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1.
Acta Pharmacol Sin ; 45(2): 327-338, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37845344

ABSTRACT

Tricyclic antidepressants (TCAs) are widely used to treat depression and anxiety-related mood disorders. But evidence shows that TCAs elevate blood glucose levels and inhibit insulin secretion, suggesting that TCAs are a risk factor, particularly for individuals with diabetes. Curcumin is a bioactive molecule from the rhizome of the Curcuma longa plant, which has shown both antidepressant and anti-diabetic activities. In the present study, we investigated the protective effect of curcumin against desipramine-induced apoptosis in ß cells and the underlying molecular mechanisms. In the mouse forced swimming test (FST), we found that lower doses of desipramine (5 and 10 mg/kg) or curcumin (2.5 mg/kg) alone did not affect the immobility time, whereas combined treatment with curcumin (2.5 mg/kg) and desipramine (5, 10 mg/kg) significantly decreased the immobility time. Furthermore, desipramine dose-dependently inhibited insulin secretion and elevated blood glucose levels, whereas the combined treatment normalized insulin secretion and blood glucose levels. In RIN-m5F pancreatic ß-cells, desipramine (10 µM) significantly reduced the cell viability, whereas desipramine combined with curcumin dose-dependently prevented the desipramine-induced impairment in glucose-induced insulin release, most effectively with curcumin (1 and 10 µM). We demonstrated that desipramine treatment promoted the cleavage and activation of Caspase 3 in RIN-m5F cells. Curcumin treatment inhibited desipramine-induced apoptosis, increased mitochondrial membrane potential and Bcl-2/Bax ratio. Desipramine increased the generation of reactive oxygen species, which was reversed by curcumin treatment. Curcumin also inhibited the translocation of forkhead box protein O1 (FOXO1) from the cytoplasm to the nucleus and suppressed the binding of A-kinase anchor protein 150 (AKAP150) to protein phosphatase 2B (PP2B, known as calcineurin) that was induced by desipramine. These results suggest that curcumin protects RIN-m5F pancreatic ß-cells against desipramine-induced apoptosis by inhibiting the phosphoinositide 3-kinase/AKT/FOXO1 pathway and the AKAP150/PKA/PP2B interaction. This study suggests that curcumin may have therapeutic potential as an adjunct to antidepressant treatment.


Subject(s)
Curcumin , Mice , Animals , Curcumin/pharmacology , Desipramine/pharmacology , Blood Glucose , Phosphatidylinositol 3-Kinases/metabolism , Apoptosis , Antidepressive Agents/pharmacology
2.
Ecotoxicol Environ Saf ; 270: 115849, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38134639

ABSTRACT

Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM2.5) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM2.5 exposure (PM) group, the concentrated PM2.5 treated with low-dose DES (DL) group, and the concentrated PM2.5 treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM2.5 for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM2.5 exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM2.5-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM2.5-induced IR.


Subject(s)
Air Pollutants , Insulin Resistance , Female , Animals , Mice , Particulate Matter/toxicity , Desipramine/pharmacology , Mice, Inbred C57BL , Liver , Air Pollutants/toxicity
3.
J Sep Sci ; 46(21): e2300323, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37691072

ABSTRACT

This study introduces a reliable and inexpensive magnetic dispersive solid phase extraction to extract imipramine and its primary metabolite (desipramine) from urine samples. To accomplish this aim, Fe3 O4 magnetic nanoparticles were synthesized by sonication, subsequently, polycarbonate was precipitated gradually onto the surface of them to form the adsorbent. Extraction recoveries of 85% and 76%, enrichment factors of 57 and 51, limits of detection of 2.5 and 2.8 µg/L, and limits of quantification of 8.3 and 9.3 µg/L were obtained for imipramine and desipramine under the optimal conditions, respectively. In addition, relative standard deviations for intra- (n = 6) and inter-day (n = 5) precisions at two concentrations (50 and 100 µg/L of each analyte) were less than or equal to 4%. Short extraction time, good repeatability, high enrichment factors, and simplicity are the main advantages of the proposed method.


