Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stereospecific form of the known acetylenic mechanism-based MAO-inhibitor AGN1135 (Rasagiline, TVP-1012) is devoid of sympathomimetic amphetamine-like properties. To evaluate the efficiency and selectivity of subcutaneous injections of TVP-1012 (dose range from 0.01 up to 10 mg/kg for 7 days) the activities of monoamine oxidases A and B (MAO-A,-B) were determined in different brain regions of the common marmoset. At a dose of 0.1 mg/kg TVP-1012, almost 80% of MAO-B activity is inhibited in all brain regions investigated (prefrontal and occipital cortex, cerebellum, caudate nucleus, putamen, nucleus accumbens). In contrast, MAO-A is not inhibited in putamen and nucleus accumbens. However, by increasing the TVP-1012 dose to 0.5 mg/kg, MAO-A is inhibited to a significant extent as well, concomitant to total inhibition of MAO-B. The results obtained indicate that TVP-1012 irreversibly inhibits both types of MAO in the common marmoset with selectivity for MAO-B at doses less than 0.5 mg/kg. TVP-1012 could be useful in studies requiring selective MAO-B inhibition without concomitant sympathomimetic amphetamine-like effects and could thus be of therapeutic interest for Parkinson's disease and retarded depression.
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PMID:Chronic TVP-1012 (rasagiline) dose--activity response of monoamine oxidases A and B in the brain of the common marmoset. 956 27

The onset of action (during the first 2 weeks of treatment) of moclobemide (450 mg/day), a reversible MAO-A inhibitor, was compared in a double-blind, multi-center trial with clomipramine (150 mg/day) on dimensional and global depressive symptoms in 124 hospitalized patients suffering from a major depressive episode according to DSM-III-R criteria and with blunted affect and retardation. An earlier efficacy was found for moclobemide with significant treatment differences in favor of moclobemide, which were detected on negative symptoms (anhedonia, blunted affect and retardation) on days 7 and 10. The overall effect on depression at the end of the 4-week trial period was similar in both groups. However, a higher termination rate due to lack of efficacy was found with moclobemide (10 vs. 3). The tolerability was significantly better for moclobemide, as shown by the lower frequency of adverse events.
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PMID:Dimensional assessment of onset of action of antidepressants: a comparative study of moclobemide vs. clomipramine in depressed patients with blunted affect and psychomotor retardation. 970 73

Depression is common in multiple sclerosis (MS) patients, but tricyclic compounds are not well tolerated and newer antidepressants have not been studied. Effects of 150-400 mg/day of moclobemide, a reversible monoamine oxidase A inhibitor, were studied in a 3-month open design in 10 MS patient with DSM-IV-diagnosed depression. Nine patients reached complete remission. No adverse effects were noted. Four patients reported side effects including nausea and insomnia. The authors conclude that moclobemide is a well tolerated and efficient treatment for depression comorbid with MS.
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PMID:Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. 1033

Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.
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PMID:A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action. 1048 60

We describe an animal model of long-term depression based on active immunization of albino rats against BSA-conjugated inhibitor of monoamine oxidase, antidepressant, pargyline. Immunization resulted in anti-pargyline antibody formation and significant activation of monoamine oxidase A in brain. Immunized rats demonstrated potent decrease of motor, orientation and exploratory activity, increase of the immobility time ("despair") in Porsolt test, as well as notable signs of fear and anxiety in elevated plus maze. The cognitive processes were not significantly affected: the speed of learning with negative and positive reinforcement was not diminished. Complex effect on craving for alcohol (long-term suppression after short-term increase) was also demonstrated. The long-term (more than 45 days) depression achieved in this model makes it potentially important tool for testing new antidepressant pharmaceuticals.
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PMID:Pargyline conjugate-induced long-term activation of monoamine oxidase as an immunological model for depression. 1048 86

