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Neuropsychopharmacology : Official... Oct 2023Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and...
Tricyclic antidepressants (TCAs), such as desipramine (DMI), are effective at managing neuropathic pain symptoms but often take several weeks to become effective and also lead to considerable side effects. Tianeptine (TIAN) is an atypical antidepressant that activates the mu-opioid receptor but does not produce analgesic tolerance or withdrawal in mice, nor euphoria in humans, at clinically-relevant doses. Here, we evaluate the efficacy of TIAN at persistently alleviating mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain, even well after drug clearance. After finding an accelerated onset of antiallodynic action compared to DMI, we used genetically modified mice to gain insight into RGS protein-associated pathways that modulate the efficacy of TIAN relative to DMI in models of neuropathic pain. Because we observed similar behavioral responses to both TIAN and DMI treatment in RGS4, RGSz1, and RGS9 knockout mice, we performed RNA sequencing on the NAc of TIAN- and DMI-treated mice after prolonged SNI to further clarify potential mechanisms underlying TIANs faster therapeutic actions. Our bioinformatic analysis revealed distinct transcriptomic signatures between the two drugs, with TIAN more directly reversing SNI-induced differentially expressed genes, and further predicted several upstream regulators that may be implicated in onset of action. This new understanding of the molecular pathways underlying TIAN action may enable the development of novel and more efficacious pharmacological approaches for the management of neuropathic pain.
Topics: Humans; Mice; Animals; Neuralgia; Antidepressive Agents; Hyperalgesia; Antidepressive Agents, Tricyclic; Disease Models, Animal
PubMed: 37474762
DOI: 10.1038/s41386-023-01645-w -
Journal of Separation Science Nov 2023This study introduces a reliable and inexpensive magnetic dispersive solid phase extraction to extract imipramine and its primary metabolite (desipramine) from urine...
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, Fe O 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.
Topics: Imipramine; Desipramine; Magnetite Nanoparticles; Solid Phase Extraction; Chromatography, High Pressure Liquid; Magnetic Phenomena
PubMed: 37691072
DOI: 10.1002/jssc.202300323 -
Sleep Medicine Mar 2024The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear...
The hippocampus (HPC) plays a pivotal role in fear learning and memory. Our two recent studies suggest that rapid eye movement (REM) sleep via the HPC downregulates fear memory consolidation and promotes fear extinction. However, it is not clear whether and how the dorsal and the ventral HPC regulates fear memory differently; and how the HPC in wake regulates fear memory. By chemogenetic stimulating in the HPC directly and its afferent entorhinal cortex that selectively activated the HPC in REM sleep for 3-6 h post-fear-acquisition, we found that HPC activation in REM sleep consolidated fear extinction memory. In particular, dorsal HPC (dHPC) stimulation in REM sleep virtually eliminated fear memory by enhancing fear extinction and reducing fear memory consolidation. By contrast, chemogenetic stimulating HPC afferent the supramammillary nucleus (SUM) induced 3-hr wake with HPC activation impaired fear extinction. Finally, desipramine (DMI) injection that selectively eliminated REM sleep for >6 h impaired fear extinction. Our results demonstrate that the HPC is critical for fear memory regulation; and wake HPC and REM sleep HPC have an opposite role in fear extinction of respective impairment and consolidation.
Topics: Humans; Fear; Extinction, Psychological; Sleep; Learning; Hippocampus; Memory Consolidation
PubMed: 38367358
DOI: 10.1016/j.sleep.2024.02.022 -
Colloids and Surfaces. B, Biointerfaces Feb 2024The antidepressant drug imipramine, and its metabolite desipramine show different extents of interaction with, and passive permeation through, cellular membrane models,...
HYPOTHESIS
The antidepressant drug imipramine, and its metabolite desipramine show different extents of interaction with, and passive permeation through, cellular membrane models, with the effects depending on the membrane composition. Through multimodal interrogation, we can observe that the drugs have a direct impact on the physicochemical properties of the membrane, that may play a role in their pharmacokinetics.
