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)

Pro-inflammatory cytokines are known to be elevated in several pathological conditions that are associated with deficits in cognition. We have previously demonstrated that interleukin-18 (IL-18) inhibits long-term potentiation (LTP) in the dentate gyrus in vitro. In this study we have examined the involvement of the inflammatory mediators COX-2 and iNOS in IL-18-mediated inhibition of LTP. The effect of an anti-inflammatory PPARgamma agonist was also investigated. We report that the impairment of LTP by IL-18 is significantly attenuated by prior application of the COX-2 inhibitor, SC-236 and the iNOS inhibitor 1400W. These agents had no effect on paired pulse depression in the dentate gyrus. Furthermore, application of the PPARgamma agonist ciglitazone also attenuated IL-18-mediated inhibition of LTP. We discuss a role for p38 MAP kinase in these effects. This study provides novel evidence for the involvement of inflammatory mediators in IL-18-mediated inhibition of LTP in the rat dentate gyrus in vitro.
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PMID:A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus. 1745 25

Sepsis is a major cause of morbidity and mortality. NO, an endogenous vasodilator, has been associated with the hypotension, catecholamine hyporesponsiveness, and myocardial depression of septic shock. Although iNOS is thought to be responsible for the hypotension and loss of vascular tone occurring several hours after endotoxin administration, little is known on the effects of constitutive eNOS on LPS-induced organ dysfunction. This study assessed the distribution of eNOS and iNOS in various vascular beds in conscious pigs challenged with LPS. Cardiac and regional hemodynamic parameters were recorded over 8 h in the presence and absence of aminoguanidine, a rather selective inhibitor of iNOS activity, and N-methyl-L-arginine, a nonspecific NOS inhibitor. Our data show that LPS-induced cardiac depression was associated with coronary, renal, and mesenteric vasoconstrictions and a hepatic vasodilatation. LPS also induced increases in eNOS in the heart and lungs, whereas iNOS was mostly detected in the liver. Nitrotyrosine formation was mainly detected in the lungs, with traces in the kidney, liver, and gut. Accordingly, our results suggest that the early decrease in blood pressure and cardiac depression are likely due to activated eNOS, whereas both isoforms are involved in the hepatic vasodilation. In contrast, carotid, coronary, mesenteric, and renal vasoconstrictions were significant at 5 and/ or 6 h after LPS infusion, suggesting that NO is not the primary mediator, facilitating and/or unmasking the release of vasoconstrictor mediators. Consequently, developing newer tissue- or isoform-specific NOS inhibitors can lead to novel therapeutic agents in septic shock.
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PMID:Distribution of NOS isoforms in a porcine endotoxin shock model. 1790 54

Agmatine is an endogenous neuromodulator that, based on animal studies, has the potential for new drug development. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared with other monoamines. Agmatine was long thought to be synthesised only in lower life forms, until its biosynthetic pathway (decarboxylation of arginine) was described in the mammalian brain in 1994. Human arginine decarboxylase has been cloned and shown to have 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon neuronal depolarisation. Other evidence of a neuromodulation role for agmatine is the presence of a specific cellular uptake mechanism and a specific metabolic enzyme (agmatinase; which forms putrescine).Initially, agmatine was conceptualised as an endogenous clonidine-displacing substance of imidazoline receptors; however, it has now been established to have affinity for several transmembrane receptors, such as alpha(2)-adrenergic, imidazoline I(1) and glutamatergic NMDA receptors. In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase. Endogenous agmatine is induced in response to stress and/or inflammation. Stressful conditions that induce agmatine include hypoxic-ischaemia and cold-restraint stress of ulcerogenic proportion. Induction of agmatine in the brain seems to occur in astrocytes, although neurons also synthesise agmatine. The effects of injected agmatine in animals include anticonvulsant-, antineurotoxic- and antidepressant-like actions. Intraperitoneal or intracerebroventricular injections of agmatine rapidly elicit antidepressant-like behavioural changes in the rodent forced swim test and tail suspension test. Intraperitoneal injections of agmatine into rats and mice also elicit acute anxiolytic-like behavioural changes in the elevated plus-maze stress test. In an animal model of acute stress disorder, intraperitoneal agmatine injections diminish contextual fear learning. Furthermore, intraperitoneal injections of agmatine reduce alcohol and opioid dependence by diminishing behaviour in a rat conditioned place preference paradigm. Based on these findings, agmatine appears to be an endogenous neuromodulator of mental stress. The possible roles and/or beneficial effects of agmatine in stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, merit further investigation.
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PMID:Agmatine : metabolic pathway and spectrum of activity in brain. 1792 94