The dichloromethane fraction from Areca catechu was found to inhibit monoamine oxidase type A isolated from the rat brain with an IC50 of 665 +/- 65.1 microg/ml. Studies with pharmacological models of depression, i.e., forced swim and tail-suspension tests, indicated that it caused significant reduction in the immobility time similar to that of moclobemide (a selective inhibitor of MAO-A) without causing a significant change in motor performance. Alkaloids such as arecaidine, arecoline, and a few other constituents, reported to be present in Areca catechu were also tested, but none of them were found to inhibit MAO. Present study suggests that the dichloromethane fraction from A. catechu possesses antidepressant property via MAO-A inhibition.
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PMID:Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut. 1063 28

A reduction in glucocorticoid receptor (GR) function leads to hippocampus-dependent allocentric spatial learning deficits, altered novelty exploration and disrupted hippocampal long-term potentiation (LTP) in transgenic mice expressing a GR antisense construct. After continuous long-term treatment of these mice with moclobemide (a reversible inhibitor of monoamine oxidase A), spatial navigation performance but not accuracy improved during initial acquisition. These changes were associated with a shift of the threshold for the induction of hippocampal LTP at low stimulation frequencies. Moreover, novel object exploration increased in both control and transgenic animals following long-term treatment with moclobemide. These findings open the possibility that antidepressants might improve hippocampal function under conditions of impaired stress hormone regulation, and that these drugs might in part act through this mechanism to attenuate cognitive deficiency in disorders such as depression.
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PMID:Effects of the monoamine oxidase A inhibitor moclobemide on hippocampal plasticity in GR-impaired transgenic mice. 1128 54

Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished corticosteroid receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of neurological impairment, 2.0--6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the moclobemide group vs. 225.8 +/- 65.1 in the steroid alone group; mean +/- SEM]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 vs.177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 vs. 199.2 +/- 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with corticosteroids favors normalization of the HPA response in relapsing-remitting MS.
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PMID:Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial. 1129 92

Idiopathic Parkinson's disease (PD) is a common neurodegenerative disorder with prominent motor symptoms. However, depression is common in PD, affecting about 40% of PD patients. Since there is extensive evidence of degeneration of serotonin (5HT) neurons and loss of the 5HT transporter (5HTT) in PD, we assessed whether a functional polymorphism in the promoter of the 5HTT gene (5HTT gene-linked polymorphic region, 5HTTLPR), which determines high or low 5HT uptake, is associated with depressive symptomatology in PD patients. We found that patients with the short allele of the 5HTTLPR had significantly higher scores on the Hamilton Depression Scale. A functional promoter polymorphism of the monoamine oxidase A (MAOA) gene showed no association. Thus, the 5HTTLPR but not the MAOA gene promoter-associated polymorphism may be a risk factor for depression in PD patients, while neither polymorphism increases the risk for development of Parkinson's disease itself.
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PMID:Allelic variation of serotonin transporter expression is associated with depression in Parkinson's disease. 1132 8

Alteration of monoaminergic neurotransmission is implicated in the pathophysiology of bipolar disorder (manic-depressive illness). Candidate genes participating in monoaminergic neurotransmission, especially serotonin transporter and monoamine oxidase A, may be associated with bipolar disorder. And the regulating regions of these genes and the molecules participating in intracellular signal transduction are now under investigation. To date, 13 whole genome positional cloning studies have been performed and many candidate loci identified. Using patients from a pedigree in which schizophrenia, depression or bipolar disorder have been linked with a balanced translocation at 1 and 11, candidate pathogenetic genes were cloned as DISC1 (disrupted in schizophrenia-1) and DISC2. Recently, pathogenetic mutations have been identified in two genetic diseases frequently co-morbid with mood disorder; WFS1 for Wolfram syndrome and ATP2A2 (SERCA2) for Darier's disease. Transmission of bipolar disorder may be characterized by anticipation and parent-of-origin effect, and extended CTG repeat at SEF2-1B gene was identified from a bipolar patient. However, its pathogenetic role was not supported by subsequent studies. Association of bipolar disorder with mitochondrial DNA has also been suggested. The role of genomic imprinting is also possible because linkage to 18p11 is limited to paternally transmitted pedigrees. These results warrant further study of molecular genetics of bipolar disorder.
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PMID:Molecular genetics of bipolar disorder. 1137 48


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