Schiff bases of tryptamine as potent inhibitors of nucleoside triphosphate diphosphohydrolases (NTPDases): Structure-activity relationship.

Overexpression of NTPDases leads to a number of pathological situations such as thrombosis, and cancer. Thus, effective inhibitors are required to combat these pathological situations. Different classes of NTPDase inhibitors are reported so far including nucleotides and their derivatives, sulfonated dyes such as reactive blue 2, suramin and its derivatives, and polyoxomatalates (POMs). Suramin is a well-known and potent NTPDase inhibitor, nonetheless, a range of side effects are also associated with it. Reactive blue 2 also had non-specific side effects that become apparent at high concentrations. In addition, most of the NTPDase inhibitors are high molecular weight compounds, always required tedious chemical steps to synthesize. Hence, there is still need to explore novel, low molecular weight, easy to synthesize, and potent NTPDase inhibitors. Keeping in mind the known NTPDase inhibitors with imine functionality and nitrogen heterocycles, Schiff bases of tryptamine, 1-26, were synthesized and characterized by spectroscopic techniques such as EI-MS, HREI-MS, 1H-, and 13C NMR. All the synthetic compounds were evaluated for the inhibitory avidity against activities of three major isoforms of NTPDases: NTPDase-1, NTPDase-3, and NTPDase-8. Cumulatively, eighteen compounds were found to show potent inhibition (Ki = 0.0200-0.350 µM) of NTPDase-1, twelve (Ki = 0.071-1.060 µM) of NTPDase-3, and fifteen compounds inhibited (Ki = 0.0700-4.03 µM) NTPDase-8 activity. As a comparison, the Kis of the standard inhibitor suramin were 1.260 ±â€¯0.007, 6.39 ±â€¯0.89 and 1.180 ±â€¯0.002 µM, respectively. Kinetic studies were performed on lead compounds (6, 5, and 21) with human (h-) NTPDase-1, -3, and -8, and Lineweaver-Burk plot analysis showed that they were all competitive inhibitors. In silico study was conducted on compound 6 that showed the highest level of inhibition of NTPDase-1 to understand the binding mode in the active site of the enzyme.

Does the Anti-Migraine Drug Rizatriptan Affect Early Neural Tube Development in Chick Embryos?

AIM: To investigate the impact of rizatriptan on neural tube development using early chick embryos as a model organism. MATERIAL AND METHODS: A total of 36 pathogen-free Leghorn chicken eggs were selected and categorized in three groups: sham, therapeutic, and supra-therapeutic. After 24 hours, the eggs were opened and injected with sterile drugs, and then reclosed using plastic tape. After a period of 72 hours, the eggs were opened and assessed using the Hamburger-Hamilton chick embryology classification method. TUNEL staining was used to identify apoptosis, and hematoxylin-eosin staining was used to investigate neural tube closure. RESULTS: Treatment with rizatriptan significantly slowed down neural tube development. The supra-therapeutic group showed neural tube closure defects. CONCLUSION: Rizatriptan had a negative effect on neural tube closure. Further research is needed to identify a safe and effective drug for treating migraines during pregnancy.

Trigeminal ganglion transcriptome analysis in 2 rat models of medication-overuse headache reveals coherent and widespread induction of pronociceptive gene expression patterns.

We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. Of note, qualitative transcriptomic analysis shows that eletriptan and indomethacin prompt nearly identical, increased expression of genes coding for proteins involved in migraine pathogenesis and central pain sensitization such as neuropeptides, their cognate receptors, prostanoid, and nitric oxide-synthesizing enzymes, as well as TRP channels. These genes, however, were not affected in thoracic dorsal root ganglia. Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism-based treatment options.

Antiedematogenic activity of the indole derivative N-salicyloyltryptamine in animal models.

The N-salicyloyltryptamine (NST) is an indole derivative compound analogue to the alkaloid N-benzoyltryptamine. In the present study, the antiedematogenic activity of NST was investigated in animal models. Firstly, the acute toxicity for NST was assessed according to the OECD Guideline no. 423. The potential NST-induced antiedematogenic activity was evaluated by carrageenan-induced paw edema in rats, as well as by dextran-, compound 48/80-, histamine-, serotonin-, capsaicine-, and prostaglandin E2-induced paw edema in mice. The effect of NST on compound 48/80-induced ex vivo mast cell degranulation on mice mesenteric bed was investigated. No death or alteration of behavioral parameters was observed after administration of NST (2000 mg/kg, i.p.) during the observation time of 14 days. The NST (100 and 200 mg/kg, i.p.) inhibited the carrageenan-induced edema from the 1st to the 5th hour (**p<0.01; ***p<0.001). The edematogenic activity induced by dextran, compound 48/80, histamine, serotonin, capsaicin, and prostaglandin E2 was inhibited by NST (100 mg/kg, i.p.) throughout the observation period (**p<0.01; ***p<0.001). The pretreatment with NST (50, 100 or 200 mg/kg, i.p) attenuates the compound 48/80-induced mast cell degranulation (**p<0.01; ***p<0.001). Thus, the inhibition of both mast cell degranulation and release of endogenous mediators are probably involved in the NST-induced antiedematogenic effect.

