Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver

ABSTRACTThe etiology of non-alcoholic fatty liver disease (NAFLD) consists of various factors, including neural signal pathways. However, the molecular mechanisms of the autonomic neural signals influencing NAFLD progression have not been elucidated. Therefore, we examined the involvement of the gut-liver neural axis in NAFLD development and tested the therapeutic effect of modulation of this axis in this study. To test the contribution of the gut-liver neural axis, we examined NAFLD progression with respect to body weight, hepatic steatosis, fibrosis, intestinal tight junction, microbiota and short-chain fatty acids in NAFLD models of choline-deficient defined L-amino-acid and high-fat diet-fed mice with or without blockades of autonomic nerves from the liver. Blockade of the neural signal from the liver to the gut in these NAFLD mice models ameliorated the progression of liver weight, hepatic steatosis and fibrosis by modulating serotonin expression in the small intestine. It was related to the severity of the liver pathology, the tight junction protein expression, microbiota diversity and short-chain fatty acids. These effects were reproduced by administrating serotonin antagonist, which ameliorated the NAFLD progression in the NAFLD mice models. Our study demonstrated that the gut-liver neural axis is involved in the etiologies of NAFLD progression and that serotonin expression through this signaling network is the key factor of this axis. Therefore, modulation of the gut-liver neural axis and serotonin antagonist ameliorates fatty and fibrotic changes in non-alcoholic fatty liver, and can be a potential therapeutic target of NAFLD.This article has an associated First Person interview with the first author of the paper.

Serotonin and MAOA enable the organizer and tip dominance in Dictyostelium

The embryonic organizer is essential to determine one or more developmental polarities during chordate early development1,2. Functionally similar organizers also occur in more ancient animals3, and even in some protozoans such as Dictyostelium, in which the tip of the multicellular mound acts as an organizer4, establishing the main developmental axis, and regulating the size of the fruiting body5. However, our understanding of how the Dictyostelium organizer arises, and functions, is limited. Here we show that monoamine oxidase A (maoA), which degrades serotonin, confers the fate of an organizer to the Dictyostelium tip. Conversely, once a tip has formed, serotonin contributes to tip dominance. It inhibits further tip formation, and thus ensures the mound retains the size specified during an earlier developmental stage. Reducing the expression of maoA through RNA interference or by adding MAO specific inhibitors suppresses tip formation. Conversely, adding human MAOA enzyme, or an antagonist or antibodies against serotonin, restores tip formation in maoA knockdowns. Overexpression of maoA or adding a serotonin antagonist to the wildtype induces multiple tips from a single mound in a dose dependent manner. Using an array of genetic and molecular techniques, we show that serotonin’s inhibition of cAMP signalling and cell-cell adhesion is the basis of its regulation of tip formation. Our study demonstrates that serotonin, recently appreciated for its developmental roles in widespread phyla6, also has a novel and ancient role in the formation and function of an organizer.

The Effects of Dopamine and Serotonin on Yawning Behavior in the Rat Model of Social Isolation

A sample of 80 Male rats (21-day post weaning) were chosen, and were put for 6 weeks in separate cages with black plastic buffers. Eight rats were put in one group of 8 rats in a single cage (the control group) and the rest were put in individual cages: one male rat in each cage. In group 1 or the control group (social conditions) 8 rats were put in one cage. They received saline carrier and their yawning behavior was recorded for 60 minutes. Group 2 (n=8; in separate cages) (social isolation conditions) received no treatment with serotonin and dopamine agonist and antagonist and were kept in separate cages with one rat in each cage. Their yawning behavior was also recorded for 60 minutes. Group 3 (n=8; in separate cages) included the rats that received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg via subcutaneous injection (SC), and their yawning behavior was recorded for 60 minutes. Rats in group 4 (n=8; in separate cages) received serotonin agonist (m-CPP) at a dose of 0.5 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 5 (n=8; in separate cages) included rats that received Serotonin Antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection, and their yawning behavior was recorded for 60 minutes. Group 6 (n=8; in separate cages) included rats receiving dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via Intraperitoneal (IP) injection, and their yawning behavior was recorded for 60 minutes. Group 7 (n=8; in separate cages) included rats receiving Serotonin antagonist (Mianserin) at a dose of 0.2 mg/kg via subcutaneous injection 15 minutes before injection of apomorphine (dopamine agonist) and their yawning behavior was recorded for 60 minutes. Rats in group 8 (n=8; in separate cages) received dopamine antagonist (haloperidol) at a dose of 0.1 mg/kg via intraperitoneal injection (IP) 15 minutes before the injection of serotonin agonist (m-ccp), and their yawning behavior was recorded for 60 minutes. Rats in group 9 (n=8; in separate cages) received Apomorphine (dopamine agonist) at a dose of 0.08 mg/kg and Serotonin agonist (m-CPP) injected subcutaneously (SC) at a dose of 0.5 mg/kg and their yawning behavior was recorded for 60 minutes. Group 10 (n=8; in separate cages) included rats that received dopamine antagonists (haloperidol) at 0.1 mg/kg via intraperitoneal injection (IP) and antagonist serotonin (Mianserin) at 0.2 mg/kg injected subcutaneously and their yawning belabor was recorded for 60 minutes. Dopamine agonist (apomorphine) and serotonin antagonist (Mianserin) induce yawning in the social conditions and injection of haloperidol (dopamine antagonist) before serotonin agonist (m-ccp) reduces yawning in social conditions. Yawning is different in social conditions and social isolation conditions. Using Meta-Chlorophenylpiperazineserotonin (serotonin agonist), Mianserin (serotonin antagonist), apomorphine (dopamine agonist), haloperidol (dopamine antagonist) the role of serotonin and dopamine in yawning, fear, erection etc. can be investigated as a model for human studies.

Фармакотерапевтична ефективність перитолу та водорозчинного аспірину у лікуванні поросят, хворих на гастроентерит

Розглянуто питання лікування поросят відлучноговіку хворих на гастроентерит. Метою нашого дослід-ження було застосування в комплексному лікуванніхворих поросят препаратів, а саме: антагоністасеротоніну – перитолу та препарату з групи саліци-латів – водорозчинну форму ацетилсаліцилової кис-лоти [15]. Встановлено, що препарати, які ми за-стосовували, виявляють різнобічну дію на організмпоросят, зокрема на показники еритропоезу, деякіпоказники антиоксидантної системи та концентра-цію тіреоїдних гормонів. За результатами дослідіввизначено терапевтичну ефективність запропонова-них нами схем лікування. We dealed with a subject of piglets'gastroenteritis treatment. The aim of our study wasANNOTATIONS№ 3 • 2015 • ВІСНИК Полтавської державної аграрної академії 207to use in the treatment of patients pigletspreparations, namely serotonin antagonist – peritoland drugs from the group of salicylates – watersoluble form of aspirin. It was established that thedrugs we used exhibit diverse effects on the pigs, inparticular, on the performance of erythropoiesis,some indicators of antioxidant system and thyroidconcentration of hormones. According to the resultsof experiments determined the therapeutic efficacyof our proposed treatment regimens.