Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α7 nicotinic acetylcholine receptor in Wistar rats

Kohnomi, Shuntaro; Suemaru, Katsuya; Goda, Mitsunori; Choshi, Tominari; Hibino, Satoshi; Kawasaki, Hiromu; Araki, Hiroaki

doi:10.1016/j.brainres.2010.07.037

Cited by 30 publications

(22 citation statements)

References 39 publications

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“…The fact that palonosetron attenuated TNF-␣, but not MyD88, may be either because of unspecific binding of tropisetron to other receptors than 5-HT 3 R, or because of the limited number of experiments we could perform with palonosetron. For example, tropisetron is known to act as a partial agonist of the ␣7-acetylcholine receptor through which TLR4-dependent signaling might by modulated or other anti-inflammatory effects might be triggered (Abdrakhmanova et al, 2010;Kohnomi et al, 2010). Nevertheless, our findings might be of clinical importance because several previous studies from various groups clearly showed that an impairment of the intestinal barrier, which results in enhanced translocation of bacterial lipopolysaccharides, is a major mechanism leading to fatty liver disease (Arteel, 2003;Bode and Bode, 2003;Bergheim et al, 2008).…”

Section: Discussionmentioning

confidence: 74%

“…Another particular feature of tropisetron is its anti-inflammatory effect that has been shown in experimental colitis in the rat, for example (Mousavizadeh et al, 2009). It is not clear from the literature to which extent this effect is dependent on 5-HT 3 R blockage or on other mechanism such as modulation of the ␣7-acetylcholine receptor pathway that also mediates anti-inflammatory effects (Abdrakhmanova et al, 2010;Kohnomi et al, 2010). Alternatively, the calcineurin pathway in human Tcells might play a role in the anti-inflammatory effects of tropisetron.…”

Section: Discussionmentioning

confidence: 99%

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Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Haub¹,

Ritze²,

Ladel³

et al. 2011

J Pharmacol Exp Ther

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Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT 3 R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT 3 R antagonists tropisetron and palonosetron on the development of NA-FLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotoninreuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (Ϫ29%), liver inflammation (Ϫ56%), and liver cell necrosis (Ϫ59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-␣ mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Haub¹,

Ritze²,

Ladel³

et al. 2011

J Pharmacol Exp Ther

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“…Studies involving α7-nAChR agonists (e.g., RG-3487, SEN-12333, TC-5619, and tropisetron) have routinely demonstrated positive effects in their ability to attenuate apomorphine-induced PPI disruption (Hauser et al 2009; Kohnomi et al 2010; Roncarati et al 2009; Wallace et al 2011); however, fewer PPI studies have shown consistent effects (Dunlop et al 2009; Ghiron et al 2010, but see Kohnomi et al 2010) with α7-nAChR agonist-induced modulation of NMDA receptor antagonists. Our results demonstrated a robust effect of GTS-21 on reversing the MK-801 PPI deficit in a manner similar to that of the antipsychotic clozapine (Levin et al 2007; Mansbach et al 2001; Terry et al 2006) thereby strengthening the observations that α7-nAChR agonists can modulate depressed NMDA receptor function.…”

Section: Discussionmentioning

confidence: 99%

“…Our results demonstrated a robust effect of GTS-21 on reversing the MK-801 PPI deficit in a manner similar to that of the antipsychotic clozapine (Levin et al 2007; Mansbach et al 2001; Terry et al 2006) thereby strengthening the observations that α7-nAChR agonists can modulate depressed NMDA receptor function. Additionally, the effects of α7-nAChR agonists on sensori-motor gating appear to be receptor specific as the improved PPI response is attenuated by the α7-nAChR antagonist MLA (Kohnomi et al 2010). …”

Section: Discussionmentioning

confidence: 99%

“…Effects of α7-nAChR agonists on information gating have been extended to include reversal of pharmacologic-induced disruption of prepulse inhibition (PPI) of acoustic startle. The majority of studies have focused on attenuating the PPI impairment induced by the dopamine agonist apomorphine (Hauser et al 2009; Kohnomi et al 2010; Roncarati et al 2009; Wallace et al 2011) with fewer studies assessing the role of NMDA receptor function on sensorimotor gating (Dunlop et al 2009; Ghiron et al 2010; Kohnomi et al 2010). …”

Section: Introductionmentioning

confidence: 99%

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Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats

2014

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Rationale Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy. Objectives and methods We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21. Results In the PPI task, GTS-21 (1–10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1–10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313–5 mg/kg). Conclusions The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders.

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Recent advances with 5‐HT₃ modulators for neuropsychiatric and gastrointestinal disorders

Jůza

Vlček

Mezeiová

et al. 2020

Medicinal Research Reviews

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Serotonin (5‐hydroxytryptophan [5‐HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5‐HT receptors (5‐HT1‐7Rs). The 5‐HT3R is a ligand‐gated ion channel belonging to the Cys‐loop receptor family. There is a wide variety of 5‐HT3R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy‐induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid‐1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5‐HT3R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5‐HT3R modulators developed over the past 10 years.

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Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α7 nicotinic acetylcholine receptor in Wistar rats

Cited by 30 publications

References 39 publications

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats

Recent advances with 5‐HT₃ modulators for neuropsychiatric and gastrointestinal disorders

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Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α7 nicotinic acetylcholine receptor in Wistar rats

Cited by 30 publications

References 39 publications

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats

Recent advances with 5‐HT3 modulators for neuropsychiatric and gastrointestinal disorders

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Product

Resources

About

Recent advances with 5‐HT₃ modulators for neuropsychiatric and gastrointestinal disorders