Investigation of Solution Behavior of Antidepressant Imipramine Hydrochloride Drug and Non-Ionic Surfactant Mixture: Experimental and Theoretical Study

In this paper, the interaction of imipramine hydrochloride (IMP, antidepressant drug) and a non-ionic surfactant Triton X-100 (TX-100) mixture in five different ratios through the tensiometric method in different solvents (aqueous/0.050 mol·kg−1 aqueous NaCl/0.250 mol·kg−1 aqueous urea (U)) were examined thoroughly at a temperature of 298 K. UV–Visible studies in an aqueous system of IMP + TX-100 mixtures were also investigated and discussed in detail. The pure (IMP and TX-100) along with the mixtures’ critical micelle concentration (cmc) were assessed by a tensiometric technique. The obtained deviation of the mixtures’ cmc values from their ideal values revealed the nonideal behavior of IMP + TX-100 mixtures amongst IMP and TX-100. Compared to aqueous systems, in the presence of aqueous NaCl, several changes in micelles/mixed micelles occurred, and hence a synergism/attractive interaction amongst components was found increased while in the existence of U, the synergism/attractive interaction between them decreased. The evaluated interaction parameter (βRb) value of mixed micelles showed the attractive or synergism between the IMP and TX-100. Various evaluated thermodynamic parameters in an aqueous system showed that the mixed micellization of the IMP + TX-100 mixture was an entropically spontaneous phenomenon, although the existence of salt in all studied systems can somewhat increase the spontaneity of the micellization process and in the aqueous U system, the spontaneity of the micellization process decreased. In an aqueous system, the interaction between IMP and TX-100 was also confirmed by UV–Visible study.

Inhibition of Neutrophil Secretion Upon Adhesion as a Basis for the Anti-Inflammatory Effect of the Tricyclic Antidepressant Imipramine

Recent studies demonstrate the involvement of inflammatory processes in the development of depression and the anti-inflammatory effects of antidepressants. Infiltration and adhesion of neutrophils to nerve tissues and their aggressive secretion are considered as possible causes of inflammatory processes in depression. We studied the effect of the antidepressant imipramine on the adhesion and accompanied secretion of neutrophils under control conditions and in the presence of lipopolysaccharides (LPS). As a model of integrin-dependent neutrophil infiltration into tissues, we used integrin-dependent adhesion of neutrophils to the fibronectin-coated substrate. Imipramine inhibited neutrophil adhesion and concomitant secretion of proteins, including matrix metalloproteinase 9 (MMP-9) and neutrophil gelatinase-associated lipocalin (NGAL), which modify the extracellular matrix and basement membranes required for cell migration. Imipramine also significantly and selectively blocked the release of the free amino acid hydroxylysine, a product of lysyl hydroxylase, an enzyme that affects the organization of the extracellular matrix by modifying collagen lysine residues. In contrast, imipramine enhanced the release of ROS by neutrophils during adhesion to fibronectin and stimulated apoptosis. The anti-inflammatory effect of imipramine may be associated with the suppression of neutrophil infiltration and their adhesion to nerve tissues by inhibiting the secretion of neutrophils, which provides these processes.

Antidepressants are complex regulators of lipoprotein(a) macropinocytosis

The regulation of Lp(a) clearance from circulation by cellular uptake remains enigmatic. While multiple receptors have been implicated in Lp(a) uptake, each receptor only partially accounts for this uptake, and no endocytic mechanism has yet been prescribed for Lp(a) internalisation into the cell. In this study, we define macropinocytosis as the endocytic pathway responsible for internalising Lp(a). In both liver and macrophage cells, Lp(a) uptake is dependent on extracellular calcium and is inhibited by amiloride or its derivative EIPA. The uptake of apo(a) alone is mediated by macropinocytosis, indicating the apo(a) protein component is a primary regulator of Lp(a) uptake. Importantly, we found that common antidepressants modulate Lp(a) macropinocytosis in cell-type dependent manners. In macrophages, the tricyclic antidepressant, imipramine and selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and sertraline all inhibit Lp(a) uptake. In liver cells, imipramine and citalopram strongly stimulated Lp(a) uptake, while sertraline inhibited uptake. Imipramine and citalopram enhanced Lp(a) uptake by enhancing cell surface binding of Lp(a) rather than upregulating macropinocytosis per se, indicating that immobilisation of Lp(a) on the plasma membrane is an important regulatory step in Lp(a) macropinocytosis. As the liver is the major catabolic route for Lp(a), we dissected the functional consequences of imipramine and citalopram stimulated uptake in liver cells. Both drugs increased Lp(a) delivery to Rab11-positive recycling endosomes, but not late endosomes or lysosomes, resulting in increased apo(a) recycling into the cellular media. Given that free apo(a) is reported to undergo consistent proteolysis in the extracellular space or in circulation, these results support the potential for the already approved drugs, imipramine and citalopram, as promising therapeutics to lower Lp(a) levels. This approach displays special utility in the large group of people who suffer from depression and anxiety for whom these drugs are commonly prescribed.SummaryElevated lipoprotein(a) (Lp(a)) levels are an important independent risk factor for developing cardiovascular disease (CVD). Efforts to effectively reduce Lp(a) levels in circulation have been hampered due to a limited understanding of its cellular metabolism. Our data shows that Lp(a) uptake is mediated by the fluid-phase endocytic process, macropinocytosis. Interestingly, commonly prescribed antidepressants can differentially modulate Lp(a) macropinocytosis in vitro, increasing Lp(a) uptake in liver cells while decreasing it in macrophages. Our finding that Lp(a) is internalised by macropinocytosis represents a major paradigm shift in Lp(a) biology, potentially reconciling the often contradictory and incongruous studies investigating receptor-mediated Lp(a) uptake.