Subject(s)
Imipramine , Magnetite Nanoparticles , Desipramine , Solid Phase Extraction , Chromatography, High Pressure Liquid , Magnetic Phenomena
4.
J Integr Neurosci ; 22(4): 80, 2023 Jun 27.
Article in English | MEDLINE | ID: mdl-37519173

ABSTRACT

BACKGROUND: Early life social experience and the function of the central serotonin (5-Hydroxytryptophan, 5-HT) system are involved in development of behavioral impulsivity in which individuals act without forethought or before all necessary information is available. However, most of the evidence has been obtained from acute 5-HT manipulation, whereas, the present study aimed to investigate the effects of subchronic regimen targeting of 5-HT1A receptors on motoric waiting impulsivity in socially isolated rats. METHODS: A two-week protocol of buspirone (0.5 mg/kg/day) and desipramine (2.5 mg/kg/day) was employed for rats following social isolation rearing (IR) to examine their behavioral performance in a 5-choice serial reaction time task (5-CSRTT) during the treatment regimen. Responses in any one of the apertures prior to an informative signal were recorded as a premature response. RESULTS: IR rats presented with more locomotor activity than socially reared (SR) rats. Buspirone progressively increased the baseline level of premature responding in a time-dependent manner that was not observed in IR rats. Both IR and SR rats exhibited less premature responding following acute buspirone challenge. For a subchronic desipramine regimen, IR rats followed the same trend of SR controls to increase the prematurity of baseline response. CONCLUSIONS: Buspirone but not desipramine-induced time-dependent effects of motoric waiting impulsivity can be reversed by IR, indicating a role for early life social experience on 5-HT1A receptor-associated ability to control impulsiveness.


Subject(s)
Buspirone , Serotonin , Rats , Animals , Reaction Time/physiology , Buspirone/pharmacology , Desipramine/pharmacology , Social Isolation , Impulsive Behavior
5.
Ecotoxicol Environ Saf ; 242: 113914, 2022 Sep 01.
Article in English | MEDLINE | ID: mdl-35878501

ABSTRACT

Silicosis is a systemic disease characterized by diffuse fibrosis of the lung tissue caused by long-term inhalation of large amounts of free silica (SiO2) dust. The pathogenesis of silicosis has not been fully elucidated, and there is a lack of effective treatment methods. N-acetylcysteine (NAC) can potentially treat pulmonary fibrosis by exerting antioxidant effects. Desipramine (DMI) can influence pulmonary fibrosis development by inhibiting acid sphingomyelinase (ASMase) activity and regulating ceramide concentrations. Both can interfere with pulmonary fibrosis through different mechanisms, but the intervention effects of NAC combined with DMI on silicosis fibrosis have not been reported. Therefore, this study established a rat silicosis model using a single tracheal drip of SiO2 dust suspension in Wistar rats to investigate the effect of NAC combined with DMI on SiO2 dust-induced silicosis and its related molecular mechanisms. The histopathological examination of the SiO2 dust-induced silicosis rats suggested that NAC and DMI alone or in combination could decrease the severity of pulmonary fibrosis in rats. The combined intervention had a better effect on reducing fibrosis than the individual interventions. NAC and DMI, alone or in combination, decreased the levels of markers related to pulmonary fibrosis in rats (smooth muscle α-actin (α-SMA), collagen (Col) I, Col III, hydroxyproline (HYP), inflammatory factors (transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α)), and lipid peroxidase malondialdehyde (MDA)). The nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1) and ASMase/ceramide pathways were inhibited to some extent by increasing the superoxide dismutase (SOD) levels of antioxidant enzymes and 8-iso-prostaglandin F2α (8-iso-PGF2α) levels of lipid peroxides. The combined intervention and NAC alone inhibited the SiO2 dust-induced elevation of matrix metalloproteinase 1 (MMP-1) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1), but the effect was not significant in the DMI-treated group. Combining DMI and NAC inhibited Col I deposition and reduced HO-1, TIMP-1, and ASMase levels in lung tissues compared to individual treatments. In summary, the SiO2 dust could induce oxidative stress and inflammation in rats, resulting in an imbalance in extracellular matrix (ECM) synthesis/catabolism and ASMase/ceramide signaling pathway activation, leading to silicosis development.The combined intervention of DMI and NAC may synergistically regulate the Nrf2/HO-1 pathway, maintain the anabolic balance of the ECM, inhibit ASMase/ceramide signaling pathway activation by suppressing the inflammatory response and effectively delay silicosis fibrosis progression.


