tropisetron and Inflammation

As a serotonin antagonist, tropisetron positively affects blood glucose lowering, insulin synthesis, pancreas inflammation, and apoptosis in diabetes. Reproductive disorders are one of the diabetes-induced chronic complications. The present study aimed to evaluate the effect of tropisetron on diabetes-induced testicular inflammation, its signaling pathway, and mir146a. To this end, animals were assigned to the control, tropisetron, diabetes (DM), DM-tropisetron, and DM-glibenclamide groups. Streptozotocin (50 mg/kg) was intraperitoneally injected to provide diabetes. Tropisetron and glibenclamide were then administrated intraperitoneally for 2 weeks after diabetes induction. Testes histology, real-time polymerase chain reaction, western blot analysis, ELISA, and immunohistochemistry assays were also performed. The finding revealed that tropisetron significantly improved diabetes-induced testis damages, lowered TLR4, TRAF6, IRAK1, NF-κB, and caspase3 protein expressions, and decreased TNF-α and IL-1 levels. Moreover, the mir146a expression declined following the tropisetron treatment. This study demonstrated that the significant role of tropisetron in lowering testicular inflammation and apoptosis might have been due to the inhibition of the TLR4/IRAK1/TRAF6 signaling pathway and thereby the attenuation of NF-κB and caspase3 expression and inflammatory cytokines. Furthermore, the downregulation of mir146a, as an inflammatory microRNA interacting with TLR4, showed another pathway, through which tropisetron improved diabetes-induced testicular injuries.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Glyburide; Inflammation; Male; NF-kappa B; Rats; Streptozocin; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4; Tropisetron

Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Inflammation; Interleukin-1; Rats; Streptozocin; Tropisetron; Tumor Necrosis Factor-alpha

Confident relationships between diabetes andliver damagehave previously been established. This study was designed to evaluate hepaticinflammation, apoptosis, and endocannabinoid system alterations in diabetes with or withouttropisetrontreatment. Rats were assigned to five equal groups: control, tropisetron, diabetes, tropisetron+diabetes, and glibenclamide+diabetes (n = 7 in each group). Rats were treated with tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) as a positive control for two weeks after type 1 diabetes induction.Inflammatory cytokines tumor necrosis factor-alpha and interleukin 6 (TNF-α and IL-6) levels, apoptotic cells, and fatty acid amide hydrolase (FAAH) enzyme, at both transcriptional and protein levels increased, while the gene expression of cannabinoid receptor 1 (CB1) and its protein level decreased in the diabetic liver compared to the control. Treatment with tropisetron reversed TNF-α, apoptotic index, and endocannabinoid system components. These effects were equipotent with glibenclamide, indicating that tropisetroncan protect liver tissue against diabetic disturbances. These findings strongly support the idea that diabetes-induced liver abnormality is mediated by inflammatory reactions, apoptosis, and endocannabinoid system, and that these effects can be alleviated by using tropisetron as an antioxidant and anti-inflammatory agent.

Topics: Amidohydrolases; Animals; Apoptosis; Diabetes Complications; Endocannabinoids; Hepatitis; Humans; Inflammation; Interleukin-6; Liver; Male; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Serotonin 5-HT3 Receptor Antagonists; Tropisetron; Tumor Necrosis Factor-alpha

The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 (SIRT1).. Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene (SIRT1) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed.. Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate SIRT1 gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology.. Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via SIRT1 signaling activation.

Topics: Aging; Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Brain; Drug Administration Schedule; Galactose; Gene Expression Regulation; Inflammation; Injections, Intraperitoneal; Injections, Subcutaneous; Interleukin-6; Male; Mice; Mitochondria; Neurons; Nitric Oxide; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Serotonin 5-HT3 Receptor Antagonists; Sirtuin 1; Tropisetron; Tumor Necrosis Factor-alpha

