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Background: Monoamine oxidase inhibitors (MAOIs) are considered third‐line treatments for treatment resistant depression; however, they are underused in clinical practice. Aims: This study aimed to assess the efficacy, tolerability, and acceptability of MAOIs for the treatment of depression in comparison with other antidepressant treatments. Methods: A systematic review and network meta‐analysis of randomised clinical trials was performed to compare the efficacy, tolerability and acceptability between MAOIs and other antidepressant treatments for the treatment of depressive episodes. Results: A total of 83 double‐blinded, randomised controlled trials were included in the analysis, with 7765 participants assigned to an active treatment and 1844 assigned to placebo. Several MAOIs, including isocarboxazid, phenelzine, tranylcypromine and moclobemide, showed significantly higher efficacy compared with placebo. The tolerability and acceptability of MAOIs was comparable to other antidepressants. Limitations: A disproportionate number of studies investigating the most commonly used MAOIs, such as moclobemide and phenelzine, and a lack of specific studies focusing on treatment‐resistant and atypical depression. Conclusions: MAOIs are similar in efficacy to other antidepressants for the treatment of depression. However, more studies are needed comparing MAOI treatment in people with treatment‐resistant, atypical and bipolar depression. [ABSTRACT FROM AUTHOR]

Data on medication interactions with psychedelics are limited. Here we present what may be the first published report of a hypertensive emergency following the combination of psilocybin mushrooms with a monoamine oxidase inhibitor (MAOI). A 42-year-old man with treatment-resistant major depressive disorder took 1 g of Psilocybe cubensis mushrooms, while prescribed tranylcypromine, extended-release dextroamphetamine-amphetamine, and other medications. Approximately half an hour later, he developed severe hypertension with chest pain, palpitations, and headache. Upon hospital presentation, the electrocardiogram demonstrated ST-elevation. The patient was diagnosed with a myocardial infarction and treated with lorazepam, nitroglycerin, and aspirin. He subsequently underwent emergency cardiac catheterization, which revealed no significant cardiac abnormalities. Following overnight hospitalization, he was discharged home with no lasting physical sequelae. Though data are few, past studies suggest that classic serotonergic psychedelics (5HT-2A receptor agonists) such as dimethyltryptamine (DMT), lysergic acid (LSD), and synthetic psilocybin should not produce hypertensive emergency when combined with MAOIs. We suspect phenylethylamine, found in Psilocybe cubensis and other species of psilocybin mushrooms, interacted with tranylcypromine and dextroamphetamine-amphetamine to produce this hypertensive emergency. Patients prescribed MAOIs should be warned of the potential for hypertensive emergency when consuming psilocybin mushrooms, particularly when also prescribed norepinephrine releasers such as dextroamphetamine-amphetamine. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5HT) homeostasis is essential for many physiological processes in the central nervous system and peripheral tissues. Hyperserotonemia, a measurable sign of 5HT homeostasis disruption, can be caused by 5HT-directed treatment of psychiatric and gastrointestinal diseases. Its impact on the long-term balance and function of 5HT in the peripheral compartment remains unresolved and requires further research due to possible effects on human health. We explored the effects of perinatal 5HT imbalance on the peripheral organs responsible for serotonin metabolism—the jejunum, a synthesis site, and the liver, a catabolism site—in adult rats. Hyperserotonemia was induced by subchronic treatment with serotonin precursor 5-hydroxytryptophan (5HTP) or serotonin degradation inhibitor tranylcypromine (TCP). The jejunum and liver were collected on postnatal day 70 and analyzed histomorphometrically. Relative mRNA levels of 5HT-regulating proteins were determined using qRT-PCR. Compared to controls, 5HTP- and TCP-treated rats had a reduced number of 5HT-producing cells and expression of the 5HT-synthesising enzyme in the jejunum, and an increased expression of 5HT-transporter accompanied by karyomegaly in hepatocytes, with these differences being more pronounced in the TCP-treated animals. Here, we report that perinatal 5HT disbalance induced long-term cellular and molecular changes in organs regulating 5HT-metabolism, which may have a negative impact on 5HT availability and function in the periphery. Our rat model demonstrates a link between the developmental abnormalities of serotonin homeostasis and 5HT-related changes in adult life and may be suitable for exploring the neurobiological substrates of vulnerability to behavioral and metabolic disorders, as well as for modeling the adverse effects of the prenatal exposure to 5HT enhancers in the human population. [ABSTRACT FROM AUTHOR]

