Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment.
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SUBMITTER: Asensi-Canto A
PROVIDER: S-EPMC9265090 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A number of tricyclic antidepressants (TCAs) are commonly prescribed off-label for the treatment of neuropathic pain. The blockade of neuronal calcium ion channels is often invoked to partially explain the analgesic activity of TCAs, but there has been very limited experimental or theoretical evidence reported to support this assertion. The N-type calcium ion channel (CaV2.2) is a well-established target for the treatment of neuropathic pain and in this study a series of eleven TCAs and two closely related drugs were shown to be moderately effective inhibitors of this channel when endogenously expressed in the SH-SY5Y neuroblastoma cell line. A homology model of the channel, which matches closely a recently reported Cryo-EM structure, was used to investigate via docking and molecular dynamics experiments the possible mode of inhibition of CaV2.2 channels by TCAs. Two closely related binding modes, that occur in the channel cavity that exists between the selectivity filter and the internal gate, were identified. The TCAs are predicted to position themselves such that their ammonium side chains interfere with the selectivity filter, with some, such as amitriptyline, also appearing to hinder the channel's ability to open. This study provides the most comprehensive evidence to date that supports the notion that the blockade of neuronal calcium ion channels by TCAs is at least partially responsible for their analgesic effect.
| S-EPMC8864487 | biostudies-literature
Project description:Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis, the final common pathway leading to cirrhosis and liver failure for nearly every cause of chronic liver disease. Activation of HSCs in response to injury represents the key step in hepatic fibrogenesis, and is characterized by a phenotypic change from a non-fibrogenic, quiescent HSC to a fibrogenic HSC myofibroblast that secretes extracellular matrix proteins responsible for the fibrotic scar. We developed a small molecule screen to identify compounds that revert fibrotic human HSC myofibroblasts to an inactive phenotype through the quantification of lipid droplets with fluorescent microscopy. Conditions were optimized in a 384-well format using culture in Matrigel as a positive control. We screened 1600 compounds and identified 30 small molecules that induce reversion to an inactive phenotype. Among the hits, we identified five tricyclic antidepressants (TCAs) and showed that this class of drugs also repressed ACTA2 and COL1A1 while promoting PPAR-gamma expression. RNA sequencing analysis implicated extracellular matrix proteins and the sphingolipid pathway as a target of the TCAs.
2017-03-02 | GSE78853 | GEO
Project description:BACKGROUND: Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. RESULTS: Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 microM and 1.87 microM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. CONCLUSION: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.
| S-EPMC2680826 | biostudies-other
Project description:BackgroundMigraine, ranked as the 7th-highest specific cause of disability worldwide, has caused an enormous burden on the economy and society. Tricyclic antidepressant (TCA) is one of the most commonly drugs for migraine prevention. However, evidence about the efficacy and tolerability of TCAs in the prophylaxis of migraine in adults is somewhat confusing.MethodsA computerized literature search of the PubMed, Embase, Cochrane, and Web of Science databases from inception to July 2016 was conducted. We reviewed all randomized controlled trials that assigned adults with a clinical diagnosis of migraine to TCAs or other treatments (placebo or other antidepressants). Reduction in migraine frequency or index and response rates to treatment were defined as the efficacy outcomes. Rates of dropout due to adverse effects were defined as the tolerability outcomes.ResultsIn total 12 trials consisting of 1006 participants were identified: 9 trials compared TCAs with placebo, and the other 3 compared amitriptyline with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). A significant advantage of TCAs compared with placebo in the prevention of migraine in adults was observed (standardized mean difference [SMD] = -.75; 95% confidence interval [CI] = -1.05 to -.46; P?<?.00001). Participants receiving TCAs were more likely to experience an ?50% reduction in their headache burden than those receiving placebo (risk ratio [RR] =1.40; 95% CI = 0.89-2.20; P?=?.14). In addition, the efficacy between amitriptyline and SSRIs or SNRIs did not differ for migraine prevention in adults (SMD = -.01; 95% CI = -0.31 to 0.28; P?=?.94) based on the available limited trials. However, TCAs were less well tolerated than placebo (RR = 1.73; 95% CI = 1.00-2.99; P?=?.05) and SSRI or SNRI (RR = 2.85; 95% CI = 0.97-8.41; P?=?.06) on account of adverse events.ConclusionsThis research reveals that TCAs were more effective than placebo, but no more than SSRI or SNRI in ameliorating the headache burden in adults with migraine. However, TCAs appeared to be less tolerated than placebo and SSRIs or SNRIs for some side effects.
| S-EPMC5459715 | biostudies-literature
Project description:The striatal protein Regulator of G protein signaling-2 (RGS9-2) plays a key modulatory role in opioid, monoamine and other GPCR 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 a and bg subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5 (HDAC5), that are important for TCA responsiveness. Furthermore, information from RNA-seq 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. The RNAseq study was designed in order to reveal the impact of RGS9-2 on gene regulation in the Nucleus Accumbens under neuropathic pain and antidepressant treatment conditions. A total of 18 samples was used, coprising 6 different groups , and each group consisted of three different biological replicates.
