-
Psychopharmacology Nov 2022The pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson's disease...
Behavioral and neurochemical interactions of the tricyclic antidepressant drug desipramine with L-DOPA in 6-OHDA-lesioned rats. Implications for motor and psychiatric functions in Parkinson's disease.
RATIONALE
The pharmacological effects of antidepressants in modulating noradrenergic transmission as compared to serotonergic transmission in a rat model of Parkinson's disease under chronic L-DOPA therapy are insufficiently explored.
OBJECTIVES
The aim of the present study was to investigate the effect of the tricyclic antidepressant desipramine administered chronically alone or jointly with L-DOPA, on motor behavior and monoamine metabolism in selected brain structures of rats with the unilateral 6-OHDA lesion.
METHODS
The antiparkinsonian activities of L-DOPA and desipramine were assessed behaviorally using a rotation test and biochemically based on changes in the tissue concentrations of noradrenaline, dopamine and serotonin and their metabolites, evaluated separately for the ipsi- and contralateral motor (striatum, substantia nigra) and limbic (prefrontal cortex, hippocampus) structures of rat brain by HPLC method.
RESULTS
Desipramine administered alone did not induce rotational behavior, but in combination with L-DOPA, it increased the number of contralateral rotations more strongly than L-DOPA alone. Both L-DOPA and desipramine + L-DOPA significantly increased DA levels in the ipsilateral striatum, substantia nigra, prefrontal cortex and the ipsi- and contralateral hippocampus. The combined treatment also significantly increased noradrenaline content in the ipsi- and contralateral striatum, while L-DOPA alone decreased serotonin level on both sides of the hippocampus.
CONCLUSIONS
The performed analysis of the level of monoamines and their metabolites in the selected brain structures suggests that co-modulation of noradrenergic and dopaminergic transmission in Parkinson's disease by the combined therapy with desipramine + L-DOPA may have some positive implications for motor and psychiatric functions but further research is needed to exclude potential negative effects.
Topics: Animals; Rats; Levodopa; Oxidopamine; Antidepressive Agents, Tricyclic; Parkinson Disease; Desipramine; Dopamine; Serotonin; Antipruritics; Platelet Aggregation Inhibitors; Antiparkinson Agents; Corpus Striatum; Norepinephrine
PubMed: 36178508
DOI: 10.1007/s00213-022-06238-x -
The Medical Letter on Drugs and... Feb 2020
Topics: Antidepressive Agents; Depressive Disorder, Major; Drug Interactions; Humans
PubMed: 32320387
DOI: No ID Found -
Angewandte Chemie (International Ed. in... Oct 2019Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally... (Review)
Review
Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy-amino-λ -sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.
Topics: Alcohols; Amines; Molecular Structure; Nitriles; Sulfamerazine; Sulfonamides
PubMed: 31390133
DOI: 10.1002/anie.201906001 -
Cell Cycle (Georgetown, Tex.) Sep 2023Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER)...
Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.
Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET. To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms. Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH] from high performance liquid chromatography. Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC. Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.
Topics: Humans; Nitric Oxide Donors; Nitroprusside; Eryptosis; Calcium; Acetylcysteine; Desipramine; Erythrocytes; Glutathione; Annexins; Phosphatidylserines; Cell Size; Ceramides; Reactive Oxygen Species; Oxidative Stress
PubMed: 37522842
DOI: 10.1080/15384101.2023.2234177 -
Biomolecules Jan 2020The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a...
The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structure of a NET constructed by homology modeling on dopamine transporter templates. We further examined molecular construction of primary binding pocket (S1) together with secondary binding site (S2) and extracellular loop 4 (EL4). The next stage involved docking of transporter inhibitors: Reboxetine, duloxetine, desipramine, and other commonly used drugs. The procedure revealed the molecular orientation of residues and disclosed ones that are the most important for ligand binding: Phenylalanine F72, aspartic acid D75, tyrosine Y152, and phenylalanine F317. Aspartic acid D75 plays a key role in recognition of the basic amino group present in monoamine transporter inhibitors and substrates. The study also presents a comparison of hNET models with other related proteins, which could provide new insights into their interaction with therapeutics and aid future development of novel bioactive compounds.
Topics: Animals; Binding Sites; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila Proteins; Drosophila melanogaster; Humans; Molecular Dynamics Simulation; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Protein Binding
PubMed: 31936154
DOI: 10.3390/biom10010102 -
Frontiers in Neurology 2021Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus... (Review)
Review
Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of progressive neurodegenerative diseases characterized by iron deposition in the globus pallidus and the substantia nigra. As of today, 15 distinct monogenetic disease entities have been identified. The four most common forms are pantothenate kinase-associated neurodegeneration (PKAN), phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN), beta-propeller protein-associated neurodegeneration (BPAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN). Neurodegeneration with Brain Iron Accumulation disorders present with a wide spectrum of clinical symptoms such as movement disorder signs (dystonia, parkinsonism, chorea), pyramidal involvement (e.g., spasticity), speech disorders, cognitive decline, psychomotor retardation, and ocular abnormalities. Treatment remains largely symptomatic but new drugs are in the pipeline. In this review, we discuss the rationale of new compounds, summarize results from clinical trials, provide an overview of important results in cell lines and animal models and discuss the future development of disease-modifying therapies for NBIA disorders. A general mechanistic approach for treatment of NBIA disorders is with iron chelators which bind and remove iron. Few studies investigated the effect of deferiprone in PKAN, including a recent placebo-controlled double-blind multicenter trial, demonstrating radiological improvement with reduction of iron load in the basal ganglia and a trend to slowing of disease progression. Disease-modifying strategies address the specific metabolic pathways of the affected enzyme. Such tailor-made approaches include provision of an alternative substrate (e.g., fosmetpantotenate or 4'-phosphopantetheine for PKAN) in order to bypass the defective enzyme. A recent randomized controlled trial of fosmetpantotenate, however, did not show any significant benefit of the drug as compared to placebo, leading to early termination of the trials' extension phase. 4'-phosphopantetheine showed promising results in animal models and a clinical study in patients is currently underway. Another approach is the activation of other enzyme isoforms using small molecules (e.g., PZ-2891 in PKAN). There are also compounds which counteract downstream cellular effects. For example, deuterated polyunsaturated fatty acids (D-PUFA) may reduce mitochondrial lipid peroxidation in PLAN. In infantile neuroaxonal dystrophy (a subtype of PLAN), desipramine may be repurposed as it blocks ceramide accumulation. Gene replacement therapy is still in a preclinical stage.
