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)

Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.
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PMID:The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. 1908 93

The effects of irreversible synthetic inhibitor of dipeptidyl peptidase IV (DPPIV) methionyl-2(S)-cyano-pyrrolidine on behavior of adolescent and adult rats were studied. The inhibitor was administered in early postnatal period from day 5 to day 19 (1 mg/kg, i.p.) in rat pups (males and females). In 1-2-month-old males treated with inhibitor of DPPIV, increased anxiety was revealed in the elevated plus maze and in the open field, 2- and 7-month-old males demonstrated the increased anxiety in a special battery of tests for evaluating anxiety-phobic states, whereas in female 1-3 months-old rats, the increased anxiety was observed in the elevated plus-maze. The depression-like behavior in the forced swimming test was revealed in 2-3 month-old males and in 2- and 7-month-old females. Adolescent and adult (1-2-month-old) rats of both genders and 7-month-old females demonstrated anhedonia in sucrose consumption/preference test. The findings prove the development of anxiety-depression-like state in rats postnatally exposed to inhibitor of DPPIV and suggest the DPPIV involvement in the development of anxiety and depression.
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PMID:[Experimental model of anxiety-depression state in rats exposed to inhibitor of dipeptidyl peptidase IV methionyl-2(S)-cyano-pyrrolidine in early postnatal period]. 1959 3

We studied the dynamics of activity of dipeptidyl peptidase IV (DP-IV) and prolyl endopeptidase (PEP) in the frontal cortex, hypothalamus, striatum, nucleus accumbens, and hippocampus of rats with experimental anxiety-depression state induced by administration of methionyl-2(s)-cyano-pyrrolidine, an inhibitor of DPP-IV, in the early postnatal period. In 1-month-old experimental males, PEP and DP-IV activities increased in the frontal cortex and hypothalamus, while in 1-month-old experimental females PEP activity increased in the hippocampus and DP-IV activity increased in all studied brain structures. At the age of 3 months, increased PEP activity in the hypothalamus and nucleus accumbens was detected in males and decreased DP-IV activity in the nucleus accumbens and decreased PEP activity in the hippocampus were detected in females. At the age of 7 months, PEP activity increased in the frontal cortex and striatum and DP-IV activity increased in all studied brain structures in males; in 7-months-old females, activity of both enzymes increased in the striatum.
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PMID:Activities of proline-specific peptidases in brain structures of rats with experimental anxiety-depressive state caused by administration of dipeptidyl peptidase IV inhibitor in the early postnatal period. 2248 5

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.
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PMID:Effect of imipramine and prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in the brain of rats with experimental anxious-depressive syndrome. 2280 98

In two models of depression-like state--"behavioral despair" and experimental dopamine deficit-dependent MPTP-induced depression-like syndrome--as well as in a model of anxiety-depression-like state induced by dipeptidyl peptidase IV inhibitor methionyl-2(s)-cyanopyrrolidine administered in early postnatal period, the symptoms of behavioral depression in rats in the forced swim test were accompanied by the increase of corticosterone level in blood serum. In every model non-competitive prolyl endopeptidase (PEP) inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine showed antidepressant-like properties preventing the development of depressive-like behavior. PEP Inhibitor also prevented the increase of serum corticosterone level in the models of "behavioral despair" and anxiety-depressive state, but not in the model of MPTP-induced depression-like syndrome. These findings testify for the involvement of hypothalamic-pituitary-adrenal system in the implementation of depression-like behavior in the specified models of depression-like state.
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PMID:[Blood serum corticosterone level in modeling depression-like states in rats]. 2464 Jul 66

The plasma activity of nine aminopeptidases was monitored over a year in first-episode psychotic patients. We observed significant differences in aminopeptidase B (APB), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPPIV), but not in puromycin-sensitive aminopeptidase (PSA), prolyl endopeptidase (PEP), cysteine aminopeptidase (Cys-AP), aspartate aminopeptidase (Asp-AP), glutamate aminopeptidase (Glu) or piroglutamate aminopeptidase (PGI) in these patients compared to controls, and also a progressive increase in plasma activity, correlated to changes in scores on clinical scales, Global Assessment of Functioning scale (GAF) and Hamilton Depression Rating Scale (HDRS), at 1 month of follow-up. At 1 month after diagnosis, the median score obtained by patients on the GAF was negatively associated with the plasma activity of APB and PEP measured at the beginning of the psychotic episode, indicating a role as a negative prognostic factor that can predict psychiatric symptomatology. In the case of HDRS, scores at 1 month after diagnosis were found to be positively associated with the initial plasma activity of DPPIV, APN and PSA, indicating that their initial elevation is a negative prognostic factor that can predict subsequent depressive symptomatology. Taken together, these results suggest a pathophysiological involvement of plasma peptidases and indicate that aminopeptidase activity can predict the course of first-episode psychosis patients, acting as a prognostic indicator.
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PMID:Plasma peptidases as prognostic biomarkers in patients with first-episode psychosis. 2599 98

The inhibitors of proline specific peptidase dipeptidyl peptidase-IV (DPP-IV, CD 26; EC 3.4.14.5) diprotin A (2 mg/kg) and sitagliptin (4 mg/kg) upon daily systemic exposure in rat pups on postnatal days 1-7 induced emotional and motivational disorders in one- and two-month-old rats. In adolescent rats, both the inhibitors produced a decreased locomotion in the automated open field test and an in- creased depression-like behavior in the Forced Swimming Test. At the same time, diprotin A increased sucrose consumption (a percent of the body weight) while sitagliptin decreased anxiety in the Elevated Plus Maze (EPM). In adult rats, diprotin A caused an increase in anxiety according to the reduced pref- erence for open arms of the maze and both the inhibitors decreased the percentage of rats entering open. arms in the EPM. Adult diprotin A-treated animals demonstrated increased aggression in social contact test. as compared to sitagliptin-treated rats. The one-and two-month-old animals in both experimental groups exhibited a decreased weight as compared to the controls. The results of the study show that diprotin A compared with sitagliptin negatively affects emotional and motivational behavior in adolescent and adult rats by increased number of indices increasing depression, anxiety, and aggression, while the main result of sitagliptin is increased depression when the animals were treated with the DPP-IV inhibitors in the first postnatal week. The findings support the hypothesis that DPPIV is involved in the genesis of emotional-motivational disorders.
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PMID:[Emotional Motivational Disorders in Rats as a Result of Diprotin A and Sitagliptin Administration in the First Postnatal Week]. 3069 19


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