Beyond the 5-HT3 receptors: A role for α7nACh receptors in neuroprotective aspects of tropisetron.

Accumulation of reactive oxygen species, such as hydrogen peroxide (H2O2), generated by inflammatory cells or other pathological conditions, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders such as Alzheimer's disease. Recent investigations have described effective properties of tropisetron, such as antiphlogistic action or protection against ß-amyloid induced-neuroinflammation in rats. Our data revealed that H2O2-induced cell death in rat pheochromocytoma cell line (PC12) can be inhibited by tropisetron, as defined by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay, caspase 3 and caspase 12 levels. We further showed that tropisetron exerts its protective effects by upregulation of heme oxygenase-1, glutathione, catalase activity, and nuclear factor-erythroid 2 p45-related factor 2 level. Moreover, tropisetron was recently found to be a partial agonist of α7 nicotinic acetylcholine receptor (α7nAChR). The activation of α7nAChR could inhibit inflammatory and apoptotic signaling pathways in the oxidative stress conditions. In this study, selective α7nAChR antagonists (methyllycaconitine) reversed the effects of tropisetron on caspase 3 level. Our findings indicated that tropisetron can protect PC12 cells against H2O2-induced neurotoxicity through α7nAChR in vitro.

Anti-inflammatory effects of 5-HT receptor antagonist, tropisetron on experimental colitis in rats.

BACKGROUND: There is a pressing need for research that will lead to the development of new therapeutic approaches for treating inflammatory bowel disease (IBD). The aim of this study was to investigate the effects of tropisetron, a 5-Hydroxytryptamine (5-HT)-3 receptor antagonist with anti-inflammatory properties in a model of experimental colitis in rat. MATERIALS AND METHODS: Acetic acid model of colitis in rats was used. Colitis was induced by intracolonal instillation of 4% (v/v) acetic acid. One hour after induction of colitis, intraperitoneal (IP) or intrarectal (IR) tropisetron (2 mg kg(-1), either route) or dexamethasone (1 mg kg(-1), either route) was administered. The severity of colitis was assessed 24 h later using macroscopic and microscopic changes of damaged colon, measurement of inflammatory cytokines interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha levels and oxidative stress markers myeloperoxidase (MPO) and malondialdehyde (MDA) in colonic tissues. RESULTS: Tropisetron decreased colonic macroscopic and microscopic damage scores. This was associated with significant reduction in both neutrophil infiltration indicated by decreased colonic MPO activity and lipid peroxidation measured by MDA content, as well as a decreased colonic inflammatory cytokines. IR tropisetron decreased colonic damage that was associated with decreased neutrophil infiltration, lipid peroxidation and colonic inflammatory cytokines. Beneficial effects of tropisetron were lower than those of dexamethasone. No significant differences were observed between IP and IR administration with the exception of MDA level more diminished by IP tropisetron and dexamethasone. CONCLUSIONS: Tropisetron exert beneficial effects in experimental rat colitis and therefore might be useful in the treatment of IBD.

Calcium release by diltiazem from isolated sarcoplasmic reticulum of rabbit skeletal muscle.

1. The effect of diltiazem on isolated sarcoplasmic reticulum (SR) from rabbit skeletal muscle was studied. To observe calcium movement into and out of the SR, a fluorescent chelate probe technique with chlortetracycline (CTC) as a reagent was employed. 2. Tris-ATP-induced calcium accumulation by the isolated SR was associated with a rise in the CTC fluorescence. The effect of ATP was dose dependent. 3. Diltiazem (6 x 10(-4)M, 2 x 10(-3)M) prevented ATP-induced calcium accumulation by the SR. 4. Addition of EGTA to the media chelates external calcium and caused calcium release that can be reversed by further addition of calcium chloride. Similarly diltiazem caused a rapid release of accumulated calcium from the SR, which is not reversed by the addition of calcium chloride. 5. It seems that the effect of diltiazem may be related to SR membrane-bound calcium being available for release.

Cyclosporin A-induced functional and morphological changes in pilocarpine treated rat submandibular glands.

The effects of long-term administration of Cyclosporin A (CSA), an immunosuppressive agent, on submandibular glands of male albino rats were investigated. Sialochemistry studies revealed a reduction of pilocarpine-stimulated flow rates to 54% compared to the controls. Salivary Mg(2+) and K+ were elevated and a marked decrease in total protein concentration was observed. Light and electron microscopic features of treated glands show marked changes at tissue level. An irregular pattern of the nucleus, mitochondrial alterations, reduction in the number of secretory granules and their aggregation, disturbances of cytoplasmic organelles, and isometric vacuolation were among the most striking findings. Our results show that CSA causes marked functional and morphological alterations in rat submandibular glands, which may be due to the drug's direct effects on the tissue.

Conditions that lithium inhibits or potentiates vasopressin V1-receptor-mediated platelet aggregation and [Ca++]i mobilization.