The objective of the present investigation was to explore the possible effect of the 5-HT3 receptor antagonist tropisetron on the expression levels of the inflammatory factors interleukin 6 (IL-6), creatine kinase isoenzyme (CK-MB), soluble growth stimulating gene 2 protein (sST2) and immunoglobulin E (IgE), as well as the cardiac action potential in septic rats.. The cecal ligation and perforation (CLP) method was utilized to construct abdominal infarction in rats. A total of 68 male adult Sprague Dawley rats were used, including 40 for assessing survival and 28 for detecting the expression levels of IL-6 and IgE, myocardial injury, cardiac dysfunction and the cardiac action potential. These 28 rats were divided into the sham (6 rats), sham + Tropisetron (6 rats), CLP (8 rats) and CLP + Tropisetron (8 rats) groups. Twenty-four hours after establishment of the sepsis rat model, immunohistochemistry was used to analyze 5-HT3 receptor protein expression, and enzyme-linked immunosorbent assay (ELISA) was employed to monitor the serum levels of IL-6, CKMB, sST2 and IgE. Furthermore, the structure of the myocardium in various groups was examined by H&E staining.. The levels of IL-6, CK-MB, sST2 and IgE in the sepsis group were significantly higher than those of the sham group (P <  0.01). Furthermore, the heart rate in the sepsis group was lower than that of the sham group (P <  0.01), and the time of atrial ventricular action potential in the sepsis group was longer than that of the sham group (P <  0.05). In addition, immunohistochemical analyses showed that the area, intensity and index of 5-HT3 receptor in the sepsis group were significantly lower than those of the sham group (P <  0.01). Importantly, the 5-HT3 receptor antagonist Tropisetron exhibited significant inhibitory effects IL-6, CK-MB, sST2 and IgE expression levels, and inductive effects on atrial ventricular action potential in the sepsis group.. Sepsis leads to systemic inflammatory reaction, resulting in myocardial injury, structural changes and immune imbalance. The inhibitory effect of tropisetron on inflammation, and the regulatory inflammatory disorder by the efferent vagus nerve may be one of the important mechanisms leading to cardiac electrophysiological changes in sepsis.

Topics: Action Potentials; Animals; Disease Models, Animal; Heart; Inflammation; Inflammation Mediators; Isolated Heart Preparation; Male; Rats; Rats, Sprague-Dawley; Sepsis; Serotonin 5-HT3 Receptor Antagonists; Tropisetron

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Despite this, there are no drugs for preventing the onset of AD. Preclinical studies suggest that the interaction between amyloid-β peptides (Aβ) and the α7 nicotinic acetylcholine receptor (α7 nAChR) plays a key role in AD pathology, and that α7 nAChR agonists could act as potential therapeutic drugs for AD. A recent study demonstrated that tropisetron, a potent α7 nAChR agonist and serotonin 5-hydroxytryptamine3 receptor antagonist, also bound to the ectodomain of amyloid precursor protein. Furthermore, tropisetron promoted greater improvements in memory than current AD therapeutic drugs, such as memantine and donepezil. Positron emission tomography studies detected Aβ deposition and inflammation in the brains of subjects with amnestic mild cognitive impairment (MCI) before the onset of AD. Given the role of α7 nAChR in Aβ deposition and inflammation, tropisetron represents an attractive potential therapeutic drug to delay or prevent MCI and AD. Additionally as this drug is used internationally to treat chemotherapy-induced emesis, its safety record is already known.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Animals; Humans; Indoles; Inflammation; Nicotinic Agonists; Quinuclidines; Serotonin Antagonists; Thiophenes; Tropisetron

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 NAFLD 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, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (-29%), liver inflammation (-56%), and liver cell necrosis (-59%) 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-α 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.

Topics: Actins; Animals; Azo Compounds; Drug Evaluation, Preclinical; Duodenum; Endotoxins; Fatty Liver; Indoles; Inflammation; Isoquinolines; Leptin; Liver; Mice; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Palonosetron; Proteins; Quinuclidines; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Tropisetron; Tumor Necrosis Factor-alpha

The role of central serotonin 3 receptors on neural activities recorded from superficial laminae of trigeminal subnucleus caudalis/upper cervical spinal cord junction region was investigated using rats with (Complete Freund's Adjuvant day 7 group) or without (non-Complete Freund's Adjuvant group) persistent temporomandibular joint inflammation evoked by Complete Freund's Adjuvant for 7 days. We identified two types of units, Deep-wide dynamic range units and Skin-wide dynamic range units from extracellular recordings. Deep-wide dynamic range units have mechanoreceptive fields in the deep craniofacial tissues including masseter muscle but do not have cutaneous mechanoreceptive fields. Deep-wide dynamic range unit discharges evoked by the formalin injection into masseter muscle were significantly enhanced in the late phase in Complete Freund's Adjuvant day 7 group. Discharges of Skin-wide dynamic range units evoked by the noxious pinch stimulation to facial skin in Complete Freund's Adjuvant day 7 group were significantly enhanced compared with those in non-Complete Freund's Adjuvant group. Topical administration of central serotonin 3 receptor antagonist, tropisetron, onto trigeminal subnucleus caudalis/upper cervical spinal cord junction region significantly reduced both formalin-evoked Deep-wide dynamic range unit and pinch-evoked Skin-wide dynamic range unit discharges in non-Complete Freund's Adjuvant and Complete Freund's Adjuvant day 7 groups significantly. The inhibitory effects of tropisetron on pinch-evoked Skin-wide dynamic range unit discharges were prolonged in Complete Freund's Adjuvant day 7 group compared with those in non-Complete Freund's Adjuvant group. The role of central serotonin 3 receptors in trigeminal subnucleus caudalis/upper cervical spinal cord junction region was also tested by orofacial formalin test in Complete Freund's Adjuvant day 7 group. Intracisternal administration of tropisetron decreased the orofacial nocifensive behavior in the late phase evoked by the injection of formalin into the masseter muscle. These results suggest that central serotonin 3 receptors in trigeminal subnucleus caudalis/upper cervical spinal cord junction region are involved in mediating pronociceptive effects in both superficial and deep craniofacial tissues nociception during persistent temporomandibular joint inflammation.

Topics: Action Potentials; Administration, Topical; Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Facial Pain; Formaldehyde; Freund's Adjuvant; Indoles; Inflammation; Male; Nociceptors; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Temporomandibular Joint Disorders; Time Factors; Trigeminal Caudal Nucleus; Tropisetron

The role of peripheral 5HT3 receptors in the orofacial nocifensive behavior induced by the injection of formalin into masseter muscle was evaluated. The behavioral activities evoked by the formalin injection exhibited a biphasic response in the rats with or without temporomandibular joint (TMJ) inflammation (CFA group or non-CFA group). The orofacial nocifensive behavioral activity was enhanced after TMJ inflammation. Systemic administration of tropisetron, 5HT3 receptor antagonist, reduced the nocifensive behavioral activities in the late phase of orofacial formalin test in CFA group, but not in non-CFA group. Local administration of tropisetron into the masseter muscle in CFA group, but not in non-CFA group also attenuated the behavioral activities in the late phase. Unexpectedly, low dose of local tropisetron reduced the nocifensive behavioral activities in the early phase of orofacial formalin test in CFA group. These data suggest that induction of TMJ inflammation causes the elevation of the orofacial nocifensive behavioral activities evoked by formalin injection into masseter muscle, and that peripheral 5HT3 receptors may play a critical role in nociception and the transmission of orofacial pain.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Facial Pain; Formaldehyde; Freund's Adjuvant; Indoles; Inflammation; Male; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Temporomandibular Joint Disorders; Time Factors; Tropisetron

There is evidence from both human and animal research that 5-hydroxytryptamine (5-HT)3 receptor antagonists, particularly tropisetron, exert analgesic and antiinflammatory effects. However, the underlying mechanisms of these effects have not yet been investigated in detail. Therefore, the antiinflammatory effects of tropisetron and ondansetron were investigated in human monocytes. In human monocytes, both lipopolysaccharide (LPS)-stimulated tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion were dose-dependently inhibited by tropisetron starting at a concentration of 5 microg/mL and reaching maximal levels at 25 microg/mL (IC50: 32 microg/mL and 12 microg/mL, respectively). LPS-induced IL-6 and PGE2 release was only slightly inhibited at high doses, whereas LPS-induced release of IL-8 and matrix metalloprotease (MMP)-9 was not affected. In conclusion, our data show that the binding of tropisetron to 5-HT3 receptors results in antiinflammatory effects through inhibition of TNF-alpha/IL-1beta, which might explain the antiphlogistic effects of 5-HT3 antagonists.

Topics: Cells, Cultured; Humans; Indoles; Inflammation; Lipopolysaccharides; Monocytes; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Tropisetron

Experiments were performed in carrageenin-treated rats to study, the antinociceptive and anti-inflammatory effects of paracetamol intravenously (i.v.) or intrathecally (i.t.) injected on rats submitted to a mechanical noxious stimulus. The influence of intrathecal tropisetron, a 5 hydroxytryptamine(3) (5-HT(3)) receptor antagonist, on the antinociceptive effects of paracetamol, was also studied. Paracetamol induced a significant antinociceptive effect after (100, 200 and 300 mg/kg) i.v. and (50, 100 and 200 microg/rat) i.t. injection, but no change occurred on edema volume. The effect of paracetamol was totally inhibited by tropisetron (10 microg/rat, i.t.). The foregoing results demonstrate that, in conditions of inflammatory pain, paracetamol exerts a central antinociceptive effect involving spinal 5-HT(3) receptors, without inducing any anti-inflammatory action. These data, give further arguments to consider paracetamol as a central analgesic drug which must be distinguished from non-steroidal anti-inflammatory drugs (NSAIDs), which justifies the usual combination of paracetamol in post-operative pain.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Drug Interactions; Edema; Indoles; Inflammation; Injections, Intravenous; Injections, Spinal; Male; Pain; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Tropisetron

The role of 5-hydroxytryptamine and its receptor subtypes in the development of acute inflammation was investigated using the rat paw formalin test as a model for pain (measured by flinching behavior) and edema formation (measured by plethysmometry). The role of endogenously released 5-hydroxytryptamine was assessed using 5-hydroxytryptamine receptor subtype-selective antagonists co-injected with 2.5% formalin, while the receptor subtypes involved in the inflammatory process were further defined by co-injection of 5-hydroxytryptamine or 5-hydroxytryptamine receptor subtype-selective agonists with 0.5% formalin in anticipation of an augmented response. When co-administered with 2.5% formalin, propranolol, tropisetron or GR113808A, but not ketanserin, effectively blocked nociceptive behavior. In the presence of 0.5% formalin, 5-carboxamidotryptamine, 1-(m-chlorophenyl) biguanide or 5-methoxytryptamine, but not (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, augmented the flinching response. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in peripheral nociception. There may be some dissociation of nociception and edema formation, since no single 5-hydroxytryptamine receptor antagonist inhibited edema formation with 2.5% formalin; however, with 0.5% formalin, edema formation was enhanced by co-administration of 5-hydroxytryptamine, 5-carboxamidotryptamine, (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane or 5-methoxytryptamine, but not 1-(m-chlorophenyl) biguanide. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine2 and possibly 5-hydroxytryptamine4 receptors in edema formation. These results confirm the involvement of 5-hydroxytryptamine1 and 5-hydroxytryptamine3 receptor subtypes in peripheral nociception associated with acute inflammation and further suggest an involvement of the more recently characterized 5-hydroxytryptamine4 receptor in this process. There appears to be a dissociation in 5-hydroxytryptamine receptors involved in peripheral nociception and edema formation.

Topics: Animals; Edema; Formaldehyde; Indoles; Inflammation; Ketanserin; Male; Pain; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

Intraplantar co-administration of sub-anesthetic doses of bupivacaine (2.5 microg) or lidocaine (7.5 microg) increased the dose- and time-dependent analgesic effects of the 5-HT3 receptor antagonist, 3-a-tropanyl-1-H-indole-3-carboxylic ester (ICS-205 930) (1-100 microg; 50 microl) against inflammatory pain induced by hindpaw inoculation with complete Freund's adjuvant. The effects of bupivacaine were greater than lidocaine at all doses of ICS-205 930 tested. These findings may reflect facilitation of ICS-205 930 effects through negative allosteric modulation by bupivacaine and lidocaine of peripheral 5-HT3 receptors involved in nociceptive processing.

Topics: Analgesia; Anesthetics, Local; Animals; Bupivacaine; Drug Synergism; Indoles; Inflammation; Lidocaine; Male; Pain; Pain Measurement; Rats; Serotonin Antagonists; Tropisetron

The effect of ICS 205-930 (ICS), a specific 5-HT3 receptor antagonist, was analyzed on the sensitization of ventrobasal (VB) thalamic neuronal responses produced by an intraplantar injection of carrageenin. ICS was injected locally in the plantar paw, simultaneously, or after carrageenin (at 20 min or later than 70 min). The progressive increase of the VB neuronal responses to pinch (total number of spikes in the discharge) due to carrageenin sensitization, was prevented, blocked, or reversed, by intraplantar ICS, at a dose as low as 3.2 ng/kg, when injected, simultaneously or in the first half-hour following the carrageenin injection itself. The carrageenin sensitization then reappeared, 50-90 min after the initiation of the inflammation. By contrast to these early injections of ICS, a later administration of ICS (70 min or more, after the carrageenin injection), did not influence the sensitization. The time course of the effects of this 5-HT3 antagonist receptor agrees well with the time course of 5-HT release into the inflammatory exudate. These data, and those previously reported on the action of aspirin and of a peripheral antihistamine on carrageenin sensitization, are compared. These results indicate the relative participation of the various inflammatory substances released in the exudate, and the importance of timing of administration for an effective antagonism of the hyperalgesia elicited by this inflammation.

Topics: Action Potentials; Animals; Carrageenan; Indoles; Inflammation; Male; Pain; Peripheral Nerves; Rats; Rats, Inbred Strains; Receptors, Serotonin; Sensory Thresholds; Thalamic Nuclei; Tropisetron