Insufficient recovery of monoamine oxidase in a bioequivalence study of the monoamine oxidase inhibitor tranylcypromine: Recommendation of the tranylcypromine enantiomer test.

OBJECTIVE: To investigate the recovery of monoamine oxidase (MAO) activity in the liver and gut of healthy subjects after a dose of 10 mg of the irreversible MAO inhibitor tranylcypromine (TCP). MATERIALS AND METHODS: A bioequivalence study of TCP with a wash-out of 1 week between 2 doses of 10 mg TCP was re-analyzed for changes of the plasma concentrations of TCP enantiomers. Plasma concentrations of (+)-TCP and the ratio of (+)-TCP and (-)-TCP plasma concentrations were used as a measure of MAO activity because (+)-TCP is a more effective suicide inhibitor of MAO than (-)-TCP and, therefore considerably more metabolized by MAO. RESULTS: The area under the curve from the first to the last measured concentration (AUCt) and the maximum plasma concentration (Cmax) of (+)-TCP increased significantly in the second dose (p < 0.0001) by 43.1% (11.8%) and 66.5% (26.4%), respectively, (mean with 95%CI in each case). The ratios (+)-TCP/(-)-TCP of AUCt and Cmax also increased significantly (p < 0.0001) by 27.3% (6.4%) and 25.9% (6.2%), respectively. No changes were found for the half-lives (T1/2) of both enantiomers. CONCLUSION: For the first dose, MAO is the main drug-metabolizing enzyme of (+)-TCP. MAO activity in the liver and gut is not completely recovered within 1 week after 1 dose of TCP. One week of wash-out may be insufficient in bioequivalence studies of irreversible MAO inhibitors. Prolonged inhibition of MAO after the treatment with irreversible MAO inhibitors may explain drug interactions during the switch from another MAO inhibitor to TCP. Enantiomer plasma concentrations of TCP after a dose of racemic TCP may be used as a test for gastrointestinal and hepatic MAO activity.

Combination of Tranylcypromine and Mirtazapine in Difficult-to-Treat Depression.

BACKGROUND: About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy-resistant major depression. METHODS: In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy-resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression-Severity and Improvement Scales. RESULTS: All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement. CONCLUSIONS: Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.

Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis.

PURPOSE: We conducted a comprehensive meta-analysis of the comparison of tranylcypromine (TCP) and tricyclic antidepressants (TCAs) in the treatment of depression because such work is lacking in medical scientific literature. METHODS: Literature was searched for studies of TCP controlled by TCAs in multiple databases and in reviews of TCP and monoamine oxidase inhibitors. The natural logarithm of the odds ratio (logOR) and the pooled logOR according to a fixed effect model were calculated for the numbers of responders and nonresponders. RESULTS: A total of 227 studies of TCP were found including 75 controlled studies of TCP-monotherapy. Twelve of 23 studies of TCP monotherapy and TCAs were excluded for several reasons (duplicates, safety studies, retrospective, cross-over), leaving 11 prospective and parallel controlled studies of TCP monotherapy versus TCAs (6 randomized double-blind). One study was excluded from the meta-analysis because of low quality of study design according to the Food and Drug Administration guidelines of studies of antidepressant drugs and high risk of bias according to the Cochrane's tool. Two studies with equal efficacy of TCP and TCAs in continuous endpoints did not provide dichotomous response data. A pooled logOR of 0.480 (95% confidence interval, 0.105-0.857, P = 0.01) resulted for the remaining eight studies in the primary meta-analysis, which favors TCP significantly over TCAs (test for heterogeneity: Х = 8.1, df = 7, P > 0.3, not heterogenous; I = 13.6%, heterogeneity not important). The result is robust with respect to inclusion of hypothetical response data of the 2 studies with continuous data only: pooled logOR, 0.350 (95% confidence interval, 0.028-0.672, P = 0.03). Visual inspection of forest plots and subgroup analysis suggest that superiority of TCP over TCAs is determined by 2 studies in psychomotor-retarded (anergic) depression. CONCLUSIONS: Tranylcypromine and TCAs have an equal antidepressant effect in a mean sample of depressed patients with mixed psychomotor symptoms. Tranylcypromine might be superior to TCAs in depression with predominant psychomotor retardation.