2015-08-25 | E-GEOD-71527 | biostudies-arrayexpress
Project description:BackgroundIdiosyncratic drug-induced liver injury (IDILI) is common in hepatology practices and, in some cases, lethal. Increasing evidence show that tricyclic antidepressants (TCAs) can induce IDILI in clinical applications but the underlying mechanisms are still poorly understood.MethodsWe assessed the specificity of several TCAs for NLRP3 inflammasome via MCC950 (a selective NLRP3 inhibitor) pretreatment and Nlrp3 knockout (Nlrp3-/-) BMDMs. Meanwhile, the role of NLRP3 inflammasome in the TCA nortriptyline-induced hepatotoxicity was demonstrated in Nlrp3-/- mice.ResultsWe reported here that nortriptyline, a common TCA, induced idiosyncratic hepatotoxicity in a NLRP3 inflammasome-dependent manner in mildly inflammatory states. In parallel in vitro studies, nortriptyline triggered the inflammasome activation, which was completely blocked by Nlrp3 deficiency or MCC950 pretreatment. Furthermore, nortriptyline treatment led to mitochondrial damage and subsequent mitochondrial reactive oxygen species (mtROS) production resulting in aberrant activation of the NLRP3 inflammasome; a selective mitochondrial ROS inhibitor pretreatment dramatically abrogated nortriptyline-triggered the NLRP3 inflammasome activation. Notably, exposure to other TCAs also induced aberrant activation of the NLRP3 inflammasome by triggering upstream signaling events.ConclusionCollectively, our findings revealed that the NLRP3 inflammasome may act as a crucial target for TCA agents and suggested that the core structures of TCAs may contribute to the aberrant activation of NLRP3 inflammasome induced by them, an important factor involved in the pathogenesis of TCA-induced liver injury. Video Abstract.
| S-EPMC10214596 | biostudies-literature
Project description:In this experiment we compare the effect of tibial nerve transection on gene expression within the dorsal root ganglion (DRG) of rats.
2014-08-01 | E-MTAB-2260 | biostudies-arrayexpress
Project description:Oxaliplatin (OXL) therapy often causes side effects including chronic peripheral neuropathy. We investigated the pain-relieving effects of recombinant human lactoferrin (rhLf) as well as a long-acting IgG-Fc fused rhLf (rhLf-Fc) on OXL-induced neuropathic pain. We used the hLf in this study, because the homology between mouse Lf and hLf is higher than that of bovine Lf. In addition, rhLf-Fc is expected to enhance the analgesic effect due to the life extension effect in the body. We administered OXL (2 mg/kg, i.v.) to mice twice weekly for 4 weeks. Phosphate buffered saline (PBS), rhLf (100 mg/kg, i.p.) or rhLf-Fc (100 mg/kg, i.p.) was administered once a week from day 15 to 32. We also assessed the continuous infusion of same drugs (10 mg/kg/day) into the external jugular vein by using an osmotic pump. Both of rhLf and rhLf-Fc significantly reduced the hypersensitivity to mechanical stimulation when they were administered intraperitoneally. The continuous infusion of rhLf resulted in a more pronounced effect. Histopathological analysis of sciatic nerve showed that both rhLf and rhLf-Fc tended to reduce nerve fiber damage, but no significant difference was observed in nerve fiber cross-sectional area. Therefore, it was suggested that rhLf or rhLf-Fc injection could be an option for controlling neuropathic pain, which are side effects of OXL.
| S-EPMC7719891 | biostudies-literature
Project description:The striatal protein Regulator of G protein signaling-2 (RGS9-2) plays a key modulatory role in opioid, monoamine and other GPCR 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 a and bg subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5 (HDAC5), that are important for TCA responsiveness. Furthermore, information from RNA-seq 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.
2015-08-25 | GSE71527 | GEO
Project description:Background: Dysfunction at the ocular system via nociceptive or neuropathic mechanisms can lead to chronic ocular pain. While many studies have reported on responses to treatment for nociceptive pain, fewer have focused on neuropathic ocular pain. This retrospective study assessed clinical responses to pain treatment modalities in individuals with neuropathic component ocular surface pain. Methods: 101 individuals seen at the University of Miami Oculofacial Pain Clinic from January 2015 to August 2021 with ≥3 months of clinically diagnosed neuropathic pain were included. Patients were subcategorized (postsurgical, post-traumatic, migraine-like, and laterality) and self-reported treatment outcomes were assessed (no change, mild, moderate, or marked improvement). One-way ANOVA (analysis of variance) was used to examine relationships between follow up time and number of treatments attempted with pain improvement, and multivariable logistic regression was used to assess which modalities led to pain improvement. Results: The mean age was 55 years, and most patients were female (64.4%) and non-Hispanic (68.3%). Migraine-like pain (40.6%) was most common, followed by postsurgical (26.7%), post-traumatic (16.8%) and unilateral pain (15.8%). The most common oral therapies were α2δ ligands (48.5%), the m common topical therapies were autologous serum tears (20.8%) and topical corticosteroids (19.8%), and the most common adjuvant was periocular nerve block (24.8%). Oral therapies reduced pain in post-traumatic (81.2%), migraine-like (73%), and unilateral (72.7%) patients, but only in a minority of postsurgical (38.5%) patients. Similarly, topicals improved pain in post-traumatic (66.7%), migraine-like (78.6%), and unilateral (70%) compared to postsurgical (43.7%) patients. Non-oral/topical adjuvants reduced pain in postsurgical (54.5%), post-traumatic (71.4%), and migraine-like patients (73.3%) only. Multivariable analyses indicated migraine-like pain improved with concomitant oral α2δ ligands and adjuvant therapies, while postsurgical pain improved with topical anti-inflammatories. Those with no improvement in pain had a shorter mean follow-up (266.25 ± 262.56 days) than those with mild (396.65 ± 283.44), moderate (652 ± 413.92), or marked improvement (837.93 ± 709.35) (p < 0.005). Identical patterns were noted for number of attempted medications. Conclusion: Patients with migraine-like pain frequently experienced pain improvement, while postsurgical patients had the lowest response rates. Patients with a longer follow-up and who tried more therapies experienced more significant relief, suggesting multiple trials were necessary for pain reduction.
| S-EPMC8733738 | biostudies-literature