PubMed: 33935938
DOI: 10.3389/fneur.2021.629414 -
Frontiers in Immunology 2023Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such...
Due to the high prevalence of depression among cancer patients, antidepressant medications are frequently administered as adjuvant treatment. However, the safety of such medications in the development of metastasis is unclear. In this study, we investigated the effects of fluoxetine, desipramine, and mirtazapine on the liver metastasis of murine C26 colon carcinoma (cc). Balb/c male mice were administered these antidepressants intraperitoneally (i.p.) for 14 days following intrasplenic injections of C26 colon carcinoma cells. Desipramine and fluoxetine, but not mirtazapine, significantly increased the number of tumor foci and total volume of the tumor in liver tissue. This effect was associated with a decrease in the ability of splenocytes to produce interleukin (IL)-1β and interferon (IFN)-γ and an increase in their ability to produce interleukin (IL)-10. Similar changes were observed in plasma IL-1β, IFN-γ, and IL-10 levels. The current study demonstrates that the stimulatory effect of desipramine and fluoxetine, but not mirtazapine, on experimental colon cancer liver metastasis is associated with a suppression of immune defenses against the tumor.
Topics: Male; Mice; Animals; Fluoxetine; Mirtazapine; Desipramine; Cytokines; Antidepressive Agents; Liver Neoplasms; Carcinoma; Colonic Neoplasms
PubMed: 37409130
DOI: 10.3389/fimmu.2023.1160977 -
BMC Pharmacology & Toxicology Dec 2023The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The main purpose was to evaluate the efficacy and tolerability of different medications used to treat bulimia nervosa (BN).
METHODS
Randomized controlled trials (RCTs) were identified from published sources through searches in PubMed, Cochrane Library, Web of Science, and Embase from inception to November 2022. Primary outcomes were changes in the frequency of binge eating episodes and vomiting episodes from baseline to endpoint. Secondary outcomes were differences in the improvement of scores in depressive symptoms, tolerability (dropout due to adverse events) and weight change.
RESULTS
The literature search ultimately included 11 drugs, 33 studies and 6 types of drugs, 8 trials with TCAs (imipramine, desipramine), 14 with SSRIs (fluoxetine, citalopram and fluvoxamine), 6 with MAOIs (phenelzine, moclobemide and brofaromine), 3 with antiepileptic drugs (topiramate), 1 with mood stabilizers (lithium), and 1 with amphetamine-type appetite suppressant (fenfluramine). The reduction in binge eating episodes was more likely due to these drugs than the placebo, and the SMD was -0.4 (95% CI -0.61 ~ -0.19); the changes in the frequency of vomiting episodes (SMD = -0.16, 95% CI -0.3 ~ -0.03); weight (WMD = -3.05, 95% CI -5.97 ~ -0.13); and depressive symptoms (SMD = -0.32, 95% CI -0.51 ~ -0.13). However, no significant difference was found in dropout due to adverse events (RR = 1.66, 95% CI 1.14 ~ 2.41).
CONCLUSIONS
This meta-analysis indicates that most pharmacotherapies decreased the frequency of binge-eating and vomiting episodes, body weight, and depressive symptoms in BN patients, but the efficacy was not significant. In each drug the efficacy is different, treating different aspects, different symptoms to improve the clinical performance of bulimia nervosa.
Topics: Humans; Bulimia Nervosa; Bulimia; Fluoxetine; Selective Serotonin Reuptake Inhibitors; Vomiting
PubMed: 38042827
DOI: 10.1186/s40360-023-00713-7 -
Journal of Lipid Research 2021Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to... (Review)
Review
Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) has emerged as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.
Topics: Sphingolipids
PubMed: 32948663
DOI: 10.1194/jlr.TR120000972 -
Acta Pharmacologica Sinica Feb 2024Tricyclic antidepressants (TCAs) are widely used to treat depression and anxiety-related mood disorders. But evidence shows that TCAs elevate blood glucose levels and...
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 β 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 β-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 β-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.
Topics: Mice; Animals; Curcumin; Desipramine; Blood Glucose; Phosphatidylinositol 3-Kinases; Apoptosis; Antidepressive Agents
PubMed: 37845344
DOI: 10.1038/s41401-023-01176-6