Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.

Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.

Activation of NOP receptor increases vulnerability to stress: role of glucocorticoids and CRF signaling.

RATIONALE: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVES: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists. METHODS: Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570. RESULTS: The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session. CONCLUSIONS: Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.

Antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise (Kinixys Spekii).

Some of the most commonly used analgesic drugs in animals are of questionable efficacy or present adverse side effects among the various species of reptiles. Tricyclic antidepressants have been demonstrated to have antinociceptive effects in several animal models of pain and could be a good alternative for use in reptiles. The aim of the study was to investigate the antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise. A total of 24 animals weighing 600-1000 g were used for nociceptive tests, i.e., formalin, capsaicin, and hot plate tests. Drugs were administered intracoelomically 30 min before starting the tests. The time spent in nocifensive behavior and the associated observable effects during the tests were recorded. Only the highest dose of 40 mg/kg of nortriptyline hydrochloride caused statistically significant decrease in nocifensive behavior in both the formalin and the capsaicin test. Desipramine hydrochloride at doses of 20 and 40 mg/kg caused statistically significant decrease in nocifensive behavior in the formalin test. Also, desipramine hydrochloride at doses of 15, 20, and 60 mg/kg caused statistically significant decrease in nocifensive behavior in the capsaicin test. None of the doses used for both drugs had any statistically significant effect on nocifensive behavior in the hot plate test. The results show that nortriptyline and desipramine hydrochloride have significant antinociceptive effects in the chemical but not thermal inflammatory pain-related behavior in the Speke's hinge-back tortoise. The most common associated side effect following administration of the higher doses of either of the drugs is excessive salivation.

Inhibitory Effects of Tricyclic Antidepressants on Human Liver Microsomal Morphine Glucuronidation: Application of IVIVE to Predict Potential Drug-Drug Interactions in Humans.

BACKGROUND: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation. OBJECTIVE: This study aimed to (i) examine the inhibitory effects of TCAs (viz., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing in vitro-in vivo extrapolation (IVIVE) approaches. METHOD: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the in vitro system containing 2% BSA. The Ki values were employed to predict the DDI magnitude in vivo by using static and dynamic mechanistic PBPK approaches Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective Ki values of 91 ± 7.5 and 82 ± 11 µM, 23 ± 1.3 and 14 ± 0.7 µM, 103 ± 5 and 90 ± 7 µM, and 115 ± 5 and 110 ± 3 µM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was <5% for amitriptyline or nortriptyline. PBPK modelling predicted an increase of less than 10% in the morphine AUC due to the inhibition of clomipramine and imipramine in both virtual healthy and cirrhotic populations. CONCLUSION: The results suggest that the likelihood of potential clinical DDIs arising from tricyclic antidepressant inhibition on morphine glucuronidation is low.

Beneficial effects of Cyclosporine A in combination with Nortriptyline on germ cell-specific apoptosis, oxidative stress and epididymal sperm qualities following testicular ischemia/reperfusion in rats: a comparative study.

BACKGROUND: Testicular torsion is a pathological condition which needs emergency surgical intervention. However, after surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. The study was planned to evaluate the efficacy of simultaneous use of Cyclosporine A (CsA) and Nortriptyline (Nort) to repair testicular damages in an experimental torsion/detorsion (T/D) rat model. METHODS: Male rats (n = 112) were allocated into 7 groups 16 each in; (Group 1); Control group, (Group 2); T/D group, (Group 3-4); CsA 1 and 5 mg/kg, (Group 5-6); Nort 2 and 10 mg/kg and (Group 7); concurrent group, CsA (1 mg/kg) + Nort (2 mg/kg). Right uni-lateral torsion was inducted by twisting testis 720 degrees in the clockwise direction for 1 h. For short-term and mid-term studies, lipid peroxidation, antioxidant enzyme activities, caspase-3 level, histopathological changes and germ cell apoptosis were evaluated. Moreover, in long-term investigation, semen analysis was performed. RESULTS: After T/D induction, testis abnormalities both functional and structural were appeared. Pre- and post-treatment with CsA and Nort, separately, reduced MDA and caspase-3 levels, normalized antioxidant levels, ameliorate tissue injury and improved sperm criteria. CONCLUSION: The antioxidant and anti-apoptotic characteristics of CsA and Nort and their protective effects have been shown in our study. Concurrent administration of CsA and Nort in selected low-dose indicated a significant positive effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress in short-term, apoptosis, and histologic changes in mid-term, as well as semen criteria in the long-term appraisal.

Polymer-mediated electrospun nanofibrous mats on supramolecular assembly of nortriptyline in the ß-cyclodextrin medium for antibacterial study.

