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- How treatable is refractory depression? [JOURNAL ARTICLE]
- J Affect Disord 2014 Jun 4.:148-152.
Patients who do not remit following one or more attempts at treatment present a clinical challenge, as well as prolonged suffering and disability. Discouragement is common, so knowledge of likelihood of eventual remission as well as which treatments might ultimately be effective would help patient and clinician alike.Thirty-one patients with major depression were recruited, 28 beginning study treatment. All had remained significantly depressed following adequate (4 weeks taking ≥ PDR maximum dose) trials on ≥ two antidepressants having different presumed mechanisms. Patients were begun on tranylcypromine to 60mg/d, were then treated with up to 120mg/d and then had dextroamphetamine added. Following two week wash-out, patients were then treated with nortriptyline+lithium, and then phenelzine was added. Each successive phase was entered only if remission had not been achieved, and phases could be skipped.Eighteen of the 28 patients (65%) remitted in one of the five phases of the study, plus 5 additional patients with open post-study treatment (total remitting, 82%). By study phase, Eight of 27 (30%) patients remitted with initial dosing of tranylcypromine up to 60mg/d, 6/18 (33%) remitted with above PDR dosing of tranylcypromine up to 120mg/d, and 1/6 (17%) to adding dextroamphetamine. With nortriptyline, 1/10 (10%) remitted with nortriptyline+lithium, and 1/5 (20%) when phenelzine was added. Eighteen of the 28 patients (64%), or 78% of those who remitted, maintained their good benefit for at least six months.The majority of depressed patients refractory to two or more adequately utilized differently acting antidepressant medications can still remit and about half may maintain remission for extended periods. "Refractory depression" appears to be a relative description for many unresponsive depressed patients.(1.)
- Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells. [JOURNAL ARTICLE]
- Breast Cancer Res Treat 2014 Jun 13.
Increasing evidence suggests that dysfunction of histone lysine demethylase is associated with abnormal chromatin remodeling and gene silencing, contributing to breast tumorigenesis. In silico analysis shows that the newly identified histone demethylase lysine-specific demethylase 2 is highly expressed in breast cancer, especially in invasive tumors. However, it is currently unknown how LSD2 regulates chromatin remodeling and gene expression regulation in breast cancer. Using short hairpin RNA, we stably knocked down LSD2 (LSD2-KD) in MDA-MB-231 breast cancer cells. LSD2-KD led to accumulation of H3K4me1/2 without changing methylation levels of other key histone lysine residues, suggesting that LSD2 acts as a bona fide H3K4 demethylase in breast cancer cells. LSD2-KD resulted in decreased colony formation and attenuated global DNA methylation in MDA-MB-231 cells. Additionally, treatment with the DNMT inhibitor, 5-aza-deoxycytidine (DAC), synergistically increased mRNA expression of aberrantly silenced genes important in breast cancer development, including PR, RARβ, ERα, SFRP1, SFRP2, and E-cadherin in LSD2-KD cells. Furthermore, LSD2-KD cells are more susceptible to cell death than scramble controls, and combined treatment with tranylcypromine, an LSD2 inhibitor, and DAC resulted in synergistic growth inhibition of breast cancer cells. DNMT inhibition by DAC in LSD2-KD cells led to internucleosomal DNA fragmentation, enhanced PARP cleavage and increased sub-G1 apoptotic cell population. These results demonstrate an important role for LSD2 in regulation of DNA methylation and gene silencing in breast cancer, and suggest that inhibition of LSD2 in combination with DNA methyltransferase inhibition represents a novel approach for epigenetic therapy of breast cancer.
- Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons. [JOURNAL ARTICLE]
- Int J Neuropsychopharmacol 2014 Jun 5.:1-16.
Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.
- Lysine specific demethylase 1-mediated demethylation of histone H3 lysine 9 contributes to interleukin 1beta-induced microsomal prostaglandin E synthase-1 expression in human osteoarthritic chondrocytes. [JOURNAL ARTICLE]
- Arthritis Res Ther 2014 May 16; 16(3):R113.
Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE2, a critical mediator in the pathophysiology of osteoarthritis (OA). Histone methylation plays an important role in epigenetic gene regulation. In this study, we investigated the roles of histone H3 (H3K9) methylation in interleukin-1beta (IL-1beta)-induced mPGES-1 expression in human chondrocytes.Chondrocytes were stimulated with IL-1beta and the expression of mPGES-1 mRNA was evaluated using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). H3K9 methylation and the recruitment of the histone demethylase LSD1 to the mPGES-1 promoter were evaluated using chromatin immunoprecipitation (ChIP) assays. The role of LSD1 was further evaluated using the pharmacological inhibitors, tranylcypromine and pargyline, and siRNA-mediated gene silencing. The LSD1 level in cartilage was determined using RT-PCR and immunohistochemistry.The induction of mPGES-1 expression by IL-1beta correlated with decreased levels of mono- and dimethylated H3K9 at the mPGES-1 promoter. These changes were concomitant with the recruitment of the histone demethylase LSD1. Treatment with tranylcypromine and pargyline, potent inhibitors of LSD1, prevented IL-1beta -induced H3K9 demethylation at the mPGES-1 promoter and mPGES-1 expression. Consistently, LSD1 gene silencing with siRNA prevented IL-1beta -induced H3K9 demethylation and mPGES-1 expression, suggesting that LSD1 mediates IL-1beta -induced mPGES-1 expression via H3K9 demethylation. Finally, we showed that the level of LSD1 was elevated in OA compared to normal cartilage.These results indicate that H3K9 demethylation by LSD1 contributes to IL-1beta -induced mPGES-1 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA and possibly other arthritic conditions.
- Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists. [JOURNAL ARTICLE]
- J Med Chem 2014 May 22.
We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor with low affinity (Ki = 12.8 µM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has Ki values of 2.7 nM and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays selectivities of >10,000-fold and 223-fold over the rat and human D2 receptors, respectively. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor.
- The Antidepressant Tranylcypromine Alters Cellular Proliferation and Migration in the Adult Goldfish Brain. [JOURNAL ARTICLE]
- Anat Rec (Hoboken) 2014 May 12.
The goldfish (Carassius auratus) is a widely studied vertebrate model organism for studying cell proliferation in the adult brain, and provide the experimental advantage of growing their body and brain throughout their ∼30-year life time. Cell proliferation occurs in the teleost brain in widespread proliferation zones. Increased cell proliferation in the brain has been linked to the actions of certain antidepressants, including tranylcypromine (TCP), which is used in the treatment of depression. We hypothesized that proliferation zones in the adult goldfish brain can be used to determine the antidepressant effects on cellular proliferation. Here, we report that bromodeoxyuridine (BrdU) labeling over a 24-hr period can be used to rapidly identify the proliferation zones throughout the goldfish brain, including the telencephalon, diencephalon, optic tectal lobes, cerebellum, and facial and vagal lobes. In the first 24 hr of BrdU administration, TCP caused an approximate and significant doubling of labeled cells in the combined brain regions examined, as detected by BrdU immunohistochemistry. TCP caused the greatest increase in cell proliferation in the cerebellum. The normal migratory paths of the proliferating cells within the cerebellum were not affected by TCP treatment. These results indicate that the goldfish provide significant advantages as a vertebrate model for rapidly investigating the effects of antidepressant drugs on cellular proliferation and migration in the normal and injured brain. Anat Rec, 2014. © 2014 Wiley Periodicals, Inc.
- Severe hypertension related to caffeinated coffee and tranylcypromine: a case report. [Journal Article]
- Ann Intern Med 2014 May 6; 160(9):657-8.
- The Murine Serotonin Syndrome-Evaluation of Responses to 5-HT-enhancing Drugs in NMRI Mice. [JOURNAL ARTICLE]
- Behav Brain Res 2014 Apr 26.
In humans, the ingestion of the combination of two or more serotonin (5-HT)-enhancing drugs but also of a single drug in overdose can induce serious adverse effects, which are characteristics of the serotonin syndrome (SS). In mice, acute administration of direct and indirect 5-HT agonists also leads to behavioral and autonomic responses, but in literature different responses are thought to be essential. In order to detect common behavioral SS responses induced by 5-HT-enhancing drugs with different mechanisms of action, we investigated the effects of the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), and the monoaminooxidase (MAO) inhibitor tranylcypromine (TCP) in male NMRI mice. The drugs were administered alone or in combination to investigate additive effects or drug potentiation. Moreover, we compared the 5-HT responses to the effects induced by the dopamine, noradrenaline, and cholinergic agonists, apomorphine (APO), atomoxetine (ATO), and oxotremorine (OXO). Our results show that the studied 5-HT-enhancing drugs induced a different number of concomitant responses. The following five responses consistently and dose-dependently occurred in NMRI mice: flat body posture, hindlimb abduction, piloerection, tremor, and decreased rearings. Like in humans, the combination of 5-HT-enhancing drugs leads to a potentiation of drug effects. With the exception of flat body posture the responses are not specific for serotonergic hyperactivity. The findings demonstrate that the SS in NMRI mice is a suitable animal model for preclinical research, if it is taken into account that the spectrum of typical responses to 5-HT enhancing drugs may differ depending on drug and mouse strain and that some responses might be evoked by activation of other transmission systems, too.
- Elevation of rat brain tyrosine levels by phenelzine is mediated by its active metabolite β-phenylethylidenehydrazine. [JOURNAL ARTICLE]
- Prog Neuropsychopharmacol Biol Psychiatry 2014 Mar 6.:67-73.
Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from phenelzine. In the present report, we have found that phenelzine and E- and Z-geometric isomers of PEH significantly increased rat whole brain concentrations of l-tyrosine. In a time-response study, acute administration of phenelzine, E-PEH and Z-PEH (30mg/kg i.p.) elevated rat whole brain l-tyrosine levels at 3 and 6h following injection, reaching approximately 265-305% of vehicle-treated controls at 3h. To determine whether the effect on l-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kg i.p.) prior to administration of phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of phenelzine, but not of PEH, on brain l-tyrosine levels, suggesting that the tyrosine-elevating property of phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.
- Computational comparison of imidazoline association with the i2 binding site in human monoamine oxidases. [Journal Article]
- J Chem Inf Model 2014 Apr 28; 54(4):1200-7.
Imidazoline ligands in I2-type binding sites in the brain alter monoamine turnover and release. One example of an I2 binding site characterized by binding studies, kinetics, and crystal structure has been described in monoamine oxidase B (MAO B). MAO A also binds imidazolines but has a different active site structure. Docking and molecular dynamics were used to explore how 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) binds to MAO A and to explain why tranylcypromine increases tight binding to MAO B. The energy for 2-BFI binding to MAO A was comparable to that for tranylcypromine-modified MAO B, but the location of 2-BFI in the MAO A could be anywhere in the monopartite substrate cavity. Binding to the tranylcypromine-modified MAO B was with high affinity and in the entrance cavity as in the crystal structure, but the energies of interaction with the native MAO B were less favorable. Molecular dynamics revealed that the entrance cavity of MAO B after tranylcypromine modification is both smaller and less flexible. This change in the presence of tranylcypromine may be responsible for the greater affinity of tranylcypromine-modified MAO B for imidazoline ligands.