HBK-14 and HBK-15 do not influence blood pressure, lipid profile, glucose level, or liver enzymes activity after chronic treatment in rats

Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders

Pitolisant protects mice chronically treated with corticosterone from some behavioral but not metabolic changes in corticosterone-induced depression model

Purpose: Histamine H3 receptor ligands may have antidepressant and anxiolytic effects. They can also compensate for metabolic disorders, which affect glucose or triglyceride levels. In previous studies, we have shown that pitolisant, a histamine H3 receptor antagonist/inverse agonist and σ1 receptor agonist, prevented the development of certain metabolic and depressive-like disorders in mice that have been treated chronically with olanzapine. Methods: As a continuation of our previous experiments, this study aimed to investigate the antidepressant- and anxiolytic-like activity of pitolisant in mice using the corticosterone-induced depression model. The forced swim and the elevated plus maze tests were used as behavioral endpoints. We also studied the effect pitolisant had on the level of acetoacetic acid in the urine as well as the glucose tolerance and body weight of the mice that had been administered corticosterone. Results: Pitolisant (10 mg/kg b.w.) did not prevent depressive-like behavior in mice during the chronic corticosterone administration but did counteract anxiety-like behavior, whilst fluoxetine (10 mg/kg) was shown to protect the mice from both of these behaviors. None of the treatments that were used in the study showed an effect on the locomotor activity of the mice. Pitolisant did not prevent an increase in acetoacetic acid levels in the urine, nor did it improve glucose tolerance in the tested mice. Conclusion: Although literature data indicates that there is significant potential for finding an antidepressant and anti-diabetic drug among the histamine H3 and σ1 receptor ligands, in our study, pitolisant was shown to only slightly compensate for corticosterone-induced abnormalities. However, further research will be required to study pitolisant's anxiolytic-like activity

Preliminary evaluation of central nervous system activity of (E)-N-2-methyl-3-phenylprop-2-enyl ((E)-N- α-methylcinnamyl) derivatives of selected aminoalkanols

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2 aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors

A comparison of the anorectic effect and safety of the alpha_{2}-adrenoceptor ligands guanfacine and yohimbine in rats with diet-induced obesity

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity

H_3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice

The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H(1)receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant – H(3) histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the co-administered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radio-frequency identification system) – TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs