP suggests that 5-HT transmission contributes to the pathophysiology of S-IRA, and that 5-HTP, an over-the-counter supplement available for human consumption, may be clinically useful in preventing SUDEP.

Keywords: 5-HT; Generalized seizures; Pentylenetetrazole; SUDEP; Therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Hydroxytryptophan / therapeutic use*
  • Acoustic Stimulation
  • Animals
  • Brain Stem / drug effects
  • Brain Stem / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Evoked Potentials, Auditory, Brain Stem / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Pentylenetetrazole / toxicity
  • Respiration Disorders / drug therapy*
  • Respiration Disorders / etiology*
  • Seizures / chemically induced
  • Seizures / complications*
  • Seizures / pathology
  • Species Specificity
  • Tryptophan Hydroxylase / metabolism


  • 5-Hydroxytryptophan
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase
  • Pentylenetetrazole