Subject(s)
Acetylcysteine , Desipramine , Pulmonary Fibrosis , Silicosis , Acetylcysteine/metabolism , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Animals , Antioxidants/metabolism , Ceramides/metabolism , Desipramine/metabolism , Desipramine/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Dust , Fibrosis , Heme Oxygenase (Decyclizing) , Lung , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 1/toxicity , NF-E2-Related Factor 2 , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Rats , Rats, Wistar , Signal Transduction , Silicon Dioxide/toxicity , Silicosis/metabolism , Sphingomyelin Phosphodiesterase/metabolism , Sphingomyelin Phosphodiesterase/toxicity , Tissue Inhibitor of Metalloproteinase-1
6.
Int J Mol Sci ; 23(24)2022 Dec 19.
Article in English | MEDLINE | ID: mdl-36555818

ABSTRACT

The facilitated activity of N-methyl-D-aspartate receptors (NMDARs) in the central and peripheral nervous systems promotes neuropathic pain. Amitriptyline (ATL) and desipramine (DES) are tricyclic antidepressants (TCAs) whose anti-NMDAR properties contribute to their analgetic effects. At therapeutic concentrations <1 µM, these medicines inhibit NMDARs by enhancing their calcium-dependent desensitization (CDD). Li+, which suppresses the sodium−calcium exchanger (NCX) and enhances NMDAR CDD, also exhibits analgesia. Here, the effects of different [Li+]s on TCA inhibition of currents through native NMDARs in rat cortical neurons recorded by the patch-clamp technique were investigated. We demonstrated that the therapeutic [Li+]s of 0.5−1 mM cause an increase in ATL and DES IC50s of ~10 folds and ~4 folds, respectively, for the Ca2+-dependent NMDAR inhibition. The Ca2+-resistant component of NMDAR inhibition by TCAs, the open-channel block, was not affected by Li+. In agreement, clomipramine providing exclusively the NMDAR open-channel block is not sensitive to Li+. This Ca2+-dependent interplay between Li+, ATL, and DES could be determined by their competition for the same molecular target. Thus, submillimolar [Li+]s may weaken ATL and DES effects during combined therapy. The data suggest that Li+, ATL, and DES can enhance NMDAR CDD through NCX inhibition. This ability implies a drug−drug or ion−drug interaction when these medicines are used together therapeutically.


Subject(s)
Amitriptyline , Antidepressive Agents, Tricyclic , Rats , Animals , Antidepressive Agents, Tricyclic/pharmacology , Amitriptyline/pharmacology , Receptors, N-Methyl-D-Aspartate , Lithium/pharmacology , Calcium/metabolism , Desipramine/pharmacology , Calcium, Dietary
7.
J Neurosci Res ; 99(2): 662-678, 2021 02.
Article in English | MEDLINE | ID: mdl-32954528

ABSTRACT

The effect of stress on animal behavior and brain activity has been attracting growing attention in the last decades. Stress dramatically affects several aspects of animal behavior, including motivation and cognitive functioning, and has been used to model human pathologies such as post-traumatic stress disorder. A key question is whether stress alters the plastic potential of synaptic circuits. In this work, we evaluated if stress affects dopamine (DA)-dependent synaptic plasticity in the medial prefrontal cortex (mPFC). On male adolescent rats, we characterized anxiety- and depressive-like behaviors using behavioral testing before and after exposure to a mild stress (elevated platform, EP). After the behavioral protocols, we investigated DA-dependent long-term potentiation (DA-LTP) and depression (DA-LTD) on acute slices of mPFC and evaluated the activation of DA-producing brain regions by western and dot blot analysis. We show that exposure to the EP stress enhances DA-LTP and that desipramine (DMI) treatment abolishes this effect. We also found that DA-LTD is not affected by EP stress unless when this is followed by DMI treatment. In addition, EP stress reduces anxiety, an effect abolished by both DMI and ketamine, while motivation is promoted by previous exposure to EP stress independently of pharmacological treatments. Finally, this form of stress reduces the expression of the early gene cFOS in the ventral tegmental area. These findings support the idea that mild stressors can promote synaptic plasticity in PFC through a dopaminergic mechanism, an effect that might increase the sensitivity of mPFC to subsequent stressful experiences.