Further characterization of the effect of the prototypical antidepressant imipramine on the microstructure of licking for sucrose

We previously reported that treatment with the prototypical antidepressant imipramine induced a dose-dependent reduction of the ingestion of a 10% sucrose solution, due to reduction of the licking burst number, thus suggesting reduced motivation and/or increased satiation. Importantly, the experimental sessions were performed in an alternate order, either 1-h or 24-h after imipramine administration. The observation that imipramine effect was more pronounced in the “1-h after-treatment” sessions, i.e. at the time of the brain drug Cmax, led us to suggest that it was likely related to brain drug levels at testing time. However, such an experimental design does not allow to rule out the alternative possibility that the observed effect might be due to post-session administration, as previously observed with memantine. To determine whether imipramine-induced decrease of sucrose ingestion could be observed even in absence of post-session administration, we examined the effect of a daily 22 day treatment with imipramine (5, 10 and 20 mg/kg). In the first half of the treatment period all behavioural tests were performed 1-h after administration. In the second half of the treatment period, tests were performed alternatively either 1-h or 24-h after imipramine administration. The results confirm that imipramine reduces sucrose ingestion due to a reduction of the licking burst number. Most importantly, these results demonstrate that this effect does not require imipramine post-session administration, since it was present before the beginning of post-session administrations. This supports the interpretation of the reduction of sucrose ingestion as a consequence of reduced motivation and/or increased satiation. Thus, these findings, taken together with the results of our previous study, might be relevant in explaining the effects of imipramine in models of drug-seeking and in body weight gain reduction in rats, but not in accounting for the antidepressant therapeutic effect. At variance with the results of our previous study, an increase in burst size was present in the first half of the treatment period, which might be interpreted as a prohedonic effect and/or as a compensatory effect.

Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress

Background Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman’s risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. Methods To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6 weeks, which promotes the development of depression-like symptoms. During the final 4 weeks of CUMS, rats were treated with either AC extract (1000 or 2000 mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10 mg/kg, IP). Results We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. Conclusion These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.

The effects of agomelatine and imipramine on liver cytochrome P450 during chronic mild stress (CMS) in the rat

Background The aim of our research was to determine the effects of chronic treatment with the atypical antidepressant agomelatine on the expression and activity of liver cytochrome P450 (CYP) in the chronic mild stress (CMS) model of depression, and to compare the results with those obtained for the first-generation antidepressant imipramine. Methods Male Wistar rats were subjected to CMS for 7 weeks. Imipramine (10 mg/kg ip/day) or agomelatine (40 mg/kg ip/day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3–7 of CMS). The levels of cytochrome P450 mRNA, protein and activity were measured in the liver. Results Agomelatine and imipramine produced different broad-spectrum effects on cytochrome P450. Like imipramine, agomelatine increased the expression/activity of CYP2B and CYP2C6, and decreased the CYP2D activity. Unlike imipramine, agomelatine raised the expression/activity of CYP1A, CYP2A and reduced that of CYP2C11 and CYP3A. CMS modified the effects of antidepressants at transcriptional/posttranscriptional level; however, the enzyme activity in stressed rats remained similar to that in nonstressed animals. CMS alone decreased the CYP2B1 mRNA level and increased that of CYP2C11. Conclusion We conclude the following: (1) the effects of agomelatine and imipramine on cytochrome P450 are different and involve both central and peripheral regulatory mechanisms, which implicates the possibility of drug–drug interactions; (2) CMS influences the effects of antidepressants on cytochrome P450 expression, but does not change appreciably their effects on the enzyme activity. This suggests that the rate of antidepressant drug metabolism under CMS is similar to that under normal conditions.

Antidepressant-like action of diacamphe against the background stress-induced behavioral depression

Background. It was find out the cerebroprotective properties of diacamphe – (±)-cis-3-(2’-benzimidazolyl)-1,2,2-trimethylcyclopentan-carbonic acid hydrochloride in vivo experiments in the some models of brain injury. Aim. To investigate the neuroprotective and antidepressant-like activities of diacamphe. Materials and Methods. It was investigated an impact of diacamphe on inhibition of the pyramidal neurons field synaptic potentials evoked by N-methyl-D-aspartate, procedure anoxia/neuroaglicemia, and H2O2 in the electrophysiological experiments on hippocampal slices for evaluating of diacamphe neuroprotective activity. It was explored in behavioral experiments the impacts of diacamphe and antidepressant imipramine on basic manifestations of behavioral depression evoked by five-days swimming stress – helplessness and anhedonia. Results. It was ascertained in experiments on the hippocampal slices that diacamphe especially at conditions of systemic administration diminished of injury of the pyramidal neurons synapses induced by procedure anoxya/aglicemia, oxidative stress, but not N-methyl-D-aspartate action. The chronic administration of diacamphe in dose 10 mg/kg reduced the manifestations of induced by swimming stress behavioral depression, decrease duration of immobility in forced swimming test (helplessness) and increase preference of intake of sweet solution comparably with water (dilution of anhedonia). Antidepressant-like action of diacamphe differences from action of traditional antidepressant imipramine so far as diacamphe did not diminishes immobilization duration in swimming test after single administration and by more slow developing of action. Conclusions. Diacamphe possesses neuroprotective action and therefore manifests antidepressant-like action against the background behavioral depression evoked by swimming stress.