With the thought and strong hope of uniqueness and challenging characteristic highlights and importance of nanofibrous mats (NFMs) along with cyclodextrins (CDs) that having a significant opportunity, chances and handling a vital role in hostile to bacterial activities. For the most part, CDs are utilized to upgrade the antibacterial activity through the improvement of solubility, stability, and etc., to any molecule which can bring inside the CDs cavity via the formation of inclusion complexes. Polymer-mediated electrospun nanofibrous mats (PAN NFMs) are utilized as a nanocarrier for antibacterial activity in this article, utilizing nortriptyline (NP) as a reference molecule. As a result, NP forms an inclusion complex with ß-Cyclodextrin (ß-CD). As a result, the PAN NFMs are able to absorb it, thereby consolidating the complex NP on the nanofibrous surface. Additionally, the soaking of PAN NFMs in NP solution without ß-CD was performed for comparison. To characterize the nanofibrous mats of NP/PAN and NP:ß-CD-ICs/PAN NFMs, UV absorption, FTIR, Raman, XRD, and SEM techniques were used. The antibacterial activity of NP and NP:ß-CD-ICs have been tried against positive control antibiotics by the disc diffusion method. Thus, the action has been improved for NP:ß-CD-ICs/PAN NFMs over NP/PAN NFMs because of the solubility upgraded for the NP by the complexation of ß-CD.

The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Migraine ranked as the eighth cause of disability worldwide. Statins with anti-inflammatory and vasodilatory endothelial effects have been introduced as an option for the prevention of migraine-type headaches. The current study aimed to assess the efficacy and tolerability of atorvastatin for the prevention of migraine in adults. METHOD: This prospective, triple-blind, randomized controlled clinical trial was performed in adult migraineurs from mid-July 2019 to late-April 2020. Patients were randomly assigned to receive atorvastatin or placebo in combination with nortriptyline for 24-weeks. The frequency of headache was the primary outcome, and intensity of the headache and quality of life (QOL) were the secondary outcomes for this study. RESULTS: With 34 patients in each arm, 68 patients with migraines based on the International Headache Society (IHS) criteria were enrolled in the study. At week 24, patients in the atorvastatin group experienced significantly fewer migraine attacks than the placebo group (P-value = 0.004). Moreover, there were significant differences between the two groups in QOL at follow-up intervals of 14 (P-value = 0.001) and 24 (P-value < 0.001) weeks. However, no significant difference was observed in the intensity of headache was observed in both groups (P-value > 0.05). The most common adverse effects in intervention and control groups were constipation and insomnia, respectively. CONCLUSION: In patients with migraine, prophylaxis with atorvastatin significantly improved the frequency of headache and QOL over 24 weeks compared with placebo with no effect on the intensity of headache. Statins seem to be a potential promising drug for prophylaxis of migraine headaches.

Nortriptyline Modulates the Migration of Peripheral Blood Lymphocytes and Monocytes in Patients with Chronic Obstructive Pulmonary Disease.

In the present study, the effect of nortriptyline (1 and 10 µM), budesonide (10 nM) and their combination on the migration of peripheral blood lymphocytes and monocytes from patients with chronic obstructive pulmonary disease (COPD) towards chemokines CCL5 and CXCL10 was evaluated by flow cytometry. Nortriptyline (10 µM), both alone and in combination with budesonide, inhibited the migration of T helper cells, cytotoxic T lymphocytes, NK cells and B lymphocytes towards CCL5 and CXCL10, as well as enhanced monocyte migration towards these chemokines. The combination of nortriptyline (1 µM) and budesonide suppressed the chemotaxis of lymphocyte subpopulations towards CXCL10, but not towards CCL5, more effectively than budesonide alone. The combination of nortriptyline (10 µM) and budesonide inhibited the migration of lymphocyte subpopulations towards CCL5 and CXCL10 and activated monocyte chemotaxis towards both chemokines more effectively than budesonide alone. The results of this study demonstrate the ability of nortriptyline alone to modulate the migration of peripheral blood lymphocytes and monocytes from patients with COPD and to potentiate the effects of budesonide.

Nortriptyline enhances corticosteroid sensitivity of blood T cells from patients with chronic obstructive pulmonary disease.