Chronic, excessive alcohol consumption is associated with myocardial dysfunction in humans. The molecular mechanisms and cellular signaling pathways contributing to this cardiac dysfunction remain largely unknown. This study examined the effects of chronic alcohol consumption on myocardial function and cardiac myocyte signaling pathways. Adult male rats were fed a commercially prepared diet containing either ethanol (13 g/kg/d) or isocaloric control diet for 1 month. In vivo hemodynamics were measured in awake rats after inserting a catheter tip in the left ventricle under general anesthesia. Ventricular dysfunction was evidenced in awake, alcohol-fed rats by increased left ventricular end diastolic pressure, decreased systolic developed left ventricular pressure, and decreases in both positive and negative dp/dt compared with controls. Cardiac myocytes isolated from alcohol-fed rats also demonstrated an attenuated response to the beta-adrenergic agonist, isoproterenol, compared to controls. This response was significantly reversed by the nitric oxide synthase (NOS) inhibitor, N-monomethyl-L-arginine (L-NMMA). Western analyses confirmed inducible nitric oxide synthase (iNOS) protein synthesis in cardiac myocytes isolated from alcohol fed rats. It is therefore concluded that chronic alcohol ingestion results in iNOS-mediated attenuation of adrenergic signaling and depression in both systolic and diastolic function in rats.
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PMID:Inducible nitric oxide synthase attenuates adrenergic signaling in alcohol fed rats. 1809 87

Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. A variety of studies suggest an involvement of neuronal nitric oxide synthase in the pathophysiological mechanism of none-stress-associated depression-like behavior in rodents. It is unknown, however, whether inducible nitric oxide synthase (iNOS) also makes contributions to the mechanism of depression. Here we show that intra-hippocampal injections of the iNOS inhibitor aminoguanidine during chronic unexpected mild stress (CUMS) suppressed CUMS-induced depression-like behavioral changes, including a reduction in sucrose preference, body weight, locomotor activity, rearing and grooming in open field test, and increased duration of immobility in forced swimming test. Thus, inhibition of hippocampal iNOS may prevent the development of CUMS model of depression.
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PMID:Prevention of chronic stress-induced depression-like behavior by inducible nitric oxide inhibitor. 1824 96

Eating disorders (ED) are a group of important psychiatric disorders that affect young men and women, and can have serious consequences. Among all ED, anorexia nervosa (AN) is the most typical but also the most severe. The pathogenesis of AN is multifactorial and a great variety of cognitive deficits may contribute to its pathogenesis. The present study is aimed to measure NO and peroxynitrite production, iNOS and nNOS expression by Western immunoblot after incubation of AN lipoproteins at different times with human astrocytoma cells. The AN-HDL treated cells showed an increased production of NO at 3 h versus control-HDL treated cells and a decreased production at 24 h. Regarding LDL, a significant increase of NO production was obtained both at 3 and 24 h. The AN-HDL and AN-LDL treated cells showed an increased production of peroxynitrite both at 3 and 24 h compared to control lipoproteins. Densitometric analysis of bands indicated that both iNOS and nNOS protein levels were significantly higher in the cells incubated with AN lipoproteins compared to cells incubated with control lipoproteins both at 3 and 24 h. Although the pathogenesis of AN remains uncertain, evidence exists that modifications to the lipoprotein profile and cholesterol, structural alterations of phospholipids and integral constituents of myelin and synaptosomes may be related to psychotic disorders and body image distortion common to AN. Thus, a relevant pathophysiological association between NO and depression is certainly a possibility, as well as a central role played by NO in the pathogenesis.
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PMID:Lipoproteins obtained from anorexia nervosa patients induce higher oxidative stress in U373MG astrocytes through nitric oxide production. 1829 74

The mechanisms of tolerance to subsequent episodes of ischemia induced by cortical spreading depression (CSD) are not clear. The effects of CSD on the expression of inducible nitric oxide synthase (iNOS), hypoxia inducible factor-1alpha (HIF-1alpha), and lactate dehydrogenase-A (LDH-A) were evaluated in the present experiment. Unilateral CSD was induced in Sprague-Dawley rats by application of KCl on the right cortex and the mRNA levels of iNOS, HIF-1alpha, and LDH-A were evaluated at 15 min, 2 h, 4 h, 6 h or 24 h after CSD. RT-PCR analysis showed: 1) an increase of iNOS mRNA at 15 min, 2 h, 4 h; 2) an increase of HIF-1alpha mRNA at 6 h; 3) an increase of LDH-A mRNA at 4 h. In situ hybridization with specific digoxigenin-labeled oligonucleotides revealed that the mRNA levels were increased at 15 min-2 h for iNOS, 2-4 h for LDH-A and 6 h for HIF-1 after CSD. Immunohistochemistry analysis revealed that levels of iNOS and HIF-1alpha were increased, respectively, at 2 h and 6 h after CSD. These data suggest that CSD promotes the expression of iNOS, HIF-1alpha, and LDH-A in nervous cells giving a neuroprotective effect.
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PMID:Cortical spreading depression induces the expression of iNOS, HIF-1alpha, and LDH-A. 1835 26

The depression of cardiac contractility induced by space microgravity is an important issue of aerospace medicine research, while its precise mechanism is still unknown. In the present study, we explored effects of simulated microgravity on nitric oxide (NO) level, inducible nitric oxide synthase (iNOS) expression and related regulative mechanism using electron spin resonance (ESR) spectroscopy, immunocytochemistry and in situ hybridization. We found a remarkable increase of NO level and up-regulation of iNOS and iNOS mRNA expression in rat cardiac myocytes under simulated microgravity. Staurosporine (a nonselective protein kinase inhibitor), calphostin C (a selective protein kinase C inhibitor), partially inhibited the effect of simulated microgravity. Thus regulative effect of simulated microgravity on iNOS expression is mediated at least partially via activation of protein kinase C. These results indicate that NO system in cardiac myocytes is sensitive to simulated microgravity and may play an important role in the depression of cardiac contractility induced by simulated microgravity.
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PMID:Effects of simulated microgravity on nitric oxide level in cardiac myocytes and its mechanism. 1876 45

Nitric oxide is an intracellular messenger which is involved in several functions and pathologies such as depression, anxiety, learning and memory. In many studies nitric oxide synthase inhibitors (NOSI) were shown to possess antidepressant-like effects in animal models of depression. The aim of this study is to investigate the effects of a selective neuronal and inducible nitric oxide synthase inhibitor TRIM (30 mg/kg/day, 35 days) in mice subjected to unpredictable chronic mild stress and then compare it's effect with a conventional selective serotonin reuptake inhibitor fluoxetine (15 mg/kg/day, 35 days). Stressed vehicle animals showed a significant disturbed coat state when compared with nonstressed animals and this effect was reversed by TRIM or fluoxetine. Both TRIM and fluoxetine prevented the stress-induced deficit in the grooming behaviour in the splash test. TRIM and fluoxetine also significantly decreased the attack frequency when compared to the stressed control group in the resident-intruder test. These results support the assumption that NOS inhibitors can be a new class of antidepressant drugs possibly acting on neuronal NOS.
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PMID:Effects of neuronal and inducible NOS inhibitor 1-[2-(trifluoromethyl) phenyl] imidazole (TRIM) in unpredictable chronic mild stress procedure in mice. 1902 80

Calcium channel blockers (CCBs) are widely used in the therapy of cardiovascular diseases. Recent studies have shown that several CCBs exerted distinct anti-inflammatory effect in myocardial dysfunction models. The purpose of the present study was to evaluate therapeutic effect and possible mechanism of action of amlodipine, one of the widely used CCBs, on rat cardiac dysfunction during sepsis induced by lipopolysaccharide (LPS). Pretreatment of the rats with amlodipine (10 or 30 mg/kg, i.v.) delayed the fall of mean arterial blood pressure caused by LPS. Amlodipine also significantly inhibited the elevation of plasma tumor necrosis factor alpha (TNF-alpha) and decreased levels of inducible nitric oxide synthase (iNOS) in response to LPS challenge. To investigate the mechanism of the action of amlodipine, neonatal rat cardiomyocytes were used as a model. Amlodipine concentration-dependently decreased the release of TNF-alpha and iNOS protein expression, and suppressed the degradation and phosphorylation of inhibitor of kappaB-alpha (IkappaB-alpha) in LPS-activated neonatal rat cardiomyocytes. Further studies revealed that amlodipine markedly activated phosphatidylinositiol 3-kinase (PI3K) and Akt, downstream of the PI3K signal cascade. Application of PI3K inhibitors, wortmannin and LY294002 attenuated the depression of TNF-alpha and iNOS expression by amlodipine in LPS-induced cardiomyocytes. These findings may explain some cardioprotective effects of amlodipine in LPS-mediated sepsis and suggest that the inhibition of TNF-alpha and iNOS expression by amlodipine is, at least in part, dependent on PI3K/Akt signaling pathway.
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PMID:Amlodipine inhibits TNF-alpha production and attenuates cardiac dysfunction induced by lipopolysaccharide involving PI3K/Akt pathway. 1939 74


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