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



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.



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.



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.
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.|Department of Anesthesia, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
Honghai
H
Zhang
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.|Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Haiting
H
Zhao
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.|Department of Anesthesiology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Xiaoxuan
X
Yang
Department of Anesthesiology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Qingsheng
Q
Xue
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.
Joseph F
JF
Cotten
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.
Hua-Jun
0000-0003-1544-4248
HJ
Feng
D006916:5-Hydroxytryptophan / Q000627:therapeutic use*; D000161:Acoustic Stimulation; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010433:Pentylenetetrazole / Q000633:toxicity; D012120:Respiration Disorders / Q000188:drug therapy* / Q000209:etiology*; D012640:Seizures / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D013045:Species Specificity; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D006916:5-Hydroxytryptophan; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D010433:Pentylenetetrazole
5-HT; Generalized seizures; Pentylenetetrazole; SUDEP; Therapeutics