[Tranylcypromine and khat: a potentially fatal combination]. / Tranylcypromine en khat: een potentieel fatale combinatie.

It is well known that the use of tranylcypromine in combination with amphetamines may induce a potentially lethal hypertensive crisis. That such a complication may also occur when tranylcypromine is combined with khat, however, is less known. We describe the case of a young patient who received a low dose of tranylcypromine combined with a small amount of khat, subsequently developing a subarachnoid hemorrhage.

Antidepressant drugs can modify cytotoxic action of temozolomide.

Cancer patients often require antidepressant treatment due to comorbid depressive disorder. However, recent studies have demonstrated that antidepressant drugs affect the efficacy of chemotherapy and promote progression of cancer. Apart from the main mood-improving effect, antidepressant drugs also produce analgesic, anxiolytic, hypnotic and pro-cognitive actions. Patients suffering from brain cancer constitute the greatest percentage of depressive cancer patients. However, vital safety and efficacy issues related to combined therapy with temozolomide, the first-line cytostatic in patients diagnosed with glioblastoma multiforme, and antidepressant drugs have yet to be addressed. The aim of the present studies was to evaluate the effect of three antidepressant drugs (imipramine, fluoxetine and tranylcypromine) on the cytotoxic efficacy of temozolomide on T98G cells, a human glioblastoma cell line. In our experiments, we used a complex experimental in vitro system to mimic the instability of a tumour's oxygen supply, thereby reproducing conditions that occur inside the tumour. The effect of the interaction between temozolomide and antidepressant drugs on viability, apoptosis and intensity of divisions of glioblastoma cells was evaluated under different oxygen conditions. The results of our studies demonstrated that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects.

Tranylcypromine, a lysine-specific demethylase 1 (LSD1) inhibitor, suppresses lesion growth and improves generalized hyperalgesia in mouse with induced endometriosis.

BACKGROUND: Growing evidence indicates that endometriosis is an epigenetic disease. Encouragingly, histone deacetylases (HDACs) and DNA methyltransferases have been shown to be promising targets by numerous in vitro studies. However, only a few studies have shown promising effects of HDAC inhibition in preclinical studies in endometriosis. While lysine-specific demethylase 1 (LSD1) is recently found to be aberrantly expressed in endometriosis, and that the treatment of endometriotic stromal cells with tranylcypromine (TC), an LSD1 inhibitor, significantly reduced cellular proliferation, cell cycle progression, and invasiveness, the in vivo effect of TC treatment is currently lacking. This study sought to evaluate the effect of TC in a mouse model of endometriosis. METHODS: Forty-seven female C57BL/6 mice were used in this experimentation. All mice, except those randomly selected to form Sham surgery (M) and specificity control (S) groups, received an endometriosis-inducing surgery. Group S was set up mainly to ensure that the reduced generalized hyperalgesia in mice treated with TC is not due to any possible analgesic effect of TC, but rather resulting from the treatment effect specific to endometriosis. Two weeks after the surgery, mice that received surgery were further divided randomly into 3 groups: 1) untreated group (U); 2) low-dose TC group (L); 3) high-dose TC group (H). Group S received the same treatment as in group H. Two weeks after treatment, all mice were sacrificed and their ectopic endometrial tissues were harvested and analyzed by immunohistochemistry analysis. Hotplate test was administrated to all mice before the induction, treatment and sacrifice. Lesion size, hotplate latency, immunoreactivity against markers of proliferation, angiogenesis, H3K4 methylation, and of epithelial-mesenchymal transition (EMT). RESULTS: TC treatment significantly and substantially reduced the lesion size and improved generalized hyperalgesia in a dose-dependent fashion in mice with induced endometriosis. In addition, TC treatment resulted in reduced immunoreactivity to biomarkers of proliferation, angiogenesis, and H3K4 methylation, leading to arrested EMT and lesion growth. CONCLUSION: In light of our previously reported reduced cellular proliferation, cell cycle progression and invasiveness resulting from the LSD1 inhibition in in vitro studies, our data strongly suggest that LSD1 is a promising therapeutic target for endometriosis. TRIAL REGISTRATION: Not applicable.

MAOIs - does the evidence warrant their resurrection?

