Skipjack tuna peptides exert sleep-promoting effects by regulating neurotransmitter metabolism in pentobarbital...

It is estimated that sleep disorders affect approximately 35% of the global population, thus becoming the second most prevalent mental health disorder. In this work, the sleep-promoting effect of skipjack tuna peptide GHHAA (S4) was evaluated systematically in pentobarbital sodium (PS)-induced mice, and its mechanism was explored through measuring the content changes of sleep-related neurotransmitters and c-Fos expression levels in mouse brain regions. In comparison with the control group, S4 was able to dose-dependently reduce the sleep latency (6.33 ± 1.15 min) and prolong sleep time (60.33 ± 2.3 min) in PS-induced mice. During the gavage period, S4 did not affect the food intake and body weight of mice. S4 showed no side effects on the organs of mice by liver, kidney, and spleen organ coefficients. Moreover, S4 did not directly induce sleep in mice and had no effect on heparanase activity. Further studies have shown that S4 dose-dependently decreases the contents of excitatory neurotransmitters (dopamine, glutamate) and conversely increases the levels of inhibitory neurotransmitters (γ-aminobutyric acid, GABA) and conversion ratio (3-dihydroxyphenylacetic acid/dopamine, 5-hydroxytryptamine/5-hydroxyindole acetic acid) in the mice brain. Moreover, high dose of S4 could significantly increase the levels of GABA receptor (GABA_AR), and decreased the level of GABA transaminase (GABA-T) in mouse brain. Immunohistochemistry found that S4 could increase c-Fos-positive cells in the ventrolateral preoptic area (VLPO) of the hypothalamus of mice, exerting a sleep-promoting effect.