Subject(s)
Dopamine/physiology , Long-Term Potentiation , Prefrontal Cortex/physiopathology , Stress, Psychological/physiopathology , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Anxiety/etiology , Anxiety/physiopathology , Depression/drug therapy , Depression/etiology , Depression/physiopathology , Desipramine/pharmacology , Desipramine/therapeutic use , Elevated Plus Maze Test , Excitatory Postsynaptic Potentials/physiology , Gene Expression Regulation , Genes, fos , Ketamine/pharmacology , Male , Motivation , Open Field Test , Rats , Rats, Sprague-Dawley , Swimming , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiology
8.
Mikrochim Acta ; 188(3): 73, 2021 02 06.
Article in English | MEDLINE | ID: mdl-33550423

ABSTRACT

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.


Subject(s)
Antidepressive Agents, Tricyclic/isolation & purification , Microspheres , Nanocomposites/chemistry , Quantum Dots/chemistry , Solid Phase Extraction/methods , Adsorption , Antidepressive Agents, Tricyclic/blood , Antidepressive Agents, Tricyclic/chemistry , Antidepressive Agents, Tricyclic/urine , Citalopram/blood , Citalopram/chemistry , Citalopram/isolation & purification , Citalopram/urine , Desipramine/blood , Desipramine/chemistry , Desipramine/isolation & purification , Desipramine/urine , Gelatin/chemistry , Graphite/chemistry , Humans , Limit of Detection , Magnetic Phenomena , Magnetite Nanoparticles/chemistry , Sertraline/blood , Sertraline/chemistry , Sertraline/isolation & purification , Sertraline/urine
9.
Int J Mol Sci ; 22(9)2021 May 01.
Article in English | MEDLINE | ID: mdl-34062902

ABSTRACT

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1­adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1D­ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D­AR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.


Subject(s)
Antidepressive Agents/pharmacology , Depression/drug therapy , Receptors, Adrenergic, alpha-1/genetics , Animals , Antidepressive Agents/classification , Citalopram/pharmacology , Depression/etiology , Depression/genetics , Depression/pathology , Desipramine/pharmacology , Fluoxetine/pharmacology , Gene Expression Regulation/drug effects , Humans , Imipramine/pharmacology , Mianserin/pharmacology , Mice , PC12 Cells , Rats , Reboxetine/pharmacology , Signal Transduction/drug effects
10.
Mol Genet Metab ; 128(1-2): 75-83, 2019.
Article in English | MEDLINE | ID: mdl-31097363

ABSTRACT

The catabolism of ganglioside GM2 is dependent on the lysosomal enzyme ß-hexosaminidase A and a supporting lipid transfer protein, the GM2 activator protein. A genetically based disturbance of GM2 catabolism, leads to several subtypes of the GM2 gangliosidosis: Tay-Sachs disease, Sandhoff disease, the AB-variant and the B1-variant, all of them having GM2 as major lysosomal storage compound. Further on it is known that the gangliosides GM2 and GM3 accumulate as secondary storage compounds in mucopolysaccharidoses, especially in Hunter disease, Hurler disease, Sanfilippo disease and Sly syndrome, with chondroitin sulfate as primary storage compound. The exact mechanism of ganglioside accumulation in mucopolysaccaridoses is still a matter of debate. Here, we show that chondroitin sulfate strongly inhibits the catabolism of membrane-bound GM2 by ß-hexosaminidase A in presence of GM2 activator protein in vitro already at low micromolar concentrations. In contrast, hyaluronan, the major storage compound in mucopolysaccharidosis IX, a milder disease without secondary ganglioside accumulation, is a less effective inhibitor. On the other hand, hydrolysis of micellar-bound GM2 by ß-hexosaminidase A without the assistance of GM2AP was not impeded by chondroitin sulfate implicating that the inhibition of GM2 hydrolysis by chondroitin sulfate is most likely based on an interaction with GM2AP, the GM2AP-GM2 complex or the GM2-carrying membranes. We also studied the influence of some cationic amphiphilic drugs (desipramine, chlorpromazine, imipramine and chloroquine), provoking drug induced phospholipidosis and found that all of them inhibited the hydrolysis of GM2 massively.


Subject(s)
G(M2) Ganglioside/antagonists & inhibitors , G(M2) Ganglioside/metabolism , Mucopolysaccharidoses/physiopathology , Surface-Active Agents/pharmacology , Cations/chemistry , Chondroitin Sulfates/pharmacology , Glycosaminoglycans/pharmacology , Humans , Hydrolysis/drug effects
11.
J Neural Transm (Vienna) ; 125(12): 1837-1845, 2018 12.
Article in English | MEDLINE | ID: mdl-30191367

ABSTRACT

In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.