1. Besides clinical use, there are many explanations for the mechanism of action of lithium. Although it is shown that lithium may reduce the supply of inositol that is required to sustain phosphoinositide synthesis, evidence exists concerning the potentiating effect of lithium on this pathway. We therefore decided to evaluate conditions in which lithium inhibits or potentiates platelet aggregation and calcium response induced by vasopressin. 2. Platelet aggregation was measured by the photometric method, and changes in intracellular free calcium were measured using fura-2/AM. 3. We show an inhibitory action of neomycin on vasopressin-induced platelet aggregation. Lithium, according to the preincubation time, could both potentiate or inhibit platelet aggregation and calcium responses induced by vasopressin. The inhibitory effect of lithium on platelet aggregation is dependent on concentrations of both lithium and vasopressin and also the presence of indomethacin, for example, in the absence of indomethacin there was no clear inhibitory action of lithium on vasopressin-induced platelet aggregation. 4. These results show the importance of arachidonate metabolites concerning lithium effects on platelet V1-receptor signaling. In conclusion, because the arachidonate metabolites are responsible for the release of other active substances from platelets' granules, the aggregatory responses in the absence of indomethacin may be amplified, and this subsequently may change the net inhibitory action of lithium.

Alteration by ouabain of rat submandibular glands function.

1. Effects of various doses of intraperitoneal ouabain (1,2 and 5 mg/kg) on rat submandibular saliva were investigated in this study. 2. Potassium and calcium and their product (K+ x Ca2+) were found to be elevated in all groups. 3. Changes in salivary flow were not the major cause of the alterations in electrolytes. 4. Protein concentrations were elevated in the doses of 1 and 2 mg/kg of the drug and somewhat reduced in the dose of 5 mg/kg of ouabain but still above the base line. 5. The results show that there is an ouabain-induced close parallelism between magnesium and total protein secretion from rat submandibular glands.

On the relation of calcium channel blockers to rat parotid and submandibular glands function in vivo.

1. The effects of nifedipine, verapamil and diltiazem on rat parotid and submandibular glands function were studied. 2. Nifedipine (5 mg/kg), verapamil (5 mg/kg) and diltiazem (10 mg/kg) were injected intraperitoneally 15 min before saliva collection. 3. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and 8 mg/kg of pilocarpine was used as secretagogue. 4. Submandibular saliva was analyzed for flow rate, protein and calcium concentrations; and parotid saliva for calcium and amylase contents. 5. In treated groups, flow rate and calcium of submandibular saliva were significantly lower than controls. Parotid calcium in the nifedipine group was decreased and in verapamil and diltiazem groups was increased. Parotid amylase was significantly decreased in both the nifedipine and diltiazem groups. 6. It is concluded that a blockade of calcium channels in salivary glands acinar cells by CCBs causes some alterations in salivary secretions.

Effects of vinca alkaloids on rat parotid and submandibular glands function in vivo.

1. Vincristine (1 mg/kg) and vinblastine (2 mg/kg) were injected intraperitoneally into the rats, 24 hr before the experiments. 2. Animals were anesthetized with 50 mg/kg of sodium pentobarbital and saliva was collected from vincristine-treated, vinblastine-treated and control animals using 8 mg/kg of pilocarpine as secretagogue. 3. Parotid saliva was analyzed for protein, amylase and Ca2+ content, and submandibular saliva for flow rate, protein and Ca2+ concentration. 4. Saliva from two treated groups was significantly lower (P < 0.01) in flow rate, amylase and protein content than that of control group. Calcium level was significantly increased (P < 0.05) in treated animals. 5. It is concluded that the antisecretory effects of vinca alkaloids may be consistent with their actions on salivary cell microtubules.

Effects of atropine, pirenzepine, clonidine, and morphine on biphasic response of rat gastric fundus to field stimulation.

1. Electrically evoked contractions in isolated strips of rat gastric fundus were inhibited by atropine (IC50 = 2.5 x 10(-9) M), pirenzepine (IC50 = 2.3 x 10(-8) M), clonidine (IC50 = 3.9 x 10(-8) M) and morphine (IC50 = 3.2 x 10(-7) M) in a dose-dependent manner. 2. The inhibitory effect of morphine was antagonized by naloxone (10(-6) M). The inhibitory effect of clonidine not only was not reversed by yohimbine but also was enhanced. Yohimbine per se inhibited these contractions (IC50 = 6.4 x 10(-6) M). 3. In presence of atropine (2 x 10(-6) M) and guanethidine (5 x 10(-6) M), electrical stimulation of isolated strips of rat gastric fundus produced a non-adrenergic, non-cholinergic (NANC) inhibitory response. 4. The NANC inhibitory response was decreased by morphine (10(-8)-3 x 10(-6) M). In addition, morphine decreased the tone of the muscle. These effects of morphine was antagonized by naloxone (3 x 10(-6) M). 5. Clonidine up to 10(-6) M had no influence on the NANC inhibitory response but yohimbine per se (10(-7)-3 x 10(-5) M) blocked it (IC50 = 3 x 10(-6) M). 6. These findings indicate that electrically evoked contractions in the rat gastric fundus were mediated by muscarinic receptors. In addition, the NANC inhibitory response in the isolated 5-strips of rat gastric fundus was blocked by morphine and yohimbine.