Steroid unresponsiveness is a significant problem in the management of chronic obstructive pulmonary disease (COPD). The tricyclic antidepressant nortriptyline has been reported to reverse corticosteroid resistance induced by oxidative stress. This study examined the potential synergistic anti-inflammatory effects of nortriptyline and corticosteroids in T lymphocytes from patients with COPD and the molecular mechanisms underlying their action. Peripheral blood mononuclear cells (PBMCs) or whole blood cells from COPD patients were incubated with budesonide, nortriptyline, or their combinations and stimulated with phytohaemagglutinin (PHA) or phorbol myristate acetate (PMA) plus ionomycin. The release of interleukin 4 (IL-4), IL-5, IL-8 and other mediators from PBMCs was measured by ELISA. Intracellular pro-inflammatory cytokines, glucocorticoid receptor (GR) and its isoform GRß, histone deacetylase 2 (HDAC2), phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and p65 nuclear factor-κ (p65 NF-κB) were determined in CD4+ and CD8+ T cells using flow cytometry. Nortriptyline 10 µM decreased PHA-induced release of cytokines: IL-4, IL-5, IL-13, IL-17A, IL-33, macrophage migration inhibitory factor and thymic stromal lymphopoietin (TSLP). This drug alone also reduced the percentage of IL-4, IL-8, interferon gamma (IFNγ) positive CD4+ T cells and IL-4, IL-8 expressing CD8+ T cells stimulated with PMA/ionomycin, whereas nortriptyline 1 µM had less pronounced effect. The combination of budesonide 10 nM with nortriptyline 10 µM was more potent at suppressing IL-4, IL-5, IL-8, IL-13, IL-17A, TSLP secretion from PBMCs, as well as IL-4, IL-8, IFNγ, GRß expression by CD4+ and CD8+ T cells when compared with single budesonide treatment. The association of budesonide 10 nM and Nt (1 µM to 10 µM) effectively decreased p38 MAPK and p65 NF-κB phosphorylation and increased HDAC2 expression in both CD4+ and CD8+ T cells. In conclusion, nortriptyline alone demonstrates anti-inflammatory effects on blood T lymphocytes from COPD patients. Nortriptyline may also potentiate the effects of glucocorticoids and overcome corticosteroid insensitivity.

Depression-Associated Gene Negr1-Fgfr2 Pathway Is Altered by Antidepressant Treatment.

The Negr1 gene has been significantly associated with major depression in genetic studies. Negr1 encodes for a cell adhesion molecule cleaved by the protease Adam10, thus activating Fgfr2 and promoting neuronal spine plasticity. We investigated whether antidepressants modulate the expression of genes belonging to Negr1-Fgfr2 pathway in Flinders sensitive line (FSL) rats, in a corticosterone-treated mouse model of depression, and in mouse primary neurons. Negr1 and Adam10 were the genes mostly affected by antidepressant treatment, and in opposite directions. Negr1 was down-regulated by escitalopram in the hypothalamus of FSL rats, by fluoxetine in the hippocampal dentate gyrus of corticosterone-treated mice, and by nortriptyline in hippocampal primary neurons. Adam10 mRNA was increased by nortriptyline administration in the hypothalamus, by escitalopram in the hippocampus of FSL rats, and by fluoxetine in mouse dorsal dentate gyrus. Similarly, nortriptyline increased Adam10 expression in hippocampal cultures. Fgfr2 expression was increased by nortriptyline in the hypothalamus of FSL rats and in hippocampal neurons. Lsamp, another IgLON family protein, increased in mouse dentate gyrus after fluoxetine treatment. These findings suggest that Negr1-Fgfr2 pathway plays a role in the modulation of synaptic plasticity induced by antidepressant treatment to promote therapeutic efficacy by rearranging connectivity in corticolimbic circuits impaired in depression.

Sigma-1 receptor antagonists: promising players in fighting neuropathic pain.

Sigma-1 receptors (S1Rs) are strongly correlated to neuropathic pain (NP), since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effects. In the recent patent landscape, S1R antagonists endowed with nanomolar S1Rs affinity emerged as potent antinociceptive agents. So far, three patented compounds have been proposed for counteracting NP. Particularly PV-752 and AV1066, disclosed by the University of Pavia (Italy) and Anavex, respectively, showed good analgesic activity in preclinical studies. Moreover, E-52862 developed by Esteve (Spain) has been proved to be effective, both in preclinical and Phase II clinical trials, against several symptoms of NP. These patents ascertain S1R antagonists as potential drugs, alone or in combination with other analgesic drugs, for managing NP in humans.

Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy.

Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.

Preliminary Biochemical Description of Brain Oxidative Stress Status in Irritable Bowel Syndrome Contention-Stress Rat Model.

Background and objectives: Oxidative stress and inflammation have been implicated in the etiology of irritable bowel syndrome (IBS), a common gastrointestinal functional disease. This study aimed to further characterize the contention-stress rat model by exploring a possible correlation between oxidative stress markers measured in brain tissues with behavioral components of the aforementioned model. Thus, it is hereby proposed a possible IBS animal model relevant to pharmacological and complementary medicine studies. Materials and Methods: Wild-type male Wistar rats (n = 5/group) were chronically exposed to 6-hour/day contention, consisting of isolating the animals in small, vital space-granting plastic devices, for seven consecutive days. Following contention exposure, temporal lobes were extracted and subjected to biochemical analyses to assess oxidative stress-status parameters. Results: Our results show increased brain oxidative stress in contention-stress rat model: decreased superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde production in the IBS group, as compared to the control group. Furthermore, the biochemical ratios which are used to evaluate the effectiveness of an antioxidant system on oxidative stress could be described in this model. Conclusions: The correlations between the behavioral patterns and biochemical oxidative stress features could suggest that this may be a complex model, which can successfully mimic IBS symptomatology further providing evidence of a strong connection between the digestive system, enteric nervous system, and the central nervous system.

Modulation of the NOP receptor signaling affects resilience to acute stress.

BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.

CGRP in a gene-environment interaction model for depression: effects of antidepressant treatment.

OBJECTIVE: Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored. METHODS: We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions. RESULTS: CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels. CONCLUSION: Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.

Treatment of Adult ADHD without Stimulants: Effectiveness in A Dually Diagnosed Correctional Population.

Adult ADHD has received increased attention in the past two decades. There is a complex relationship between ADHD and substance use disorders, with ADHD being a risk factor for and a moderator in the treatment of addiction. ADHD is also a risk factor for the development of antisocial personality disorder. As a result, ADHD is prevalent in a correctional dually diagnosed population. This retrospective chart review reports on the effectiveness of the treatment for ADHD in a population with substance use disorders, residing in a correctional community center for treatment and reintegration purposes. Only patients with a primary diagnosis of ADHD were included and only nonstimulants were used. After an average of four visits, or approximately four months, patient showed a moderate response with a pretreatment to posttreatment effect size of 1.4. Sixty-four percent of patients responded and 35% remitted, according to the Clinical Global Index Severity Scale as the primary outcome measure. While stimulants are considered the first-line treatment for ADHD, they clearly present challenges in certain populations, especially in patients with significant antisocial and addiction histories. It does appear that non-stimulants are effective in this population. It is speculated that the response and remission rate could be improved by adding ADHD specific psychosocial interventions.

NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine.

RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. OBJECTIVES: The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. METHODS: Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. RESULTS: Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. CONCLUSIONS: NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.

Genetic disposition to inflammation and response to antidepressants in major depressive disorder.

BACKGROUND: Inflammation may play an important role in depression and its treatment. A previous study found that increased C-reactive protein (CRP), a marker of systemic inflammation, is associated with worse response to the serotonergic antidepressant escitalopram and better response to the noradrenergic antidepressant nortriptyline. It is unclear whether this reflects genetic disposition to inflammation. METHODS: We analyzed genotype data and weekly Montgomery-Åsberg Depression Rating Scale scores (MADRS) from 755 unrelated individuals obtained over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. We calculated a polygenic risk score for CRP level based on genome-wide meta-analysis results from the CHARGE Consortium. RESULTS: A higher polygenic risk score for CRP was associated with slightly better response to escitalopram and slightly worse response to nortriptyline, reflected in a statistically significant interaction between polygenic risk score and drug (beta = 1.07, 95% CI = 0.26-1.87, p = 0.0093). DISCUSSION: A differential association between CRP-PRS and antidepressant drug that is in a direction opposite to that found with serum CRP measurement suggests that previously observed effect of inflammation on antidepressant efficacy may be driven by state factors distinct from genetic influences on systemic inflammation.

Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain.

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.

Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation.

Candida albicans is a commensal yeast of the human body, able to form biofilms on solid surfaces such as implanted medical devices, and contributes to nosocomial infections. Biofilms have the capacity to resist higher levels of antifungals compared with planktonic cells, and can develop tolerance to commonly used treatments. The necessity to overcome acquired drug resistance and identify new active molecules with low toxicity is a significant problem. It has been reported that some antidepressants have antibacterial properties, but little is known regarding the effect of these drugs on fungi. This study demonstrated the capacity of three tricyclic antidepressants (doxepin, imipramine and nortriptyline) to inhibit the growth and biofilm formation of Candida spp. The antimicrobial potential of the drugs was assessed by studying gene expression, hyphae formation, biofilm growth and maturation. Their negative impact on the growth of C. albicans and other Candida spp. is shown in vitro and with the hepatic S9 system, which is preliminary to any in-vivo test. This study found that the antidepressants considered can inhibit not only hyphae and biofilm formation, but also kill cells in a mature biofilm. Moreover, cell lysis by nortriptyline was observed, along with its synergistic activity with amphotericin B. These findings suggest that tricyclic antidepressants, particularly nortriptyline, should be studied further in drug repositioning programmes to assess their antimycotic capacity in full.