Subject(s)
Desipramine/pharmacology , Fluoxetine/pharmacology , Imipramine/pharmacology , Lysosomes/drug effects , Phospholipids/metabolism , Sphingomyelin Phosphodiesterase/metabolism , Antidepressive Agents/pharmacology , Cell Line, Tumor , Humans , Lysosomes/metabolism
12.
Cell Biol Int ; 42(2): 248-253, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29068103

ABSTRACT

Desipramine, a commonly used antidepressant drug, induced cytosolic vacuolization in L929 cells. The level of LC3-II was elevated and that of p62 was reduced in desipramine-treated L929 cells, indicating the induction of autophagy by desipramine. Surprisingly, massive vacuolization was observed in desipramine-treated L929 cells in the presence of LY294002, an inhibitor of autophagy. On the other hand, bafilomycin A1, an inhibitor of vacuolar type H+ ATPase, almost completely inhibited vacuolization in desipramine- or desipramine/LY294002-treated L929 cells. Furthermore, desipramine-induced vacuolization was observed in autophagy-deficient Atg7-/- mouse embryonic fibroblasts (MEFs) as well as wild-type Atg7+/+ MEFs. These results demonstrate that desipramine-induced lysosomal vacuolization is independent of autophagy.


Subject(s)
Antidepressive Agents, Tricyclic/pharmacology , Desipramine/pharmacology , Lysosomes/drug effects , Vacuoles/drug effects , Animals , Autophagy , Autophagy-Related Protein 7/genetics , Cell Line, Tumor , Cells, Cultured , Macrolides/pharmacology , Mice
13.
Proc Natl Acad Sci U S A ; 112(36): E5088-97, 2015 Sep 08.
Article in English | MEDLINE | ID: mdl-26305935

ABSTRACT

The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and ßγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.


Subject(s)
Antidepressive Agents/pharmacology , Corpus Striatum/metabolism , Neuralgia/prevention & control , RGS Proteins/metabolism , Adaptation, Physiological/drug effects , Adaptation, Physiological/genetics , Animals , Blotting, Western , Corpus Striatum/physiopathology , Female , Gene Expression/drug effects , Gene Ontology , Gene Regulatory Networks/drug effects , Hyperalgesia/physiopathology , Hyperalgesia/prevention & control , Male , Mice, Inbred C57BL , Mice, Knockout , Neuralgia/genetics , Neuralgia/physiopathology , Nucleus Accumbens/metabolism , Nucleus Accumbens/physiopathology , RGS Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
14.
Brain Behav Immun ; 62: 219-229, 2017 May.
Article in English | MEDLINE | ID: mdl-28212884

ABSTRACT

Abundant evidence connects depression symptomology with immune system activation, stress and subsequently elevated levels of kynurenine. Anti-depressants, such as the tricyclic norepinephrine/serotonin reuptake inhibitor desipramine (Desip), were developed under the premise that increasing extracellular neurotransmitter level was the sole mechanism by which they alleviate depressive symptomologies. However, evidence suggests that anti-depressants have additional actions that contribute to their therapeutic potential. The Kynurenine Pathway produces tryptophan metabolites that modulate neurotransmitter activity. This recognition identified another putative pathway for anti-depressant targeting. Considering a recognized role of the Kynurenine Pathway in depression, we investigated the potential for Desip to alter expression of rate-limiting enzymes of this pathway: indoleamine-2,3-dioxygenases (Ido1 and Ido2). Mice were administered lipopolysaccharide (LPS) or synthetic glucocorticoid dexamethasone (Dex) with Desip to determine if Desip alters indoleamine-dioxygenase (DO) expression in vivo following a modeled immune and stress response. This work was followed by treating murine and human peripheral blood mononuclear cells (PBMCs) with interferon-gamma (IFNγ) and Desip. In vivo: Desip blocked LPS-induced Ido1 expression in hippocampi, astrocytes, microglia and PBMCs and Ido2 expression by PBMCs. Ex vivo: Desip decreased IFNγ-induced Ido1 and Ido2 expression in murine PBMCs. This effect was directly translatable to the human system as Desip decreased IDO1 and IDO2 expression by human PBMCs. These data demonstrate for the first time that an anti-depressant alters expression of Ido1 and Ido2, identifying a possible new mechanism behind anti-depressant activity. Furthermore, we propose the assessment of PBMCs for anti-depressant responsiveness using IDO expression as a biomarker.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Desipramine/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Animals , Female , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Interferon-gamma/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Male , Mice , Young Adult
15.
Pharmacol Res ; 118: 93-103, 2017 04.
Article in English | MEDLINE | ID: mdl-27663259

ABSTRACT

Antidepressants are one of the first line treatments for neuropathic pain but their use is limited by the incidence and severity of side effects of tricyclics and the weak effectiveness of selective serotonin reuptake inhibitors (SSRIs). Serotonin type 2A (5-HT2A) receptors interact with PDZ proteins that regulate their functionality and SSRI efficacy to alleviate pain. We investigated whether an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and associated PDZ proteins would improve the treatment of traumatic neuropathic allodynia. Tactile allodynia was assessed in spinal nerve ligation-induced neuropathic pain in rats using von Frey filaments after acute treatment with TAT-2ASCV and/or 5-HT2A receptor agonist, alone or in combination with repeated treatment with fluoxetine. In vivo microdialysis was performed in order to examine the involvement of GABA in TAT-2ASCV/fluoxetine treatment-associated analgesia. TAT-2ASCV (100ng, single i.t. injection) improved SNL-induced tactile allodynia by increasing 5-HT2A receptor responsiveness to endogenous 5-HT. Fluoxetine alone (10mg/kg, five i.p. injections) slightly increased tactile thresholds and its co-administration with TAT-2ASCV (100ng, single i.t. injection) further enhanced the anti-allodynic effect. This effect depends on the integrity of descending serotonergic bulbospinal pathways and spinal release of GABA. The anti-allodynic effect of fluoxetine can be enhanced by disrupting 5-HT2A receptor-PDZ protein interactions. This enhancement depends on 5-HT2A receptor activation, spinal GABA release and GABAA receptor activation.


Subject(s)
Fluoxetine/therapeutic use , Hyperalgesia/drug therapy , Neuralgia/drug therapy , Receptor, Serotonin, 5-HT2A/physiology , gamma-Aminobutyric Acid/metabolism , Animals , Drug Synergism , Male , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/physiology , Spinal Cord/physiology
16.
Pharmacol Res ; 117: 177-184, 2017 03.
Article in English | MEDLINE | ID: mdl-28025106

ABSTRACT

Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.


Subject(s)
Homeostasis/drug effects , Lysosomes/drug effects , Pharmaceutical Preparations/administration & dosage , Animals , Cholesterol/metabolism , Humans , Lysosomes/metabolism , Neoplasms/metabolism
17.
J Dual Diagn ; 13(3): 230-235, 2017.
Article in English | MEDLINE | ID: mdl-28481169

ABSTRACT

OBJECTIVE: The aim of the study was to compare the rate of sexual side effects of the selective serotonin reuptake inhibitor paroxetine versus the tricyclic antidepressant desipramine and to examine the effect of co-prescription of naltrexone on sexual side effects among participants in a randomized clinical trial. METHODS: This was a secondary analysis (N = 88) of veterans who participated in a 12-week trial. All veterans were randomized into one of four treatment groups: (a) desipramine/naltrexone, (b) desipramine/placebo, (c) paroxetine/naltrexone, and (d) paroxetine/placebo. The main outcome measure was the frequency of sexual side effects consisting of "decreased sex drive" and/or "impotence" reported by veterans at each weekly visit. RESULTS: Approximately 61% of the veterans reported sexual side effects at least once during the trial, and 26.4% reported sexual side effects throughout the study. There were no significant differences in the frequency of sexual side effects among the four treatment groups. The results were similar when the comparison was made between the two antidepressant groups. There were no significant differences in the reporting of sexual side effects between those receiving desipramine and paroxetine. Also, the comparison between naltrexone and placebo did not alter the results. CONCLUSIONS: This is the first study to compare frequency of sexual side effect reporting between paroxetine and desipramine. We found no statistically significant differences in sexual side effect reporting between the two antidepressants. Also, the addition of naltrexone did not show any beneficial effect on the sexual side effect profile.