OBJECTIVE: The place of monoamine oxidase inhibitors (MAOIs) in psychiatry is reviewed, and the question posed as to whether they are now justifiably disregarded by prescribers. METHOD: Multiple databases (PubMed, Medline, Embase, Cochrane) were interrogated to provide an overview regarding the use, efficacy and toxicity of MAOIs. Data regarding funded use of these agents in New Zealand were obtained from PHARMAC. RESULTS: Evidence supports the use of MAOIs in major depressive disorder, certain anxiety disorders and, to lesser extent, bipolar depression. Older non-selective agents, such as phenelzine and tranylcypromine, have distinctive efficacy in 'atypical' and treatment-resistant depression, but at the cost of serious tolerability problems. Their relegation and perception by clinicians as 'last resort' medications - if considered at all - has occurred in the context of various concerns, notably dietary restrictions, potential adverse drug interactions and the usual requirement for divided doses. CONCLUSIONS: Sufficient evidence supports consideration of MAOIs in treatment-refractory and atypical depressive disorders, and in social anxiety disorder. Psychiatrists in training need to gain experience in using these agents.

Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review.

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·

Antidepressant treatment with MAO-inhibitors during general and regional anesthesia: a review and case report of spinal anesthesia for lower extremity surgery without discontinuation of tranylcypromine.

Monoamine oxidase-(MAO)-inhibitors are a treatment of last resort in treatment resistant depression, which is regarded as a condition of increased psychiatric risk. General and regional anesthesia for elective surgery during use of long-term MAO-inhibitors remains a matter of debate because of an increased risk of drug interactions and decreased sympathetic stability. A series of case reports and new comparative studies reveal the safety of anesthesia/analgesia in non-cardiac surgery without discontinuation of the MAO-inhibitor if best effort is made for maintenance of sympathetic homeostasis and if known drug interactions are avoided. Very few reports with severe adverse incidents have been noted. Severe cardiovascular morbidity, a contraindication of MAO-inhibitors, probably contributed to peri- and postoperative complications. According to new studies, the risk of pharmacokinetic drug interactions is lower for tranylcypromine than for phenelzine. In the present case, a 66-year-old psychiatric patient on permanent treatment with 20 mg/day tranylcypromine was admitted for forefoot surgery. Anesthetic premedication consisted of 7.5 mg oral midazolam. Intravenous midazolam (0.5 mg) was dispensed for intraoperative sedation. After local anesthesia of the puncture site with 30 mg isobar prilocaine, spinal anesthesia was achieved by a single shot of 13.5 mg hyperbar bupivacaine (0.5%) intrathecally. Postoperative regional and general analgesia were accomplished by a peripheral nerve block with 50 mg isobar bupivacaine as well as oral etoricoxib and oxycodone. No peri- or postoperative complications were encountered. It is concluded that general or regional anesthesia for noncardiac surgery without discontinuation of MAO-inhibitor treatment may be a safe intervention after careful evaluation of an individual's perioperative and psychiatric risk. The increased psychiatric risk in patients treated with MAO-inhibitors outweighs the increased, however manageable, perioperative risk from continuing treatment during surgery.

Synergistic Effects of Tranylcypromine and NRF2 Inhibitor: A Repurposing Strategy for Effective Cancer Therapy.

Drug repurposing has emerged as an attractive strategy for accelerating drug discovery for cancer treatment. In this study, we investigated combining Tranylcypromine (TCP) with a number of well-characterized drugs. Among these combinations, NRF2 inhibitor (ML385) exhibited synergistic effects in combination with TCP. Specifically, our results showed that the combination of TCP and ML385 resulted in a significant reduction in tumor proliferation while neither drug affected cancer cell growth meaningfully on its own. While further studies are needed to understand fully the extent of the synergistic efficacy, the underlying respective mechanisms and the potential side effects of this approach, our study has yielded a promising start for the development of an effective combination cancer therapy.

Classics in Chemical Neuroscience: Selegiline, Isocarboxazid, Phenelzine, and Tranylcypromine.

The discovery of monoamine oxidase inhibitors (MAOIs) in the 1950s marked a significant breakthrough in medicine, creating a powerful new category of drug: the antidepressant. In the years and decades that followed, MAOIs have been used in the treatment of several pathologies including Parkinson's disease, Alzheimer's disease, and various cancers and as anti-inflammatory agents. Despite once enjoying widespread use, MAOIs have dwindled in popularity due to side effects, food-drug interactions, and the introduction of other antidepressant drug classes such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The recently published prescriber's guide for the use of MAOIs in treating depression has kindled a resurgence of their use in the clinical space. It is therefore timely to review key aspects of the four "classic" MAOIs: high-dose selegiline, isocarboxazid, phenelzine, and tranylcypromine. This review discusses their chemical synthesis, metabolism, pharmacology, adverse effects, and the history and importance of these drugs within the broader field of chemical neuroscience.

Repurposing antidepressants for anticancer drug discovery.

Drug repurposing is an attractive strategy for identifying new indications for existing drugs. Three approved antidepressants have advanced into clinical trials for cancer therapy. In particular, further medicinal chemistry efforts with tranylcypromine (TCP) have led to the discovery of several TCP-based histone lysine specific demethylase 1 (LSD1) inhibitors that display therapeutic promise for treating cancer in the clinic. Thus repurposing antidepressants could be a promising strategy for cancer treatment. In this review, we illustrate the anticancer mechanisms of action of antidepressants and also discuss the challenges and future directions of repurposing antidepressants for anticancer drug discovery, to provide an overview of approved antidepressant cancer therapies.

Review and meta-analysis of add-on tranylcypromine with antipsychotic drugs for the treatment of schizophrenia with predominant negative symptoms: a restoration of evidence.

BACKGROUND: Treatment using add-on antidepressants with antipsychotic drugs in negative symptoms of schizophrenia has been reviewed recently in comprehensive meta-analyses. Tranylcypromine (TCP), an irreversible monoamine oxidase (MAO)-A/B inhibitor applied in treatment resistant depression, was not included because of strict requirements for quality of study design. To get a clear picture of available evidence for this resource in the treatment of schizophrenia, we conducted a review and meta-analysis of add-on TCP in the treatment of predominant negative symptoms of schizophrenia (negative schizophrenia). METHODS: Seven controlled studies of add-on TCP in schizophrenia with predominant negative symptoms were found in a search of multiple databases. A subset of four studies of the prospective and parallel comparison of add-on TCP with antipsychotic drugs vs. antipsychotic drug monotherapy and meeting minimum quality criteria formed the primary meta-analysis. The effect size was calculated as the natural logarithm of the odds ratio (logOR) of responders and non-responders. RESULTS: In the primary meta-analysis, a pooled logOR = 1.092 with 95%CI 0.410-1.774 (I2 = 43.4%, moderate heterogeneity) was calculated according to a fixed-effect model. Heterogeneity was reduced for three double-blind studies of add-on TCP with trifluoperazine (TFP) vs. TFP-monotherapy and resulted a pooled logOR = 0.916 with 95%CI 0.216-1.616 (I2 negative, no heterogeneity). A significant logOR = 1.558 with 95%CI 0.340-2.776 was found for TCP/TFP compared to placebo in one study. In a meta-analysis of extrapyramidal adverse effects, studies were very heterogeneous and revealed no significant differences between treatments. The risk of exacerbation of positive symptoms with add-on TCP was found to be very low for a duration of treatment of 12-16 weeks. No cases of hypertensive crisis were reported. The main methodical limitations were insufficient description of randomization or matching of patients without randomization. The main clinical limitation is a gap of data for add-on TCP with second-generation antipsychotics. CONCLUSION: New studies are needed for add-on TCP with antipsychotic drugs in schizophrenia with predominant negative symptoms. Trials of this treatment may be possible in rare and selected cases. The therapeutic effect of add-on TCP may be explained by a strong dopaminergic activity.

A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Dynamic methylation of histone H3K18 in differentiating Theileria parasites.

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.

Double-blind comparison of 30 and 60 mg tranylcypromine daily in patients with panic disorder comorbid with social anxiety disorder.

