tegaserod and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

In a previous study, we have shown that the small organic compound tegaserod, a drug approved for clinical application in an unrelated condition, is a mimic of the regeneration-beneficial glycan polysialic acid (PSA) in a mouse model of femoral nerve injury. Several independent observations have shown positive effects of PSA and its mimetic peptides in different paradigms of injury of the central and peripheral mammalian nervous systems. Since small organic compounds generally have advantages over metabolically rapidly degraded glycans and the proteolytically vulnerable mimetic peptides, a screen for a small PSA mimetic compound was successfully carried out, and the identified molecule proved to be beneficial in neurite outgrowth in vitro, independent of its originally described function as a 5-HT4 receptor agonist. In the present study, a mouse spinal cord compression device was used to elicit severe compression injury. We show that tegaserod promotes hindlimb motor function at 6 weeks after spinal cord injury compared to the control group receiving vehicle only. Immunohistology of the spinal cord rostral and caudal to the lesion site showed increased numbers of neurons, and a reduced area and intensity of glial fibrillary acidic protein immunoreactivity. Quantification of regrowth/sprouting of axons immunoreactive for tyrosine hydroxylase and serotonin showed increased axonal density rostral and caudal to the injury site in the ventral horns of mice treated with tegaserod. The combined observations suggest that tegaserod has the potential for treatment of spinal cord injuries in higher vertebrates.

Topics: Animals; Astrocytes; Axons; Cell Count; Cell Survival; Cicatrix; Disease Models, Animal; Female; Glial Fibrillary Acidic Protein; Gliosis; Hindlimb; Indoles; Mice, Inbred C57BL; Motor Activity; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Recovery of Function; Serotonin; Spinal Cord; Spinal Cord Injuries; Tyrosine 3-Monooxygenase

Although it is known that both clonidine and loperamide cause delayed colonic transit in mice, these models of drug-induced experimental constipation have not yet been fully characterized. Therefore, the aims of this study were to validate the clonidine- and loperamide-induced delays of colonic transit in mice as models of atonic and spastic constipation, respectively, and to evaluate the effect of mustard oil, a TRPA1 agonist, in both models. Colonic transit was evaluated in mice by determining the time needed to evacuate a bead inserted into the distal colon. Both loperamide and clonidine dose-dependently prolonged the evacuation time. Clonidine (10 microg/kg) and loperamide (0.3 mg/kg) tripled the evacuation time compared to controls. These delays were antagonized by the administration of yohimbine and naloxone, respectively. Tegaserod, a gastrointestinal motor-stimulating drug, reversed the delay in both models, but the effects were diminished at high doses. Atropine, an antispastic drug, improved the loperamide-induced delay, but did not affect the clonidine-induced delay. Mustard oil accelerated the colonic transit dose-dependently in both models of drug-induced constipations. These results indicate that clonidine- and loperamide-induced delays in colonic transit are models of atonic and spastic constipation, respectively, and that mustard oil may be effective on both types of constipation.

Topics: Animals; Atropine; Clonidine; Constipation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Gastrointestinal Transit; Indoles; Loperamide; Male; Mice; Mice, Inbred Strains; Mustard Plant; Naloxone; Plant Oils; Transient Receptor Potential Channels; TRPA1 Cation Channel; Yohimbine

Acute pancreatitis remains a potentially life-threatening disease associated with gastrointestinal motility disturbances. Prokinetic agents may be useful to overcome these motility disturbances. In this study, we investigated the effect of acute necrotizing pancreatitis (ANP) on gastrointestinal motility in female mice and evaluated the effect of tegaserod, a prokinetic 5-hydroxytryptamine-4 (5HT4) receptor agonist. ANP was induced by feeding mice a choline-deficient ethionine-supplemented diet during 72 h. In vivo intestinal motility was measured as the geometric centre (GC) of 25 glass beads 30-120-360 min after gavage. Colonic peristaltic activity was studied using a modified Trendelenburg set-up. ANP significantly decreased GC 30-120-360 min after bead gavage, associated with a significant increase of myeloperoxidase in the proximal small intestine and colon, but not in the stomach or distal small intestine. Tegaserod significantly ameliorated GC 360 min after bead gavage in control and pancreatitis mice. In isolated colonic segments, ANP significantly decreased the amplitude of peristaltic waves and increased the interval between peristaltic contractions. Tegaserod normalized the disturbed interval. In conclusion, ANP impairs gastric, small intestinal and colonic motility in mice. Tegaserod improves ANP-induced motility disturbances in vivo and in vitro, suggesting a therapeutic benefit of prokinetic 5HT4 receptor agonists in the treatment of pancreatitis-induced ileus.

Topics: Animals; Colon; Disease Models, Animal; Female; Gastrointestinal Motility; Indoles; Intestine, Small; Mice; Pancreatitis, Acute Necrotizing; Peroxidase; Serotonin Receptor Agonists