Therapeutic effect of perinatal exogenous melatonin on behavioral and histopathological changes and antioxidative enzymes in neonate mouse model of cortical malformation.

BACKGROUND: Melatonin, which is an antioxidant and neuroprotective agent, can be an effective treatment for neurological disorders. We assessed the effect of melatonin administration on histological changes, antioxidant enzyme levels, and behavioral changes in a neonate mouse model of cortical malformation. MATERIALS AND METHODS: Cortical malformation was induced by two injections of 15 mg/kg methylazoxymethanol (MAM) on gestational day 15 (E15). Pregnant Balb/c mice were randomly divided into the following six groups: Control (CO), Melatonin (MEL), Luzindole (LUZ), MAM, MEL + MAM1 (co-treatment), and MEL + MAM2 (pretreatment). Melatonin was intraperitoneally injected at a dose of 10 mg/kg daily (from E15 until delivery of from E6 for 20 days after delivery). On postnatal day 31, the activity and anxiety of mice were assessed by open field and elevated plus maze tests, respectively. Histopathological changes in the neonate cortex were studied using hematoxylin and eosin staining and neurofilament immunohistochemistry. Enzyme-linked immunosorbent assays were used to measure the activity of nitric oxide (NO), malondialdehyde (MDA), and antioxidant enzymes, including catalase (CAT), super oxide dismutase (SOD), and glutathione peroxidase (GPX). RESULTS: In the behavioral assessment of neonate mice, a significant increase in the crossing activity and decrease in anxiety were recorded in groups treated with MAM plus melatonin. In histological examination, heterotopic, dysmorphic, and ectopic cells, as well as dyslamination, were seen in the MAM and LUZ groups. However, these defects were attenuated in the MAM plus melatonin groups. Significant reductions were recorded in the SOD and GPX levels in the MAM and LUZ groups compared to the control, while the NO level was increased in these groups. Groups that received MAM plus melatonin showed significant increases in the levels of SOD and GPX and a significant decrease in the level of NO, compared to the MAM group. CONCLUSION: Melatonin increased the crossing activity and decreased the anxiety in the treated mice of the neonate mouse model of cortical malformation. Histologically, the administration of exogenous melatonin in pregnant mice and their neonates had a protective effect on the cerebral cortex of neonates. Also, this effect is elicited by decreasing NO and increasing antioxidative enzymes.

Antiedematogenic activity of the indole derivative N-salicyloyltryptamine in animal models

ABSTRACT The N-salicyloyltryptamine (NST) is an indole derivative compound analogue to the alkaloid N-benzoyltryptamine. In the present study, the antiedematogenic activity of NST was investigated in animal models. Firstly, the acute toxicity for NST was assessed according to the OECD Guideline no. 423. The potential NST-induced antiedematogenic activity was evaluated by carrageenan-induced paw edema in rats, as well as by dextran-, compound 48/80-, histamine-, serotonin-, capsaicine-, and prostaglandin E2-induced paw edema in mice. The effect of NST on compound 48/80-induced ex vivo mast cell degranulation on mice mesenteric bed was investigated. No death or alteration of behavioral parameters was observed after administration of NST (2000 mg/kg, i.p.) during the observation time of 14 days. The NST (100 and 200 mg/kg, i.p.) inhibited the carrageenan-induced edema from the 1st to the 5th hour (**p<0.01; ***p<0.001). The edematogenic activity induced by dextran, compound 48/80, histamine, serotonin, capsaicin, and prostaglandin E2 was inhibited by NST (100 mg/kg, i.p.) throughout the observation period (**p<0.01; ***p<0.001). The pretreatment with NST (50, 100 or 200 mg/kg, i.p) attenuates the compound 48/80-induced mast cell degranulation (**p<0.01; ***p<0.001). Thus, the inhibition of both mast cell degranulation and release of endogenous mediators are probably involved in the NST-induced antiedematogenic effect.

Triazole rizatriptan Induces Liver Toxicity through Lysosomal/Mitochondrial Dysfunction.

Background: Triptans are used as antimigraine agents. Some cases of hepatotoxicity by triptans have been reported. However, the exact mechanism of triptan-induced hepatotoxicity is not clear yet. Methods: In this study, the cytotoxic effects of rizatriptan were investigated in freshly isolated rat hepatocytes using accelerated cytotoxicity mechanism screening. We designed experiments to evaluate toxicity markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, lysosomal membrane integrity and the amount of reduced and oxidized glutathione in the rizatriptan-treated hepatocytes. Results: Cytotoxicity caused by rizatriptan in rat hepatocytes was concentration-dependent. An increase in ROS formation accompanied by a significant rise in lipid peroxidation, mitochondrial depolarization and loss of lysosomal membrane integrity was observed. Cellular glutathione reservoirs were decreased and a significant amount of oxidized glutathione was formed. All the aforementioned rizatriptan-induced cellular events were significantly (p<0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Also, the present results demonstrated that CYP450 is involved in rizatriptan-induced oxidative stress and cytotoxicity mechanism and different CYP450 inducers had different effects on the toxicity. Conclusion: It is suggested that the adverse effect of rizatriptan towards hepatocytes is mediated by oxidative stress and the hepatocytes lysosomes and mitochondria play an important role in rizatriptan-induced cell injury.

Agomelatine, a melatonin receptor agonist with 5-HT(2C) receptor antagonist properties, protects the developing murine white matter against excitotoxicity.

Periventricular leukomalacia is a major cause of cerebral palsy. Perinatal white matter lesions associated with cerebral palsy appears to involve glutamate excitotoxicity. When injected intracerebrally into newborn mice, the glutamatergic analog, ibotenate, induces white matter cysts mimicking human periventricular leukomalacia. Intraperitoneal injection of melatonin was previously shown to be neuroprotective in this mouse model. The goal of the present study was to compare in this model the protective effects of agomelatine (S 20098), a melatonin derivative, with melatonin. Mice that received intraperitoneal S 20098 or melatonin had significant reductions in size of ibotenate-induced white matter cysts when compared with controls. Although agomelatine and melatonin did not prevent the initial appearance of white matter lesions, they did promote secondary lesion repair. Interestingly, while melatonin effects were only observed when given within the first two hours following the excitotoxic insult, agomelatine was still significantly neuroprotective when administered eight hours after the insult. The protective effects of agomelatine and melatonin were counter-acted by co-administration of luzindole or S 20928, two melatonin receptor antagonists. Agomelatine, acting through melatonin receptors, could represent a promising new drug for treating human periventricular leukomalacia and have beneficial effects on neuroplasticity.

Reactions of the putative neurotoxin tryptamine-4,5-dione with L-cysteine and other thiols.

Tryptamine-4,5-dione (1) is formed by oxidation of 5-hydroxytryptamine by reactive oxygen and reactive nitrogen species. Dione 1 is a powerful electrophile that can covalently modify cysteinyl residues of proteins and deactivate key enzymes. Thus, 1 has been suggested to play a role in the degeneration of serotonergic neurons in brain disorders such as Alzheimer's disease or evoked by amphetamine drugs. However, if formed in the brain, it is also likely that 1 would react with low molecular weight thiols such as cysteine (CySH) and glutathione (GSH). The resulting metabolites might not only contribute to the degeneration of serotonergic neurons but also, perhaps, serve as biomarkers of such neurodegeneration. In this investigation, it is shown that in oxygenated buffer at pH 7.4 dione 1 reacts with CySH and other low molecular weight sulfhydryls such as GSH, N-acetylcysteine, and cysteamine to form, first, the corresponding 7-S-thioethers of the dione. However, unlike the glutathionyl and N-acetylcysteinyl conjugates of 1, the 7-S-cysteinyl conjugate is very unstable at pH 7.4 forming a number of novel products, the nature of which are dependent on the relative concentrations of 1 and CySH. These products have been isolated, and spectroscopic and other evidence is provided in support of their proposed chemical structures.

[Blastomogenic activity of biogenic methoxyindoles]. / Blastomogennaia aktivnost' biogennykh metoksiindolov.

A considerable blastogenic activity of biogenic methoxyindoles--melatonin, 5-methoxytryptamine (5-MOT) and their common metabolite--5-methoxyindolyl-3-acetic acid (5-MIAA) was established by prolonged s.c. injection in C57BL/6 mice. However, the blastogenic effect of 5-MOT decreased by 26% when its further metabolism to 5-MIAA was blocked for some time and the synthesis of its carcinogenic metabolite was inhibited. These results showed that the blastogenic effect of 5-MOT is not direct; and it is mediated by its transformation to 5-MIAA in the body.

[A pool hemopoietic stem cells and resistance of mice to toxic substances depending upon food rations]. / Pul krovetvornykh stvolovykh kletok i ustoichivost' myshei k toksicheskim veshchestvam v zavisnmosti ot kachestva pischevykh ratsionov

Tests set up on male-mice of the CBA/I lineage demonstrated that fat carbohydrate rations of 1:7.3 and 1:3.8 in granulated combined fodder tend to increase the number of stem cells in a statistically fashion. Among mongrel mice kept on a ration with 7 per cent of fat a combination of mexamine with AET was found to loose some of its toxicity.