EXPERIMENTS
Microcavity pore-suspended lipid bilayers (MSLBs) of four different compositions, each with a different headgroup charge namely; zwitterionic dioleoylphosphatidylcholine (DOPC), mixed DOPC and negatively charged dioleoylphosphatidylglycerol (DOPG) (3:1), mixed DOPC and positively charged dioleoyltrimethylammoniumpropane (DOTAP) (3:1), and with increasing complex composition mimicking blood-brain-barrier (BBB) were prepared on gold and polydimethylsiloxane (PDMS) substrates using a Langmuir-Blodgett-vesicle fusion method. The molecular interaction and permeation of antidepressants, imipramine, and its metabolite desipramine with the lipid bilayers were evaluated using highly sensitive label-free electrochemical impedance spectroscopy (EIS) and surface-enhanced Raman spectroscopy (SERS). Drug-induced membrane packing/fluidity alterations were assessed using fluorescence lifetime imaging (FLIM) and fluorescence lifetime correlation spectroscopy (FLCS) of MSLB over microfluidic PDMS array.
FINDINGS
Using EIS to evaluate in real-time membrane admittance changes, we found that imipramine greatly increases the ion permeability of negatively charged DOPC:DOPG (3:1) membranes. The effect was observed also at neutral (DOPC) and to a lesser extent at positively charged DOPC:DOTAP(3:1) membranes. In contrast, desipramine had a much weaker impact on ion permeability across all bilayer compositions. Temporal capacitance data show that desipramine intercalates at negatively charged membrane thereby increasing the thickness of the membrane. The overall kinetics of the imipramine permeation is higher than that of desipramine. This was confirmed using SERS, which also provides an evaluation of drug passive permeation based on arrival time across the membrane. Using FLCS, we found that imipramine increases the lipid membrane fluidity, whereas desipramine lowers it, with the exception of the negatively charged membrane. A translocation rate pharmacokinetics model was established for the first time at the MSLB platform by real-time monitoring of the variation in membrane resistance of pristine DOPC and blood-brain-barrier (BBB) membrane.
Topics: Lipid Bilayers; Imipramine; Desipramine; Phosphatidylcholines; Antidepressive Agents; Permeability; Quaternary Ammonium Compounds; Fatty Acids, Monounsaturated
PubMed: 38128360
DOI: 10.1016/j.colsurfb.2023.113688 -
Chemical Biology & Drug Design Oct 2023A series of benzylaminoimidazoline derivatives was synthesized and evaluated for norepinephrine transporter (NET) targeting. Among them,...
A series of benzylaminoimidazoline derivatives was synthesized and evaluated for norepinephrine transporter (NET) targeting. Among them, N-(3-iodobenzyl)-4,5-dihydro-1H-imidazol-2-amine (Compound 9) displayed the highest affinity for NET (IC = 5.65 ± 0.97 μM). The corresponding radiotracer [ I]9 was further prepared by copper-mediated radioiodination and evaluated both in vitro and in vivo. The cellular uptake results suggested that [ I]9 was specifically taken up by the NET-expressing SK-N-SH cell line. Biodistribution studies showed that [ I]9 accumulated in the heart (5.54 ± 1.24 %ID/g at 5 min p.i. and 0.79 ± 0.08 %ID/g at 2 h p.i.) and adrenal gland (14.83 ± 3.47 %ID/g at 5 min p.i. and 3.87 ± 0.24 %ID/g at 2 h p.i.). The uptake in the heart and adrenal gland could be significantly inhibited by preinjection of desipramine (DMI). These results indicated that the benzylaminoimidazoline derivatives retained affinity for NET, which could provide structure-activity relationship data for further studies.
Topics: Iodine Radioisotopes; Ligands; Norepinephrine Plasma Membrane Transport Proteins; Tissue Distribution; Benzyl Compounds; Imidazoles
PubMed: 37328929
DOI: 10.1111/cbdd.14282 -
Analytical Chemistry Dec 2023Imipramine class tricyclic antidepressants have low ionization efficiencies that make them difficult to detect by using secondary ion mass spectrometry. Ultraviolet...
