Tert-butyl 4-((1-phenyl-1H-pyrazol-4-yl) methyl) piperazine-1-carboxylate (LQFM104)- New piperazine derivative with antianxiety and antidepressant-like effects: Putative role of serotonergic system.

The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways.

Monoamine Involvement in the Antidepressant-Like Effect of ß-Caryophyllene.

BACKGROUND: Major depressive disorder is a psychiatric disorder that affects 4.4% of the population worldwide. Although the majority of antidepressant drugs ameliorate depressive symptoms, there is still a need for safer and more effective antidepressant. OBJECTIVE: Evaluate the antidepressant-like activity of sesquiterpene compound ß-caryophyllene (BCP) for the possible contribution of the monoamine and hippocampal levels of brain-derived neurotrophic factor (BDNF). METHODS: Male albino Swiss mice were subjected to the forced swimming test after acute treatment and to the tail suspension test after repeated treatment. Hippocampal levels of BDNF were assayed by enzyme-linked immunosorbent assay. RESULTS: The anti-immobility effect of BCP was reverted by pretreatment with an inhibitor of catecholamine synthesis α-methyl-p-tyrosine (100 mg/kg, i.p.), α2-adrenergic antagonist yohimbine (1 mg/kg, i.p.), and ß-adrenergic antagonist propranolol (2 mg/kg, i.p.), but not by pretreatment with either α1-adrenergic antagonist prazosin (1 mg/kg, i.p.) or 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.), thereby suggesting the involvement of α2 and ß-adrenergic receptors, but not of the α1-adrenergic and 5-HT1A serotonergic receptors, in BCP's antidepressive-like activity. Furthermore, BCP increased BDNF levels in the hippocampus after 14 days of treatment. No treatments in this study altered locomotor activity in the open field test. CONCLUSION: This study provides a new mechanism of BCP-induced antidepressant-like effect mediated by some sub-types of catecholaminergic neurotransmitter system that could be a candidate for clinical tests of new treatments for depressive disorders.

Effect of allantoin on experimentally induced gastric ulcers: Pathways of gastroprotection.

Gastric ulcer affects people worldwide, and its inefficacy and recurrence have fueled the search for new therapeutic strategies. Despite the well-known use of allantoin in medicines and cosmetic products, its effect has not yet been studied with regard to gastric ulcer. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of allantoin against commonly harmful agents that cause injuries to the stomach. Ethanol, indomethacin, and stress-induced gastric ulcer models were adopted, in addition to pylorus ligature, a quantification of vascular permeability, glutathione (GSH), gastric adhered mucus, prostaglandin (PGE2), pro-inflammatory cytokines levels, myeloperoxidase (MPO), and catalase (CAT) activities. The gastric lesions were examined by gross, histological, and ultrastructural features. The results showed that treatment with allantoin (60mg/kg, per oral) reduced the gastric ulcer formation in all models. Furthermore, allantoin reduced the parameters of gastric acid secretion and attenuated both the vascular permeability and MPO activity. The levels of pro-inflammatory cytokines were also reduced, accompanied by a restoration of CAT activity and GSH levels. Notably, allantoin treatment preserved the gastric-adhered mucus and PGE2 levels after ethanol administration. Microscopic and ultrastructural analysis revealed that allantoin maintained tissue integrity and prevented morphological changes in cells caused by ethanol. In summary, we demonstrated for the first time that allantoin possesses gastroprotective activity through anti-inflammatory, anti-oxidative, antisecretory, and cytoprotective mechanisms. The antisecretory and cytoprotective mechanisms are probably associated with an increase in PGE2 levels.

Involvement of the monoamine system in antidepressant-like properties of 4-(1-phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester.

AIMS: Piperazinic derivatives have therapeutic potential by acting as analgesic, antidepressant-like, anticonvulsant and antipsychotic in preclinical studies. In order to develop new drugs to treat mental disorders, we designed and synthesized the 4-(1-phenyl-1H-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester (PPMP), a new piperazine derivative with putative activities on central nervous system that seems to involve serotonergic system. MATERIALS AND METHODS: In order to investigate the antidepressant-like activity of PPMP, mice were treated acutely and tested in the forced swimming test (FST) and tail suspension test. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., 4 days), and the non-selective blocker of catecholamine synthesis α-methyl para-tyrosine (AMPT, 100 mg/kg, i.p.) were used to assay the involvement of serotonergic and catecholaminergic systems. "Ex vivo" monoamine oxidase (MAO) enzymatic assay and quantification of hippocampal level of brain derived neurotrophic factor (BDNF) were carried out. KEY FINDINGS: PPMP reduced the immobility time in both tests. PCPA or AMPT (100 mg/kg, i.p.) pretreatment blocked the effects of PPMP, thereby suggesting the involvement of serotonergic and catecholaminergic systems in the antidepressant-like effect of PPMP. PPMP did not inhibit the activity of MAO. Moreover, after 14 days of treatment, PPMP 15 mg/kg/day induced antidepressant-like effect and increased hippocampal level of BDNF. None of the treatments in this study altered the locomotor activity in the open field test. SIGNIFICANCE: In conclusion, PPMP demonstrates antidepressant-like effect that involve both serotonergic and catecholaminergic systems without inhibition of MAO activity. PPMP administration increased the hippocampal levels of BDNF.