Subject(s)
Antidepressive Agents/adverse effects , Desipramine/adverse effects , Erectile Dysfunction/chemically induced , Naltrexone/adverse effects , Paroxetine/adverse effects , Sexual Behavior/drug effects , Alcoholism/complications , Alcoholism/drug therapy , Antidepressive Agents/therapeutic use , Comorbidity , Desipramine/therapeutic use , Female , Humans , Male , Middle Aged , Naltrexone/therapeutic use , Paroxetine/therapeutic use , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/drug therapy , Treatment Outcome , United States , United States Department of Veterans Affairs , Veterans
18.
Int J Mol Sci ; 18(4)2017 Apr 15.
Article in English | MEDLINE | ID: mdl-28420138

ABSTRACT

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid sphingomyelinase (SMPD1)-the principal regulator for rapid and transient generation of the lipid mediator ceramide-is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1-/- animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1-/- littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.


Subject(s)
Ceramides/metabolism , Heart Diseases/etiology , Heart Diseases/physiopathology , Lipid Metabolism , Sepsis/complications , Sepsis/metabolism , Animals , Biomarkers , Cardiac Output/drug effects , Desipramine/metabolism , Desipramine/pharmacology , Disease Models, Animal , Female , Gene Expression Profiling , Gene Expression Regulation , Heart Diseases/drug therapy , Heart Diseases/metabolism , L-Lactate Dehydrogenase/metabolism , Male , Mice , Mice, Knockout , Mice, Transgenic , Myocardium/metabolism , Oxidative Stress/drug effects , Sepsis/genetics , Sepsis/microbiology , Sphingomyelin Phosphodiesterase/genetics , Sphingomyelin Phosphodiesterase/metabolism , Troponin I/metabolism
19.
Cytokine ; 80: 26-34, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26937856

ABSTRACT

Nowadays, it is assumed that therapeutic efficacy of antidepressants depends, at least partly, on their anti-inflammatory properties. The present study investigated for the first time the effect of 21-day oral administration of desipramine on the lipopolysaccharide (LPS)-stimulated IL-1ß concentration in the olfactory bulb, hypothalamus, frontal cortex, hippocampus and plasma of rats, and on the LPS-induced IL-1ß mRNA level in the olfactory bulb. Desipramine (15mg/kg/day) reduced significantly the LPS (250 µg/kg i.p.)-induced IL-1ß concentration in the olfactory bulb, hypothalamus and in plasma, and diminished the LPS effect on IL-1ß mRNA in the olfactory bulb. Plasma concentration of desipramine was comparable to its therapeutic range. By using the α1/α2-adrenoceptor antagonist prazosin and the unspecific ß-adrenoceptor antagonist propranolol given prior to LPS, we found that the effect of desipramine on LPS-induced IL-1ß production was partially mediated by both adrenoceptors in the olfactory bulb and plasma, and that ß-adrenoceptors contributed also to its effect on the stimulated IL-1ß concentration in the hypothalamus. The effect of LPS on the cerebral IL-1ß levels was, in part, mediated by ß-adrenoceptors and, in a region-specific manner, by α1/α2-adrenoceptors. The findings provide evidence for central and peripheral anti-inflammatory activity of desipramine and confirm the impact of the noradrenergic system on IL-1ß production induced by an immunostimulatory challenge.


Subject(s)
Antidepressive Agents, Tricyclic/administration & dosage , Brain/drug effects , Desipramine/administration & dosage , Interleukin-1beta/blood , Interleukin-1beta/metabolism , Lipopolysaccharides/immunology , Administration, Oral , Animals , Antidepressive Agents, Tricyclic/blood , Antihypertensive Agents/administration & dosage , Brain/immunology , Brain/metabolism , Desipramine/blood , Drug Administration Schedule , Hypothalamus/drug effects , Hypothalamus/metabolism , Interleukin-1beta/biosynthesis , Interleukin-1beta/genetics , Olfactory Bulb/drug effects , Olfactory Bulb/metabolism , Prazosin/administration & dosage , Propranolol/administration & dosage , Rats
20.
Proc Natl Acad Sci U S A ; 110(20): 8254-9, 2013 May 14.
Article in English | MEDLINE | ID: mdl-23630294

ABSTRACT

Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.


Subject(s)
Antidepressive Agents/pharmacology , Depression/drug therapy , GTP-Binding Proteins/metabolism , Gene Expression Regulation , Neuralgia/drug therapy , RGS Proteins/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Behavior, Animal , Brain/pathology , Desipramine/pharmacology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mood Disorders/drug therapy , Signal Transduction/drug effects , Young Adult
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