Diketopiperazines (DKPs) are naturally-occurring cyclic dipeptides with a small structure and are found in many organisms and in large amounts in some foods and beverages. We found that a chicken essence beverage, which is popular among Southeast Asians as a traditional remedy and a rich source of DKPs, inhibited the serotonin transporter (SERT) and suppressed serotonin uptake from rat brain synaptosomes, which prompted us to isolate and identify the active substance(s). We purified a SERT inhibitor from the chicken essence beverage and identified it as the DKP cyclo(L-Phe-L-Phe). Interestingly, it was a naturally occurring dual inhibitor that inhibited both SERT and acetylcholinesterase (AChE) in vitro. The DKP increased extracellular levels of the cerebral monoamines serotonin, norepinephrine, and dopamine in the medial prefrontal cortex and acetylcholine in the ventral hippocampus of freely moving rats when administered orally. Moreover, cyclo(L-Phe-L-Phe) significantly shortened escape latency in the water maze test in depressed mice previously subjected to a repeated open-space swimming task, which induces a depression-like state. Cyclo(L-Phe-L-Phe) also significantly improved accuracy rates in a radial maze test in rats and increased step-through latencies in a passive avoidance test in mice with scopolamine-induced amnesia. These animal test results suggest that cyclo(L-Phe-L-Phe), which is present abundantly in some foods such as chicken essence, may abrogate the onset of depression and, thus, contribute to preventing the development of Alzheimer’s disease and other dementia, because senile depression is a risk factor for dementia.

In a previous report, evidence was presented that flavangenol supplementation has an anti-ischemic effects in rats. In the study presented here, we examined the autonomic effects of intraduodenal (ID) injection of flavangenol in urethane-anesthetized rats and found that it increased sympathetic nerve activity innervating brown adipose tissue (BAT-SNA) in a dose-dependent manner, while it suppressed gastric vagal nerve activity (GVNA). In addition, intra-oral (IO) injection of flavangenol elevated brown adipose tissue temperature (BAT-T). Furthermore, flavangenol drinking for 15 d reduced body weight gain in rats fed a high-fat diet. These results thus suggest that flavangenol supplementation exerts its reducing action on body weight through changes in autonomic neurotransmission.

Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, and body weight in rats. In this study, three molecules (peaks A, B, and C) were isolated from Lactobacillus pentosus strain S-PT84 (S-PT 84) culture supernatants. Intraduodenal (ID) injection of these molecules increased or inhibited renal sympathetic nerve activity (RSNA) in rats as follows: peak A, 134%; peak B, 40.1%; peak C, 408%. Furthermore, we identified peak C as 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP). ID injection of DDMP increased brown adipose tissue sympathetic nerve activity (BAT-SNA; 118 ± 15.3%), whereas intraoral injection of DDMP increased the body temperature above the interscapular brown adipose tissue (BAT-T; 0.72 ± 0.13 °C) in rats. These data suggest that S-PT84 produces molecules that modulate autonomic nerve activity. In addition, DDMP increased BAT-SNA and BAT-T, and these changes in BAT-T may be caused by changes in BAT-SNA.

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