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory dysfunction. However, there are currently no effective pharmacological interventions for patients with noise-induced hearing loss. Here, we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss, and elucidate its underlying regulatory mechanisms. We established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 dB for 4 hours. We found that tranylcypromine treatment led to the upregulation of Sestrin2 (SESN2) and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with tranylcypromine. The noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click, 4, 8, and 16 kHz frequencies compared with the noise exposure group treated with saline. These findings indicate that tranylcypromine treatment resulted in increased SESN2, light chain 3B, and lysosome-associated membrane glycoprotein 1 expression after noise exposure, leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3, thereby reducing noise-induced hair cell loss. Additionally, immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy pathway. Tranylcypromine treatment also reduced the production of NOD-like receptor family pyrin domain-containing 3 (NLRP3) production. In conclusion, our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2, which induced autophagy, thereby restricting NLRP3-related inflammasome signaling, alleviating cochlear hair cell loss, and protecting hearing function. These findings suggest that inhibiting lysine-specific demethylase 1 is a potential therapeutic strategy for preventing hair cell loss and noise-induced hearing loss.

The history of irreversible non-selective MAOI antidepressants in the USSR and Russia is systemized. The history of representatives’ appearance is described. The history of the study of pharmacological effects is highlighted. The history of the study of clinical effects in various mental disorders is analyzed in chronological order. The history of use in somatic pathology is summarized. The history of the use of special pharmaceutical forms is considered. The history of new experimental compounds creation is submitted. The features of history of irreversible non-selective MAOI antidepressants in the USSR and Russia in comparison with their history in other countries are characterized.

Treatment-resistant depression (TRD) remains a significant challenge for clinicians and patients alike, necessitating exploration and understanding of potent but underutilized antidepressant options, such as classic monoamine oxidase inhibitors (MAOIs). This article presents a condensed overview of the fundamental principles outlined in the international consensus guideline on using MAOIs in TRD (the Prescriber's Guide), explicitly focusing on phenelzine and tranylcypromine. These drugs are powerful treatment options for severe depression, including atypical and melancholic subtypes, that have insufficiently responded to first- and second-line treatments. MAOIs are generally indicated before electroconvulsive therapy due to their favorable side-effect profile. However, several contraindications and drug interactions must be considered. This article aims to provide clinicians with a practical, accessible resource for implementing classic MAOIs in the management of TRD. [Psychiatr Ann. 2023;53(8):347–352.] [ABSTRACT FROM AUTHOR]

We describe the history of studying of the problem of tyramine syndrome during the treatment with antidepressants, irreversible non-selective monoamine oxidase inhibitors. Data on clinical observations are presented. Early hypotheses of pathogenesis are considered. The period of discovery of the relationship between increased blood pressure and the use of foods containing tyramine is outlined. The transformation of terminology is demonstrated. The events associated with the restriction of the use of therapy are characterized. The formation of the opinion about the exaggeration of the risk of developing tyramine syndrome is analyzed. Data on the involvement in the discussion of the problem of tyramine syndrome of society as a whole are given.

The article in Acta Psychiatrica Scandinavica discusses the efficacy and tolerability of monoamine oxidase inhibitors (MAOIs) in treating depressive episodes in mood disorders. While the review found similar efficacy between MAOIs and other antidepressants, previous studies suggest potential superiority of MAOIs in certain patient subgroups. The article highlights the need for further research on MAOIs in atypical depression and treatment-resistant depression (TRD), as well as exploring barriers to their use in clinical practice. Overall, the meta-analysis emphasizes the importance of continued research to optimize the use of MAOIs in depression treatment. [Extracted from the article]

Tranylcypromine (logP = 1.34, MW = 133.19 g/mol) is a monoamine oxidase inhibitor used in treating major depressive disorder and is available only as oral tablets. Transdermal delivery of tranylcypromine minimizes hepatic and gastrointestinal side effects associated with oral dosing and prevents systemic side effects improving patient compliance. A two-day suspension-based transdermal delivery method was developed in this study, and the delivery of tranylcypromine across dermatomed porcine ear skin was evaluated. Different penetration enhancers were screened, namely, isopropyl myristate, oleyl alcohol, oleic acid, and a combination of oleic acid and oleyl alcohol. Isopropyl myristate was chosen as the penetration enhancer, and suspension-based transdermal patches were formulated with acrylate and polyisobutylene pressure-sensitive adhesives by the solvent evaporation method. The release liner and backing membrane were chosen, and the drying time for each patch was optimized. The optimized patches were characterized for their adhesive properties, drying time, peel test, shear strength, and uniformity in drug content. In vitro permeation studies were performed on dermatomed porcine ear skin using vertical static Franz diffusion cells, and the receptor samples were collected at predetermined time points for 48 h. The samples were analyzed in a validated UPLC method. Acrylate-based suspension patch delivered a significantly higher amount of drug (712 ± 21.46 μg/cm2) as compared to passive delivery from drug dissolved in propylene glycol (461.49 ± 75.55 μg/cm2), reaching the two-day therapeutic target. However, the PIB-based suspension patch delivered 559.25 ± 12.37 μg/cm2 of tranylcypromine across the skin but did not reach the required target. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine, 5HT) homeostasis is essential for many physiological processes in the central nervous system and peripheral tissues. Hyperserotonemia, a measurable sign of 5HT homeostasis disruption, can be caused by 5HT-directed treatment of psychiatric and gastrointestinal diseases. Its impact on the long-term balance and function of 5HT in the peripheral compartment remains unresolved and requires further research due to possible effects on human health. We explored the effects of perinatal 5HT imbalance on the peripheral organs responsible for serotonin metabolism—the jejunum, a synthesis site, and the liver, a catabolism site—in adult rats. Hyperserotonemia was induced by subchronic treatment with serotonin precursor 5-hydroxytryptophan (5HTP) or serotonin degradation inhibitor tranylcypromine (TCP). The jejunum and liver were collected on postnatal day 70 and analyzed histomorphometrically. Relative mRNA levels of 5HT-regulating proteins were determined using qRT-PCR. Compared to controls, 5HTP- and TCP-treated rats had a reduced number of 5HT-producing cells and expression of the 5HT-synthesising enzyme in the jejunum, and an increased expression of 5HT-transporter accompanied by karyomegaly in hepatocytes, with these differences being more pronounced in the TCP-treated animals. Here, we report that perinatal 5HT disbalance induced long-term cellular and molecular changes in organs regulating 5HT-metabolism, which may have a negative impact on 5HT availability and function in the periphery. Our rat model demonstrates a link between the developmental abnormalities of serotonin homeostasis and 5HT-related changes in adult life and may be suitable for exploring the neurobiological substrates of vulnerability to behavioral and metabolic disorders, as well as for modeling the adverse effects of the prenatal exposure to 5HT enhancers in the human population.

As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some (hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSDI-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC50 values = 0.015 and 0.005 µM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays. [ABSTRACT FROM AUTHOR]

