Monoaminergic system is implicated in the antidepressant-like effect of hyperoside and protocatechuic acid isolated from Impatiens glandulifera Royle in mice.

We have recently demonstrated that the hydroethanolic extracts of Impatiens glandulifera Royle (Balsaminaceae) have antianxiety effect in mice. The present study was aimed to investigate an antidepressant activity of hyperoside (HYP) and protocatechuic acid (PCA), two polyphenols isolated from the aerial parts of this plant, using the forced swimming test (FST) and tail suspension test (TST) in mice. The implication of the monoaminergic system in this effect was assessed and brain-derived neurotrophic factor (BDNF) expression was measured. At doses 1.875, 3.75 and 7.5 mg/kg, HYP and PCA significantly reduced immobility in the FST and TST, without affecting locomotor activity of mice. Pretreatment with p-chlorophenylalanine (PCPA 100 mg/kg, a serotonin synthesis inhibitor) or α-methyl-DL-tyrosine (AMPT 100 mg/kg, a catecholamine synthesis inhibitor) was able to prevent antidepressant-like effect of HYP and PCA (3.75 mg/kg). Sub-effective doses of fluoxetine (5 mg/kg) or reboxetine (2 mg/kg) were capable of potentiating the effect of a sub-effective dose of HYP (0.94 mg/kg) in the FST. Co-administration of sub-effective dose of PCA (0.94 mg/kg) and reboxetine (2 mg/kg) resulted in reducing immobility in the FST. The antidepressant-like effect of HYP and PCA was also prevented by the administration of sulpiride (50 mg/kg), a D2 antagonist. In addition, HYP (3.75 and 7.5 mg/kg) and PCA (7.5 mg/kg) improved the expression of hippocampal BDNF of mice subjected to TST. Altogether, our findings suggest that HYP and PCA exert antidepressant-like effects in mice, which was possibly mediated by monoaminergic system and the upregulation of BDNF level.

In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048).

Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.

Preliminary Pharmacological Screening of Some Thiosemicarbazide, s-triazole, and Thiadiazole Derivatives.

Two thiosemicarbazide derivatives 1 and 2, three 2-amino-1,3,4-thiadiazole derivatives 3-5, and three N1- substituted-4-methyl-1,2,4-triazole-5-thione derivatives 6-8 were synthesized and evaluated for their central nervous system effects using rodent behavioral models. With the exception of 6, all compounds were devoid of neurotoxicity and they did not affect the body temperature of mice. New lead structures 1-4 with potential analgesic activity were identified.