Imipramine class tricyclic antidepressants have low ionization efficiencies that make them difficult to detect by using secondary ion mass spectrometry. Ultraviolet picosecond laser desorption postionization (ps-LDPI-MS) is examined here for the detection of four tricyclic antidepressants: imipramine, desipramine, amitriptyline, and clomipramine. About 30 ps laser pulses at either 213 nm (5.8 eV) or 355 nm (3.5 eV) are used for desorption of samples under vacuum, 7.9 eV (157 nm) fluorine laser pulses are used for post-ionization, and the ions so formed are detected by time-of-flight mass spectrometry. Detection of imipramine by 213 nm ps-LDPI-MS shows less fragmentation than either 355 nm ps-LDPI-MS or prior results from 800 nm fs-LDPI-MS. Ionization energies of imipramine, desipramine, amitriptyline, and clomipramine are predicted using density functional theory calculations and used to explain the corresponding ps-LDPI-MS data for these four compounds as resulting from single-photon ionization. The experimental observation of low-mass amine-containing fragments with calculated ionization energies below 7.9 eV is attributed mostly to dissociation during laser desorption, followed by single-photon ionization of the neutral fragments rather than the more traditional mechanism of unimolecular dissociation following single-photon ionization of the parent molecule.
PubMed: 37983268
DOI: 10.1021/acs.analchem.3c02735 -
The AAPS Journal May 2024Stepwise covariate modeling (SCM) has a high computational burden and can select the wrong covariates. Machine learning (ML) has been proposed as a screening tool to...
Stepwise covariate modeling (SCM) has a high computational burden and can select the wrong covariates. Machine learning (ML) has been proposed as a screening tool to improve the efficiency of covariate selection, but little is known about how to apply ML on actual clinical data. First, we simulated datasets based on clinical data to compare the performance of various ML and traditional pharmacometrics (PMX) techniques with and without accounting for highly-correlated covariates. This simulation step identified the ML algorithm and the number of top covariates to select when using the actual clinical data. A previously developed desipramine population-pharmacokinetic model was used to simulate virtual subjects. Fifteen covariates were considered with four having an effect included. Based on the F1 score (an accuracy measure), ridge regression was the most accurate ML technique on 200 simulated datasets (F1 score = 0.475 ± 0.231), a performance which almost doubled when highly-correlated covariates were accounted for (F1 score = 0.860 ± 0.158). These performances were better than forwards selection with SCM (F1 score = 0.251 ± 0.274 and 0.499 ± 0.381 without/with correlations respectively). In terms of computational cost, ridge regression (0.42 ± 0.07 seconds/simulated dataset, 1 thread) was ~20,000 times faster than SCM (2.30 ± 2.29 hours, 15 threads). On the clinical dataset, prescreening with the selected ML algorithm reduced SCM runtime by 42.86% (from 1.75 to 1.00 days) and produced the same final model as SCM only. In conclusion, we have demonstrated that accounting for highly-correlated covariates improves ML prescreening accuracy. The choice of ML method and the proportion of important covariates (unknown a priori) can be guided by simulations.
Topics: Machine Learning; Humans; Desipramine; Computer Simulation; Antidepressive Agents, Tricyclic; Algorithms; Models, Biological
PubMed: 38816519
DOI: 10.1208/s12248-024-00934-6 -
European Journal of Pharmacology Nov 2023We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA receptor to induce proliferative and prosurvival...
We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA receptor to induce proliferative and prosurvival responses. Here, we further characterize this unique action of antidepressants by examining their effects on two additional LPA receptor family members, LPA and LPA. Human LPA receptors were stably expressed in HEK-293 cells (HEK-LPA, -LPA and -LPA cells) and their functional activity was determined by Western blot and immunofluorescence. LPA effectively stimulated the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in HEK-LPA, -LPA, and -LPA cells. The tricyclic antidepressants amitriptyline, clomipramine, imipramine and desipramine increased phospho-ERK1/2 levels in HEK-LPA and -LPA cells but were relatively poor agonists in LPA-expressing cells. The tetracyclic antidepressants mianserin and mirtazapine were active at all three LPA receptors. When combined with LPA, both amitriptyline and mianserin potentiated G-mediated phosphorylation of ERK1/2 induced by LPA in HEK-LPA, -LPA and -LPA cells, CHO-K1 fibroblasts and HT22 hippocampal neuroblasts. This potentiation was associated with enhanced phosphorylation of CREB and S6 ribosomal protein, two molecular targets of activated ERK1/2. The antidepressants also potentiated LPA-induced G-mediated phosphorylation of AMP-activated protein kinase in HEK-LPA and -LPA cells. Conversely, amitriptyline and mianserin were found to inhibit LPA-induced Rho activation in HEK-LPA and LPA cells. These results indicate that tricyclic and tetracyclic antidepressants can act on LPA, LPA and LPA receptor subtypes and exert differential effects on LPA signalling through these receptors.
Topics: Humans; Mianserin; Amitriptyline; HEK293 Cells; Antidepressive Agents; Lysophospholipids; Receptors, Lysophosphatidic Acid
PubMed: 37758013
DOI: 10.1016/j.ejphar.2023.176064 -
The Australian and New Zealand Journal... Apr 2024Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access.
INTERVENTIONS
Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations.
PRIMARY OUTCOMES
Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts.
RESULTS
Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified ( = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes.
CONCLUSIONS
Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed.
Topics: Humans; Quality of Life; Cognitive Behavioral Therapy; Psychotherapy; Methylphenidate; Treatment Outcome; Cyclobutanes
PubMed: 38179705
DOI: 10.1177/00048674231219593 -
Journal of Applied Toxicology : JAT Sep 2023The role of ASMase/ceramide signaling pathway in the development of silicosis needs to be verified by in vivo experiments. We investigated the role of the...
The role of ASMase/ceramide signaling pathway in the development of silicosis needs to be verified by in vivo experiments. We investigated the role of the ASMase/ceramide signaling pathway in the progression of silicosis and the effect of desipramine (DMI) (1 mg/mL) on the development of silicosis, by establishing a silica (1 mL, 50 mg/mL) dust-contaminated rat silicosis model and administering the ASMase inhibitor, DMI, to the dust-contaminated rats. The results showed that the levels of interleukin (IL)-1β and IL-6 were increased in the lung tissues of the rats in the dust-contaminated group at the initial stage after dusting; the inflammatory cell aggregation in the lung tissue was increased. With time progression, the hydroxyproline content in the lung tissue increased, and alpha-smooth muscle actin (α-SMA), collagen I, and vimentin substantially increased, suggesting that silicosis was formed in the lung tissue of the rats 28 days after SiO dust treatment. Moreover, the levels of ASMase, ceramide, and sphingosine-1-phosphate (S1P) were increased in the lung tissue of rats. The expression of β-catenin, fibronectin, and caspase-3 protein was increased, and E-cadherin protein expression was decreased in the lung tissue of the rats in the late stage of dust contamination. The ASMase and ceramide in the lung tissues of the rats in the DMI intervention group were reduced, as were the lung tissue inflammation levels, collagen expression, and lung fibrosis. These results suggest that SiO dust may activate the ASMase/ceramide signaling pathway in rat lung tissue, promoting pulmonary fibrosis. DMI inhibited this activation, attenuated apoptosis, blocked epithelial-mesenchymal transition, and halted silica dust-induced silicofibrosis.
Topics: Rats; Animals; Pulmonary Fibrosis; Silicon Dioxide; Ceramides; Dust; Silicosis; Lung; Inflammation
PubMed: 36942470
DOI: 10.1002/jat.4467