We aimed to evaluate how feeding a high-fat–low-fiber (F) diet to rats and dietary intervention with the implementation of a standard-fat-and-fiber (S) diet affects the response of the cardiovascular system to chromium (III) picolinate (Cr–Pic) and, alternatively, chromium nanoparticles (Cr–NPs). Young male Wistar Han rats (n/group = 12) from either the fatty group (18 weeks on F diet) or the intervention group (9 weeks on F diet + 9 weeks on S diet) received a pharmacologically relevant dose of 0.3 mg Cr/kg body weight in the form of Cr–Pic or Cr–NPs for 9 weeks. Our study on rats confirmed the pro-inflammatory effect of an F diet administered for 18 weeks. In the intervention group, both Cr–Pic and Cr–NPs decreased heart glutathione ratio (GSH+GSSG), enhanced participation of nitric oxide (NO) derived from inducible NO synthase (iNOS) in vascular relaxation to acetylcholine (ACh), increased the vasodilator net effect of cyclooxygenase-2 (COX-2)-derived prostanoids, and increased the production of superoxide anion (O2.−) in aortic rings. Meanwhile, in the fatty group, there was increased heart superoxide dismutase (SOD), decreased heart catalase (CAT), and reduced sensitivity in pre-incubated aortic rings to endogenous prostacyclin (PGI2). The factors that significantly differentiated Cr–NPs from Cr–Pic were (i) decreased blood antioxidant capacity of water-soluble compounds (0.75-fold, p = 0.0205), (ii) increased hydrogen peroxide (H2O2) production (1.59-fold, p = 0.0332), and (iii) modified vasodilator response due to PGI2 synthesis inhibition (in the intervention group) vs. modified ACh-induced vasodilator response due to (iv) COX inhibition and v) PGI2 synthesis inhibition with thromboxane receptor blockage after 18 weeks on F diet (in the fatty group). Our results show that supplementation with Cr–Pic rather than with Cr–NPs is more beneficial in rats who regularly consumed an F diet (e.g., for 18 weeks). On the contrary, in the intervention group (9 weeks on F diet + 9 weeks of dietary fat normalization (the S diet)), Cr–Pic and Cr–NPs could function as pro-oxidant agents, initiating free-radical reactions that led to oxidative stress. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are commonly known for their immune-suppressive abilities. However, our group provided evidence that it is possible to convert MSCs into potent antigen presenting cells (APCs) using either genetic engineering or pharmacological means. Given the capacity of UM171a to trigger APC-like function in MSCs, and the recent finding that this drug may modulate the epigenome by inhibiting the lysine-specific demethylase 1 (LSD1), we explored whether the direct pharmacological inhibition of LSD1 could instill APC-like functions in MSCs akin to UM171a. The treatment of MSCs with the LSD1 inhibitor tranylcypromine (TC) elicits a double-stranded (ds)RNA stress response along with its associated responsive elements, including pattern recognition receptors (PRRs), Type-I interferon (IFN), and IFN-stimulated genes (ISGs). The net outcome culminates in the enhanced expression of H2-Kb, and an increased stability of the cell surface peptide: MHCI complexes. As a result, TC-treated MSCs stimulate CD8 T-cell activation efficiently, and elicit potent anti-tumoral responses against the EG.7 T-cell lymphoma in the context of prophylactic vaccination. Altogether, our findings reveal a new pharmacological protocol whereby targeting LSD1 in MSCs elicits APC-like capabilities that could be easily exploited in the design of future MSC-based anti-cancer vaccines. [ABSTRACT FROM AUTHOR]

Introduction Tranylcypromine (TCP), an irreversible monoamine oxidase inhibitor (MAOI), is recommended for difficult-to-treat depression. Besides the requirement of a low-tyramine diet, there are concerns about the safety of TCP treatment during anaesthesia and electroconvulsive therapy (ECT). For safety reasons, many psychiatrists prefer to terminate TCP before ECT. Objectives To assess the safety of tranylcypromine treatment during ECT series in patients with difficult-to-treat depression (DTD). Methods In this retrospective study we report on n=19 patients, who were treated with tranylcypromine during the ECT series. ECT parameters, clinical and safety data were obtained from our clinical database. Results Mean age of patients was 51 years (range 29-77) at time of the first ECT sessions. 58 % (n=11) of patients were female. In total, 198 ECT sessions were analysed (mean 11, median 9,5 per patient). Mean TCP dose was 44 mg at time of first ECT (median 43). Concomitant TCP and ECT treatments were well tolerated during the entire ECT series. In one case TCP treatment was discontinued due to self-limiting bigeminus during the ECT session. In another case TCP and other drugs as well as the ECT series were stopped after the patient developed delirium. At the end of ECT series the mean TCP dosage was 37 mg. Conclusions Tranylcypromine appears to be safe during ECT series and does not necessarily have to be terminated prior to electroconvulsive therapy. Disclosure No significant relationships.