Excess cholesterol in bile and in blood is a major risk factor for the respective development of gallbladder disease and atherosclerosis. This lipid in excess negatively impacts the functioning of other smooth muscles, including the intestine. Serotonin is an important mediator of the contractile responses of the small intestine. Drugs targeting the serotonin receptor are used as prokinetic agents to manage intestinal motor disorders, in particular irritable bowel syndrome. Thus, tegaserod, acting on 5-HT4 receptor, ideally should obviate detrimental effects of excessive cholesterol on gastrointestinal smooth muscle. In this study we examined the effect of tegaserod on cholesterol-induced changes in the contractile responses of intestinal smooth muscle.. The effects of a high cholesterol (1%) diet on the in vitro contractile responses of jejunal longitudinal smooth muscle from Richardson ground squirrels to the cholinergic agonist carbachol were examined in the presence or absence of tetrodrodotoxin (TTX). Two groups of animals, fed either low (0.03%) or high cholesterol rat chow diet, were further divided into two subgroups and treated for 28 days with either vehicle or tegaserod.. The high cholesterol diet increased, by nearly 2-fold, contractions of the jejunal longitudinal smooth muscle elicited by carbachol. These cholinergic contractions were mediated by muscarinic receptors since they were blocked by scopolamine, a muscarinic receptor antagonist, but not by the nicotinic receptor antagonist, hexamethonium. Tegaserod treatment, which did not affect cholinergic contractions of tissues from low cholesterol fed animals, abrogated the increase caused by the high cholesterol diet. With low cholesterol diet TTX enhanced carbachol-evoked contractions, whereas this action potential blocker did not affect the augmented cholinergic contractions seen with tissues from animals on the high cholesterol diet. Tegaserod-treatment removed the effects of a high cholesterol diet on neuronal muscarinic receptors, as the potentiating effect of TTX on carbachol-elicited contractions was maintained in these animals.. A high cholesterol diet causes significant changes to cholinergic neurotransmission in the enteric nerves of the jejunum. The mechanisms by which these effects of cholesterol are reversed by tegaserod are unknown, but relate to removal of an inhibitory effect of cholesterol on enteric nerves.

Topics: Action Potentials; Animals; Carbachol; Cholesterol, Dietary; Cholinergic Agonists; Disease Models, Animal; Enteric Nervous System; Ganglionic Blockers; Hexamethonium; Indoles; Jejunum; Muscle Contraction; Muscle, Smooth; Sciuridae; Serotonin Receptor Agonists

To establish a model of chronic visceral hypersensitivity in rats and to investigate the effect of tegaserod, a partial 5-hydroxytryptamine-4 receptor agonist, on visceral hypersensitivity.. Neonate Sprague-Dawley rats at 8-21 days after birth underwent colorectal distension once daily. Adult rats aged 8-10 postnatal weeks underwent colorectal distension and the abdominal withdrawal reflex (AWR) during the distension was determined. The AWR score was recorded before and after intraperitoneal administration of either tegaserod (treatment group: 0.3 mg/kg) or vehicle (control group).. Changes in the AWR score were dependent on the pressure intensity of the colorectal distension (P < 0.01). At pressures of 40, 60 and 80 mmHg, the AWR scores in the model rats with visceral hypersensitivity were significantly higher than those recorded in the control group (1.95 +/- 0.16 vs 1.35 +/- 0.15, 2.82 +/- 0.12 vs 2.17 +/- 0.13, 3.20 +/- 0.14 vs 2.59 +/- 0.14, P < 0.01). Compared with the controls, tegaserod significantly decreased the AWR scores at the distension pressures of 40, 60 and 80 mmHg (1.95 +/- 0.50 vs 1.32 +/- 0.55, 3.05 +/- 0.48 vs 2.32 +/- 0.54, 3.25 +/- 0.63 vs 2.77 +/- 0.51, P < 0.05).. Adult rats can develop chronic visceral hypersensitivity after transient colorectal mechanical irritation during their postnatal period. Tegaserod increases the pain threshold to noxious stimuli, suggesting an antinociceptive property in its effect on visceral hypersensitivity.

Topics: Animals; Animals, Newborn; Colonic Diseases; Disease Models, Animal; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Pain; Rats; Rats, Sprague-Dawley; Rectal Diseases; Serotonin Receptor Agonists

To investigate the mechanisms of tegaserod, a partial 5-HT4 agonist, in reducing visceral sensitivity by observing Fos, substance P (SP) and calcitonin gene-related peptide (CGRP) expression in the lumbarsacral spinal cord induced by colonic inflammation in rats.. Twenty-four male rats with colonic inflammation induced by intraluminal instillation of trinitrobenzenesulfonic acid (TNBS) were divided into 3 groups. Treatment group 1: intra-gastric administration of tegaserod, 2 mg/kg.d; Treatment group 2: intra-gastric administration of tegaserod, 1 mg/kg.d;. intra-gastric administration of saline, 2.0 mL/d. After 7 d of intra-gastric administration, lumbarsacral spinal cord was removed and processed for Fos, SP and CGRP immunohistochemistry.. In rats of the control group, the majority of Fos labeled neurons was localized in deeper laminae of the lumbarsacral spinal cord (L(5)-S(1)). SP and CGRP were primarily expressed in the superficial laminae of the spinal cord after TNBS injection. Intra-gastric administration of tegaserod (2 mg/kg.d) resulted in a significant decrease of Fos labeled neurons (22.0+/-7.7) and SP density (12.5+/-1.4) in the dorsal horn in the lumbarsacral spinal cord compared to those of the control group (62.2+/-18.9, 35.9+/-8.9, P<0.05). However, CGRP content in dorsal horn did not significantly reduce in rats of treatment group 1 (1.2+/-1.1) compared to that of the control group (2.8+/-2.4, P>0.05). Neither Fos expression nor SP or CGRP density in the dorsal horn significantly declined in rats of treatment group 2 compared to those of the control group (P>0.05).. Tegaserod can significantly reduce Fos labeled neurons in the lumbarsacral spinal cord induced by colonic inflammation. Tegaserod may reduce visceral sensitivity by inhibiting SP expression in the dorsal horn of spinal cord.

Topics: Animals; Calcitonin Gene-Related Peptide; Colitis; Disease Models, Animal; Gastrointestinal Agents; Indoles; Male; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P; Visceral Afferents