Karolina Pytka

Essential elements in depression and anxiety. Part II

In this paper we continue to discuss the involvement of essential elements in depression and anxiety, and the possible mechanisms that link elements to the neurobiology underlying depression/anxiety. The present paper is focused on copper, selenium, manganese, iodine and vanadium. Different aspects of relationship between elements and depression or anxiety are reviewed, e.g. the association of the amount of an element in a diet or the serum level of an element and depressive or anxiety-like symptoms. Moreover, the relation of selected elements to the pathophysiology of depression or anxiety is discussed in the context of enzymes which require these elements as co-factors and are involved in the underlying pathophysiology of these disorders.

Synthesis and Evaluation of Antidepressant‐like Activity of Some 4‐Substituted 1‐(2‐methoxyphenyl)Piperazine Derivatives

A series of new derivatives of N‐(2‐methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant‐like activity. They have been evaluated toward receptors 5‐HT1A, 5‐HT6, and 5‐HT7, as well as in vivo in the tail suspension, locomotor activity, and motor co‐ordination tests. All the tested compounds proved very good affinities toward 5‐HT1A and 5‐HT7 receptors. The most promising compound was 1‐[(2‐chloro‐6‐methylphenoxy)ethoxyethyl]‐4‐(2‐methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors Ki <1 nm (5‐HT1A) and Ki = 34 nm (5‐HT7). Antidepressant‐like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.

The role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.

Depression is one of the most common mental disorders and social issue worldwide. Although there are many antidepressants available, the effectiveness of the therapy is still a serious issue. Moreover, there are many limitations of currently used antidepressants, including slow onset of action, numerous side effects, or the fact that many patients do not respond adequately to the treatment. Therefore, scientists are searching for new compounds with different mechanisms of action. Numerous data indicate the important role of glutamatergic, GABA-ergic, and cholinergic receptors in the pathomechanism of major depressive disorder. This review presents the role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

Antidepressant-like activity of a new piperazine derivative of xanthone in the forced swim test in mice: The involvement of serotonergic system

BACKGROUND The studied compound: 3-chloro-5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-9H-xanthen-9-one dihydrochloride (HBK-6) is a new xanthone derivative. In this study we investigated its antidepressant-like properties and possible mechanism of action. METHODS Antidepressant-like activity was evaluated in the forced swim test (FST) in mice. The influence on locomotor activity in mice was analyzed to determine whether the observed in FST effect is specific. Rotarod test was used to determine neurotoxic properties. RESULTS HBK-6 reduced immobility time in mice in FST at the doses 5 and 10mg/kg, whereas fluoxetine (FX) at 15 mg/kg, reboxetine (RX) at 10mg/kg and bupropion (BPR) at 5mg/kg. Joint administration of sub-effective doses of HBK-6 and FX, but not RX or BPR, reduced immobility in mice in FST. HBK-6 at the dose 5mg/kg did not show activity in FST after pretreatment with p-chlorophenylalanine. The studied xanthone derivative at the doses 5 and 10mg/kg did not impair motor coordination in mice. CONCLUSIONS We demonstrated that HBK-6 has a potent antidepressant-like activity in FST, stronger than that of FX and RX, and seems to mediate its effect through serotonergic system. Moreover, at antidepressant-like doses it does not show neurotoxic properties. Given the promising results, HBK-6 may have potential in the treatment of depression, but this needs extended studies.

Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

A series of new xanthone derivatives with piperazine moiety [1-7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α₁ and β₁ adrenergic as well as 5-HT₁A, 5-HT₆ and 5-HT₇b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT₁A receptors (Ki=24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED₅₀ determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.

The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT1A and 5-HT2A/C receptors activation

Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant-like properties. Taking this into account we investigated antidepressant-like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) - a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant-like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub-effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant-like activity of HBK-11 in the aforementioned test was blocked by p-chlorophenylalanine, and significantly reduced by serotonergic 5HT1A receptor antagonist - WAY-1006335 and 5HT2A/C receptor antagonist - ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, it can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant-like effect involves 5HT1A and 5HT2A/C receptor activation. Furthermore, at antidepressant-like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney tests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p. administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailability. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e. 5HT2A/C receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.

Antiarrhythmic, hypotensive and α1-adrenolytic properties of new 2-methoxyphenylpiperazine derivatives of xanthone.

The main goal of this study was to assess antiarrhythmic and hypotensive activity of new 2-methoxyphenylpiperazine derivatives of xanthone. In order to better understand mechanism of action of studied compounds, their abilities to antagonize the increase in blood pressure elicited by adrenaline, noradrenaline and methoxamine, as well as the antagonistic properties for α1-adrenoceptors on isolated rat aorta were evaluated. Therapeutic antiarrhythmic activity was investigated in an adrenaline-induced model of arrhythmia. Hypotensive activity in normotensive rats was evaluated after oral administration. Influence on blood vasopressor response and α1-adrenoceptors in rat thoracic aorta was evaluated to determine if the observed cardiovascular effects could be related to α1-adrenolytic properties. Tested compounds produced antiarrhythmic and hypotensive activity. The most active compound was MH-99 - (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride. All studied compounds showed α1-adrenolytic properties in the in vivo and in vitro tests. The results indicate that the new valuable compounds with antiarrhythmic and hypotensive activity might be found in the group of xanthone derivatives. Further pharmacological utility of these compounds should be investigated.

The role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in antidepressant-like effect

Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.

HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active dose it did not influence cognitive and motor function. Since 5-HT1A receptor antagonists may accelerate the occurrence of antidepressant effect, our findings highlight their potential as future antidepressants.