Our objective was to explore the dose-response relationship in patients with panic disorder and social anxiety disorder comorbidity (DSM-IV). After 1 week of no-drug washout, 36 such patients were assigned to a double-blind controlled comparison of the effects of 30 mg and 60 mg of tranylcypromine, and were followed up for 12 weeks. The main instrument used to measure the number of panic attacks was the Sheehan Panic and Anticipatory Anxiety Scale. The primary outcome measure for social anxiety disorder symptoms was the mean change from baseline in the Liebowitz Social Anxiety Scale (LSAS). After 12 weeks of treatment, panic attacks were reduced 69.6% from baseline in the 30-mg group (n=19) compared with a 74.8% reduction in the 60-mg group (n=17). Twelve patients (70.6%) of the higher dose group and 14 patients (68.4%) of the lower dose were completely free of panic attacks. There was no difference in efficacy between the tranylcypromine groups in the panic disorder symptoms. The 60-mg dose was more efficacious as measured by the LSAS scores, showing a significant difference in relation to the lower group. Mean change from baseline in LSAS total score (mean+/-SD) for 30-mg group was 17.9+/-14.7 and for the 60-mg group was 35.0+/-14.8. The social anxiety symptom scale showed a two-fold greater change with the 60-mg dose, and the 30-mg dose group could be considered the equivalent of a placebo control group. Tranylcypromine--60 mg daily--was found effective in the treatment of panic disorder and social anxiety disorder comorbidity.

The MAO Inhibitor Tranylcypromine Alters LPS- and Aß-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD.

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aß-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aß-induced neuroinflammatory responses in vitro and in vivo.

The histone demethylase LSD1 promotes renal inflammation by mediating TLR4 signaling in hepatitis B virus-associated glomerulonephritis.

Renal inflammation significantly contributes to the progression of hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN), but the mechanisms that control its precise regulation remain largely unknown. In this study, we showed that the lysine-specific demethylase 1 (LSD1) was significantly upregulated in renal tissue of HBV-GN patients, and its expression was positively correlated with inflammation. Functionally, LSD1 could promote HBV-induced release of proinflammatory mediators in HK-2 cells, a human renal tubular epithelial (RTE) cell line. Mechanistic investigations suggested that LSD1 directly promoted the transcription of the inflammatory-related gene Tlr4 by eliminating the mono- or di-methylation of H3K9 near its promoter. Knockdown of Lsd1 further inhibited TLR4-NF-κB/JNK signaling cascades, and subsequently decreased HBV-induced production of proinflammatory mediators in HK-2 cells. Co-transfection with Tlr4-expressing plasmids counteracted these effects. Meanwhile, downregulation of abovementioned TLR4-related pathways using small-molecule inhibitors attenuated inflammation. Importantly, LSD1 inhibitor tranylcypromine (TCP) could inhibit TLR4-NF-κB/JNK signaling axis and alleviate renal inflammation in HBV transgenic mice. Taken together, our data identify LSD1 as a novel regulator of renal inflammation and as a potential therapeutic target in HBV-GN.

Juvenile rats in the forced-swim test model the human response to antidepressant treatment for pediatric depression.

RATIONALE: Currently, there are limited treatment options for major depressive disorder in children and adolescents compared to the options available for adults. Many effective treatments used for adult depression, such as the tricyclic antidepressants, lack efficacy when given to children and adolescents. OBJECTIVE: To more quickly identify compounds that could be effective for treating childhood and adolescent depression, a reliable preclinical animal behavioral test of antidepressant efficacy for pediatric depression is needed. The forced-swim test (FST) with juvenile rats was assessed to determine its reliability as a predictive model for pediatric depression. MATERIALS AND METHODS: We adapted procedures from the adult FST to test 21-day-old juvenile rats. The 21-day-old animals were treated with three classes of antidepressant drugs before being assessed in the FST: the selective serotonin reuptake inhibitors escitalopram or fluoxetine; the tricyclic antidepressants desipramine or imipramine; and the monoamine oxidase inhibitor tranylcypromine. RESULTS: The 21-day-old rats showed dose-dependent changes in behaviors similar to those seen in adults when treated with escitalopram or fluoxetine. Tranylcypromine also decreased immobility in 21-day-old rats. Treatment with desipramine or imipramine, however, was not effective at reducing immobility in the 21-day-old rats. CONCLUSIONS: The juvenile FST accurately predicts the efficacy of selective serotonin reuptake inhibitors and the lack of efficacy of tricyclic antidepressants in the treatment of depression in children and adolescents. This suggests that the FST using 21-day-old rats may help to develop better treatments for childhood and adolescent depression.