CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice

Background@#CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated. @*Methods@#KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis. @*Results@#CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of β-nicotinamide adenine dinucleotide (NAD+), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1). @*Conclusion@#Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD+ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.

Melatonin inhibits nicotinic acetylcholine receptor functions in bovine chromaffin cells

Melatonin is a neurotransmitter that modulates various physiological phenomena including regulation and maintenance of the circadian rhythm. Nicotinic acetylcholine receptors (nAChRs) play an important role in oral functions including orofacial muscle contraction, salivary secretion, and tooth development. However, knowledge regarding physiological crosstalk between melatonin and nAChRs is limited. In the present study, the melatonin-mediated modulation of nAChR functions using bovine adrenal chromaffin cells, a representative model for the study of nAChRs, was investigated. Melatonin inhibited the nicotinic agonist dimethylphenylpiperazinium (DMPP) iodide-induced cytosolic free Ca²⁺ concentration ([Ca²⁺](i)) increase and norepinephrine secretion in a concentration-dependent manner. The inhibitory effect of melatonin on the DMPP-induced [Ca²⁺](i) increase was observed when the melatonin treatment was performed simultaneously with DMPP. The results indicate that melatonin inhibits nAChR functions in both peripheral and central nervous systems.

Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington's Disease

Huntington's disease (HD) is a late-onset and progressive neurodegenerative disorder that is caused by aggregation of mutant huntingtin protein which contains expanded-polyglutamine. The molecular chaperones modulate the aggregation in early stage and known for the most potent protector of neurodegeneration in animal models of HD. Over the past decades, a number of studies have demonstrated molecular chaperones alleviate the pathogenic symptoms by polyQ-mediated toxicity. Moreover, chaperone-inducible drugs and anti-aggregation drugs have beneficial effects on symptoms of disease. Here, we focus on the function of molecular chaperone in animal models of HD, and review the recent therapeutic approaches to modulate expression and turn-over of molecular chaperone and to develop anti-aggregation drugs.

Antidepressant Effect of Ethaverine / 대한정신약물학회지

The effects of a L-type calcium channel blocker, ethaverine were investigated in the rat forced swimming test, after single and repeated administration. Ethaverine in doses of 20 mg/kg, 40 mg/kg after single and repeated administration reduced significantly the duration of immobility in the forced swimming test. Fluoxetine administered in a single dose of 40 mg/kg did not influence the duration of immobility, but fluoxetine in a dose of 40 mg/kg administered repeatedly reduced significantly the duration of immobility. Ethaverine in a dose of 10 mg/kg did not affect the immobility after single and repeated administration. Imipramine and fluoxetine in doses which were not effective by themselves, increased the immobilityreducing effect when administered concormitantly with ethaverine in a dose of 10 mg/kg. Imipramine in a dose of 20 mg/kg and fluoxetine in a dose of 80 mg/kg, administered alone reduced the immobility time. The reduction of immobility after the concormitant administration of ethaverine in a dose of 10 mg/kg and imipramine in a dose of 20 mg/kg, fluoxetine in a dose of 80 mg/kg was significantly greater than after imipramine or fluoxetine, administered alone. The anti-immobility effect of the ethaverine was significantly counteracted by haloperidol in a dose of 0.5 mg/kg. The effects of ethaverine on the levels of monoamines and their metabolites were also investigated in rat striatum, cerebral cortex, cerebellum, medulla oblongata, hypothalamus, midbrain, hippocampus. Treatment with ethaverine caused alterations on the levels of dopamine and its metabolite in rat striatum, cerebral cortex, hypothalamus, medulla oblongata, cerebellum, but not on the levels of norepinephrine and serotonin and its metabolite. The observed effects of ethaverine indicate that ethaverine may have an antidepressant activity and may interact with the brain dopaminergic system. The present results suggest that the concormitant administration of ethaverine and antidepressants may have a more potent therapeutic antidepressant effect and/or may permit reduction of the dose of antidepressant and thus diminish its side effects.

Regulation of Melatonin Synthesis and Release in the pineal Gland / 대한내분비학회지

No Abstract Available.

Antidepressant Effects of Ethaverine, a Calcium Channel Antagonist, in Animal Models of Depression / 신경정신의학

OBJECTIVES: This pre-clinical study was performed to assess the effects of ethaverine in the two kinds of behavioral models of depression in rats. METHODS: We observed the changes of the immobility time in the forced swimming test and the quantity of sucrose consumed in the chronic mild stress model, using ethaverine(20mg/kg) alone, imipramine(20mg/kg) alone, or ethaverine and imipramine concomitantly. RESULTS: In the forced swimming test, both single treatment and chronic treatment(for 7 days) with imipramine or ethaverine significantly reduced the immobility time, and concomitant chronic treatment with ethaverine potentiated the effect of imipramine. In the chronic mild stress model, both imipramine and ethaverine reversed the decreased sucrose consumption induced by 3-week stress and concomitantly treated ethaverine potentiated the effect of imipramine in the early phase of treatment. CONCLUSIONS: The data suggest that ethaverine can be used alone or concomitantly with other anti-depressants in the clinical situation.