Background: Although multiple studies and meta-analyses have documented the rapid antidepressive efficacy of ketamine, there are numerous questions regarding the practical use in the clinical routine that are still unanswered. Objective: Based on personal clinical experience, by comparison and supplementation of the current data situation, answers are given to questions regarding the practical use of ketamine for depression that have not yet been satisfactorily clarified. Material and methods: The clinical experiences with antidepressive treatment using ketamine over more than 5 years were evaluated with respect to the questions at hand. This was followed by a qualitative comparison of these results with those of a narrative literature search. Results: A total of 72 patients (unipolar depression n = 53, bipolar depression n = 16, schizoaffective depression n = 3) were included in the analysis of this cohort. A statistically significant reduction of depressive symptoms and suicidal ideation after S-ketamine treatment was found. Of the patients 61% suffered from at least one secondary diagnosis. A dose of 0.5 mg/kg body weight of S‑ketamine at a frequency of three times per week was shown to be effective. The treatment appears to be safe with respect to urotoxic side effects, combination treatment with tranylcypromine and in comorbid posttraumatic stress disorder. Conclusion: Ketamine appears to be a safe and effective option for the treatment of unipolar and bipolar depression. [ABSTRACT FROM AUTHOR]

Background:Tranylcypromine is a monoamine oxidase inhibitor (MAOI)-it is a nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO). It is used as an antidepressant and anxuolytic agent in the clinical treatment of mood and anciety disorders, respectively. In this research, the effects of Tranylcypromine the serum concentrations of LH, FSH and Testosterone as well as changes in body weight and testicular tissue were studied in rats. Material and Methods: 50 adult male Wistar rats with approximate weight of 200-250 gr were divided into 5 groups of 10 animals: the control ,sham group and three experimental groups receiving 40, 20 and 10 mg/ kg Tranylcypromine, respectively. The drug was orally administered for 21 days. Following wighting at the end of this period, blood samples were taken from each rats, centrifuged to obtain serum, and testis were removed,weighted and fixed to examine their possible histological changes. Serum samples were frozen at -20 to be studied later. The serum cocentrations of LH, FSH and testosterone were measured by RIA. After tissue sectioning and staining with hematoxylin-eosin, testicular tissues were examined by light microscope. The SPSS and Excel software and ANOVA and Tukey tests were used for statistic analyze. Results: The results showed that 21 days consumption of maximum doses of Tranylcypromine, significantly increases concentrations of LH and FSH hormones and significantly reduce testosterone concentration in maximum doses and leydig cells in all three experimental groups (P≥0.05). In addition, no significant effect was observed in the body weight, testicular weight as well as Sertoli cells. Moreover, testicular tissue study indicates that 21 days of Tranylcypromine consumption significantly reduces spermatogony,spermatid , spermatocyte and thus, affects spermatogenesis. Conclusion: Tranylcypromine drug reduced levels of testosterone and increase levels of LH and FSH hormones.

The classic monoamine oxidase inhibitors (MAOIs) tranylcypromine (TCP) and phenelzine (PLZ) are powerful antidepressants that come with an equally powerful stigma, and are thus rarely prescribed—despite their well-established effectiveness. Some of these preconceptions appear to stem from unclarity, as the etiology of a rare but important side effect, 'spontaneous hypertension' (SH)—a significant increase in blood pressure absent dietary tyramine ingestion—remains improperly elucidated. This paper aims at uprooting some of the stigma surrounding MAOIs by advancing the trace amine (TA) theory as the causative underpinning of SH. This theory posits that SH results from the considerable influx of TAs observed following TCP- or PLZ-administration. TAs are known, albeit at greatly supraphysiological levels, to raise blood pressure on account of their propensity to exert potent indirect sympathomimetic effects; additionally, some research posits that TAs may induce vasoconstrictive effects partly or wholly separate therefrom, which would then constitute a second hypertensive mechanism. TAs are endogenous to the human body in low quantities. Both TCP and PLZ cause marked elevations of 2-phenylethylamine (PEA), meta- and para-tyramine (m-/p-TYR), octopamine (OA), and tryptamine (TRYP), following both acute and (sub)chronic administration. This paper holds that TYR plays a pivotal role in causing SH, due to its strong pressor effect. Cautious treatment of SH is advised, given its typically self-limiting nature. The risk of hypotensive overshoots must be taken into account. For severe cases, this paper urges reconsideration, following suitable confirmation trials, of antipsychotics (notably risperidone) as these agents may reduce striatal p-TYR levels. [ABSTRACT FROM AUTHOR]

Objectives: Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency. Experimental Approach: Disease model : Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain. Methods: In situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved. Results: Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression. Conclusion: To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region. [ABSTRACT FROM AUTHOR]

ObjectivesTbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency.Experimental ApproachDisease model: Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain.MethodsIn situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved.ResultsCortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression.ConclusionTo our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region.

Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild-type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are commonly known for their immune-suppressive abilities. However, our group provided evidence that it is possible to convert MSCs into potent antigen presenting cells (APCs) using either genetic engineering or pharmacological means. Given the capacity of UM171a to trigger APC-like function in MSCs, and the recent finding that this drug may modulate the epigenome by inhibiting the lysine-specific demethylase 1 (LSD1), we explored whether the direct pharmacological inhibition of LSD1 could instill APC-like functions in MSCs akin to UM171a. The treatment of MSCs with the LSD1 inhibitor tranylcypromine (TC) elicits a double-stranded (ds)RNA stress response along with its associated responsive elements, including pattern recognition receptors (PRRs), Type-I interferon (IFN), and IFN-stimulated genes (ISGs). The net outcome culminates in the enhanced expression of H2-Kb, and an increased stability of the cell surface peptide: MHCI complexes. As a result, TC-treated MSCs stimulate CD8 T-cell activation efficiently, and elicit potent anti-tumoral responses against the EG.7 T-cell lymphoma in the context of prophylactic vaccination. Altogether, our findings reveal a new pharmacological protocol whereby targeting LSD1 in MSCs elicits APC-like capabilities that could be easily exploited in the design of future MSC-based anti-cancer vaccines.

Purpose: The prevalence of comorbid depression and chronic kidney disease (CKD) is high. The aim of this brief report was to review 2 cases of treatment with tranylcypromine (TCP) in patients with treatment-resistant depression (TRD) and CKD. Tests of the plasma concentration of TCP were included., Methods: Medical and psychiatric notes of the 2 patients were reviewed with plasma concentrations of TCP as a key aspect of the discussion. The data are evaluated in the context of relevant medical and pharmacokinetic literature., Findings: Plasma concentrations of TCP are highly variable both in patients with and without CKD. Plasma concentrations of TCP were not increased in the 2 cases with CKD as compared with literature data of patients without CKD. No signs of intoxication were detected in 2 cases with CKD that impaired continuous treatment of depression with TCP., Implications: TCP may be considered in selected cases of TRD with concomitant CKD. More clinical data and tests of plasma concentrations of TCP are needed in patients with CKD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract Background Medulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors. Methods Expression of LSD1 was examined across a publicly-available database and correlated with patient outcomes. Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis. Resulting clusters were examined for patient outcomes associated with LSD1 and REST expression. Human SHH MB cell lines were transduced with a REST-transgene to create isogenic cell pairs. In vitro viability and cell migration assays were used to examine the effect of LSD1 knockdown or inhibition on these parameters. Results We demonstrate that subsets of SHH MB tumors have elevated LSD1 expression coincident with increased expression of its deubiquitylase, USP7, and REST. Patients with co-elevation of USP7, REST, and LSD1 have poorer outcomes compared to those with lower expression of these genes. In SHH MB cell lines, REST elevation increased cell growth and LSD1 protein levels. Surprisingly, while genetic loss of LSD1 reduced cell viability, pharmacological targeting of its activity using LSD1 inhibitors did not affect cell viability. However, a reduction in REST-dependent cell migration was seen in wound healing, suggesting that REST-LSD1 interaction regulates cell migration. Ingenuity pathway analyses validated these findings and identified Hypoxia Inducible Factor 1 alpha (HIF1A) as a potential target. In line with this, ectopic expression of HIF1A rescued the loss of migration seen following LSD1 inhibition. Conclusions A subset of SHH patients display increased levels of LSD1 and REST, which is associated with poor outcomes. REST elevation in MB in conjunction with elevated LSD1 promotes MB cell migration. LSD1 inhibition blocks REST-dependent cell migration of MB cells in a HIF1A-dependent manner.

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood.The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats.Nicotine (0, 0.05, 0.2 mg/kg, s.c.) and tranylcypromine (3 mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field.Nicotine (0.2 mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2 mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment.There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors.