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)

Eicosanoids, produced from arachidonic acid by cyclooxygenases (COXs) and lipoxygenases (LIPOXs), are involved in numerous brain processes. To explore if brief and noninjurious stimuli chronically alter expression of these enzymes, we examined the induction of COX-2 and LIPOX expression following unilateral neocortical spreading depression (SD). Expression was examined over time and in regions not experiencing SD (hippocampus) but synaptically connected to the site of stimulation (cortex). One hundred six male Wistar rats had SD induced via microinjection of 0.5 M KCl (0.5 M NaCl for sham) into left parietal cortex every 9 minutes for 1 or 3 hours. One hour before SD some animals received dexamethasone (Dex), mepacrine (Mep), indomethacin (Indo), nordihydroguaiaretic acid (Ndga), phenylephrine (Pe), sodium nitroprusside (Snp) with Pe, or N omega-nitro-L-arginine methyl ester (Lnam). Animals survived for 0, 3, or 6 hours, or 1, 2, 3, 7, 14, 21, or 28 days. Brains were processed immunohistochemically for COX-2 and LIPOX, and the optical density (OD) of the left and right cortex, dentate gyrus (DG), CA3, and CA1 immunoreactivity (IR) were measured. Induction was expressed as the log of left divided by right side OD for each region. COX-2 IR in the left cortex was elevated rapidly and was sustained for 21 days following SD. COX-2 IR was also elevated in the ipsilateral hippocampus not experiencing SD, with the rank order of induction as follows: DG > CA3 > CA1. Dex, Snp, and/or Pe significantly reduced the induction of COX-2. No changes in LIPOX IR were observed. These results show that long-term changes in COX-2 expression are induced by SD and these changes decrease with synaptic distance. Benign stimuli increase COX-2 expression and thus may influence brain function for extended periods and at distant locations.
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PMID:Long-term elevation of cyclooxygenase-2, but not lipoxygenase, in regions synaptically distant from spreading depression. 895 10

Pain is the main reason prompting patients to consult their physicians. In acute conditions, pain has a very particular significance as a warning sign, enabling the physician to attempt a diagnosis. Nevertheless, its detrimental effect upon the individual (even in the case of acute pain) and its cost to society are now widely acknowledged. There can be no doubt about the physical component of pain, but the psychological and social aspects should not be ignored, particularly in the case of chronic pain. There is no single therapeutic approach to pain and, more often than not, successful treatment comprises a combination of several. Pharmacological treatments are undeniably the most common approach. In clinical practice, recent advances have been based upon an improved understanding of 'old' substances such as morphine and, at the same time, research continues in the hope of finding the 'ideal' analgesic-effective in most situations but without adverse effects: this appears to be a somewhat utopian arm at present, considering the number of different causes of pain. An improved understanding of the physiological mechanisms of pain has led, within the field of clinical practice, to several methods of differentiating pain. These depend on whether or not pain responds to morphine, or on the type of pain: pain due to an excess of nociception, pain resulting from deafferentation (caused by damage to nerve pathways) in the central or peripheral nervous system and psychogenic (idiopathic) pain. Likewise, there are several different ways of classifying analgesic treatments: according to the intensity of pain, as with use of the WHO ladder (which is based on the notion of steps) for the treatment of cancer pain; according to the presumed physiopathological mechanism and, in particular, the response to morphine, and according to the presumed central or peripheral mechanism of the drugs. In reality, peripherally acting drugs can also have a central mechanism of action, just as drugs known to have a central mechanism of action can also have peripheral activity. As a result, several therapeutic classes have been identified. Firstly NSAIDs, which act by inhibiting the enzymes that synthesise prostaglandins, cyclooxygenases (COX-1, COX-2), but which also act upon lipo-oxygenases: Their efficacy is interesting, although somewhat limited by both their ceiling effect and the frequent adverse gastrointestinal reactions they produce. Specific inhibitors of COX-2 could well reduce the risk of adverse effects. Opioids constitute the first-line treatment for pain, particularly severe pain. There are several classifications for these drugs. Firstly, weak opioids (such as codeine) and strong opioids (such as morphine) are differentiated. Secondly, a distinction is made between pure agonists (such as morphine), partial agonists (such as buprenorphine), agonist-antagonists (such as nalbuphine) and antagonists (such as naloxone). Finally, agents are distinguished on the basis of their chemical structure (synthetic, semi-synthetic or natural derivatives). These molecules act upon different receptors (mu, delta, kappa, sigma) and, although peripheral mechanisms have been described, their activity occurs mainly at spinal and supraspinal levels. They provide a potent analgesic effect but are also responsible for various adverse effects-nausea, vomiting, sedation, constipation and respiratory depression-which seriously limit their use. As long as the indication is appropriate, these drugs should not be withheld because of fear of dependence or abuse. It has been observed that other adjuvant therapeutic approaches, generally used to treat conditions other than pain, provide pain relief in certain situations. These include corticosteroids, which are-widely used in rheumatology and oncology, and antidepressants, which are frequently used to treat chronic pain, especially that with a neuropathic component. Anti-epileptics are also used, particularly for excrutiating
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PMID:[Review of current pharmacologic treatment of pain]. 919 Mar 20

Chronic uncontrolled pain may be the greatest health care crisis facing the United States. It is the major symptom for which patients seek medical care and is associated with substantial economic and psychosocial costs. For many patients, particularly the elderly and those suffering from cancer, chronic pain is often undertreated. Because pain has an emotional component and is frequently accompanied by depression and/or anxiety, patients benefit from a comprehensive assessment and multidisciplinary approach to treatment. It is likely that coxibs (cyclooxygenase or COX-2-selective inhibitors) will assume an increasingly prominent role in the treatment of chronic pain associated with arthritis, cancer, and other diseases either as monotherapy or in combination with other drugs. In addition, the role of COX-2 inhibition in the prevention and treatment of colon cancer, Alzheimer's disease (AD), and other chronic health problems is an area currently undergoing intense investigation.
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PMID:Pain management and beyond: evolving concepts and treatments involving cyclooxygenase inhibition. 1220 82

Alterations in transcription, RNA editing, translation, protein processing, and clearance are a consistent feature of Alzheimer's disease (AD) brain. To extend our initial study (Alzheimer Reports [2000] 3:161-167), RNA samples isolated from control and AD hippocampal cornu ammonis 1 (CA1) were analyzed for 12633 gene and expressed sequence tag (EST) expression levels using DNA microarrays (HG-U95Av2 Genechips; Affymetrix, Santa Clara, CA). Hippocampal CA1 tissues were carefully selected from several hundred potential specimens obtained from domestic and international brain banks. To minimize the effects of individual differences in gene expression, RNA of high spectral quality (A(260/280) > or= 1.9) was pooled from CA1 of six control or six AD subjects. Results were compared as a group; individual gene expression patterns for the most-changed RNA message levels were also profiled. There were no significant differences in age, postmortem interval (mean < or = 2.1 hr) nor tissue pH (range 6.6-6.9) between the two brain groups. AD tissues were derived from subjects clinically classified as CDR 2-3 (CERAD/NIA). Expression data were analyzed using GeneSpring (Silicon Genetics, Redwood City, CA) and Microarray Data Mining Tool (Affymetrix) software. Compared to controls and 354 background/alignment markers, AD brain showed a generalized depression in brain gene transcription, including decreases in RNA encoding transcription factors (TFs), neurotrophic factors, signaling elements involved in synaptic plasticity such as synaptophysin, metallothionein III, and metal regulatory factor-1. Three- or morefold increases in RNAs encoding DAXX, cPLA(2), CDP5, NF-kappaBp52/p100, FAS, betaAPP, DPP1, NFIL6, IL precursor, B94, HB15, COX-2, and CEX-1 signals were strikingly apparent. These data support the hypothesis of widespread transcriptional alterations, misregulation of RNAs involved in metal ion homeostasis, TF signaling deficits, decreases in neurotrophic support and activated apoptotic and neuroinflammatory signaling in moderately affected AD hippocampal CA1.
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PMID:Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. 1239 7

Repetitive transcranial magnetic stimulation (rTMS) has been applied for treatment of several diseases such as depression. However, the safety and biological effects of rTMS have not been fully elucidated. In this study, the effects of rTMS on the levels of inflammatory mediators in the central nervous system (CNS), which may be involved in neurodegenerative disorders, were investigated in comparison with the electric convulsive model. Long-term rTMS (1500 pulses at 30 Hz/day for series of 7 days) stimulation, which did not elicit convulsion, was given to rats (rTMS rats). Single high-frequency electrical stimulation (100 Hz, 0.5-ms pulse width, 1 s duration, 50 mA), which induced convulsion, was given to rats (ES rats). mRNA levels of interleukin (IL)-1beta, IL-6, cyclooxygenase (COX)-2 and inducible nitric oxide synthetase (iNOS) in the brain were evaluated by reverse transcription-polymerase chain reaction before and after these stimulations. mRNA of IL-1beta, IL-6 and COX-2 was induced in the brains of ES rats but not in the brains of long-term rTMS rats. mRNA of iNOS was not induced in the brain of long-term rTMS rats. These results suggest that long-term rTMS may safe and modulate neural function without up-regulation of inflammatory mediators, which may be involved in neurodegenerative disorders.
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PMID:The long-term high-frequency repetitive transcranial magnetic stimulation does not induce mRNA expression of inflammatory mediators in the rat central nervous system. 1244 77

Introduction: Targeting of inflammatory states with non-steroidal anti-inflammatory drugs (NSAID'S) is an attractive proposition for cancer prevention. There is abundant epidemiological and experimental evidence that NSAID'S can inhibit tumour development in a number of organs and such drugs have given positive results in human intervention studies. It is hoped that problems with side effects can be overcome by development of specific inhibitors of cancer- and inflammation-associated enzymes. NSAID Pharmacology: Starting with the production of aspirin, NSAIDs have received an enormous amount of clinical attention. Inhibitors of the two isoforms of cyclooxygenase (COX) or prostaglanding G/H synthase, they have found widespread application with increasing interest focused on their employment for cancer prevention. Particular attention is now being drawn to specific inhibitors of the inducible C0X-2 rather than the constitutive COX-1 isoform. Mechanisms of Action: NSAIDs appear to act via depression of prostaglandin synthesis through inhibiting COX-2, often overexpressed in cancers, and the resultant suppression of proliferation, possibly through enhancement of apoptosis. Future Prospectives: The possibility of applying NSAIDs in conjunction with other chemopreventive agents and developing specific inhibitors of different stages in the pathways leading to prostaglandin production and functions hold hope for improved drugs/protocols with reduced detrimental side effects for employment in both primary and secondary cancer prevention in the future.
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PMID:NSAIDs as Cancer Preventive Agents. 1271 76

Although the ulcerogenic action of corticosteroids in the stomach is controversial, its action on ulcer healing has not been defined. In this study, we used non-ulcerogenic doses of dexamethasone (0.1 or 0.2 mg/kg/day) to explore the adverse effect on ulcer healing as well as its pathological mechanisms in rat stomach. In this regard, we measured ulcer size, mucus thickness, epithelial cell proliferation and apoptosis, and angiogenesis at the ulcer site at different time points after ulcer induction. Protein expressions of cyclooxygenase-1 and -2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) over the ulcer margin were evaluated, and the mucosal prostaglandin E2 (PGE2) level was also determined. Dexamethasone treatment in the current doses did not produce mucosal damage in intact animals. However, the drug dose-dependently delayed gastric ulcer healing. It also decreased mucus content and epithelial cell proliferation at the ulcer margin as well as angiogenesis at the ulcer margin and base. These were associated with a significant decrease of COX-2 expression and PGE2 level but not COX-1 at the ulcer margin. The drug only marginally reduced the cPLA2 expression without affecting the apoptosis at the ulcer margin. PGE2 treatment reversed the adverse effects of dexamethasone on ulcer healing. It is concluded that nonulcerogenic doses of dexamethasone can delay ulcer repair via depression of COX-2 expression and PGE2 formation in the gastric mucosa.
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PMID:Non-ulcerogenic dose of dexamethasone delays gastric ulcer healing in rats. 1296 48

Scopoletin (1-50 microg/ml) inhibited the release of PGE2, TNF-alpha, IL-1beta and IL-6 and suppressed the expression of COX-2 in a concentration-dependent manner. These results suggest that scopoletin might suppress the production of such pro-inflammatory cytokines and exert inhibitory activity on LPS-induced PGE2 production through the depression of COX-2 expression.
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PMID:Scopoletin suppresses pro-inflammatory cytokines and PGE2 from LPS-stimulated cell line, RAW 264.7 cells. 1515 82

An endotoxin (lipopolysaccharide, LPS) is known to activate the hypothalamo-pituitary adrenocortical axis, as well as norepinephrine and indolamine metabolism. Systemically administered LPS produces depression in the forced swimming-induced despair behaviour model in mice. The present study was designed to investigate the effect of green tea extract (GTE) on LPS-induced despair behaviour and to explore the mechanism involved in modulation of LPS-induced immobility by GTE. GTE (10-100 mg/kg) pretreatment reversed LPS-induced immobility in a dose-dependent manner. Rofecoxib (2 mg/kg) and nimesulide (2 mg/kg), COX-2 inhibitors, also reversed the LPS-induced immobility, which was significantly potentiated by concomitant administration of GTE. On the other hand, GTE did not show any potentiating effect on immobility with naproxen (10 mg/kg), which is a nonselective COX blocker. Interestingly the antioxidant, carvedilol (2 mg/kg) did not produce any effect on immobility either in normal or in LPS treated mice. The results of the study implicate the role of COX-2 inhibition by GTE in the reversal of LPS-induced immobility.
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PMID:Reversal of LPS-induced immobility in mice by green tea polyphenols: possible COX-2 mechanism. 1547 5

Despite that many drugs are available for pain treatment, many patients are still suffering because of wrong choice or wrong use of analgesics. Both are determined by the degree and the nature of pain to be treated. Non-opioid drugs, especially COX-2-inhibitors are extensively evaluated. If treatment with these drugs is not sufficient, opioids have to be used. Their efficiency is outstanding and their side effects are appropriate. However, doctors and nurses are still reluctant to use opioids because of overestimation of respiratory depression and addiction.
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PMID:[Clinical pharmacology of analgesics: outlook and risks]. 1603 81


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