Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine, a modulator of pain processing in the spinal cord, is metabolized by adenosine kinase and adenosine deaminase. In this study we determined which of these mechanisms is more important for the regulation of endogenous adenosine levels in the rat spinal cord. The effects of the adenosine kinase inhibitors, 5'-amino-5'-deoxyadenosine (NH2dAD) and iodotubercidin (IOT), and the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF), on adenosine release in a spinal cord superfusion model were studied. DCF markedly increased basal adenosine levels detected in perfusates and was more potent than NH2dAD and IOT in this regard. Coadministration of DCF with NH2dAD produced an enhanced effect compared to the inhibitors alone. NH2dAD, but not DCF, potentiated morphine-evoked adenosine release. These results suggest that adenosine deaminase may be the predominant pathway for adenosine metabolism in this experimental model.
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PMID:Modulation of adenosine release from rat spinal cord by adenosine deaminase and adenosine kinase inhibitors. 861 36

This study examined the ability of an adenosine kinase inhibitor (5'-amino-5'-deoxyadenosine; NH2dAD), an adenosine deaminase inhibitor (2'-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1-100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of adenosine and activation of cell surface adenosine receptors as it was blocked by the adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an inhibitory tone of adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2'-Deoxycoformycin 0.1-100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the adenosine kinase and deaminase inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous adenosine which accumulates following the peripheral inhibition of adenosine kinase; this action is due to activation of an adenosine A1 receptor.
Pain 1998 Jan
PMID:Peripheral antinociceptive effect of an adenosine kinase inhibitor, with augmentation by an adenosine deaminase inhibitor, in the rat formalin test. 951 63

The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 microl), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7-10 days prior to drug testing (antagonist experiments). N6-cyclohexyladenosine (CHA; adenosine A1 receptor agonist; 0.01-1 nmol), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine (CGS21680; adenosine A2A receptor agonist; 0.1-10 nmol), 5'-amino-5'-deoxyadenosine (NH2dAdo; adenosine kinase inhibitor: 10-300 nmol), and 5-iodotubercidin (ITU; adenosine kinase inhibitor; 0.1-100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2'-deoxycoformycin (dCF; an adenosine deaminase inhibitor; 100-300 nmol). Reversal of drug effects by caffeine (non-selective adenosine A1/A2 receptor antagonist; 515 nmol) confirmed the involvement of the adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; adenosine A2A receptor antagonist; 242 nmol), evidenced an adenosine A1 receptor mediated spinal antinociception by NH2dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH2dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting adenosine agents, when administered spinally, produce antinociception through activation of spinal adenosine A1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected adenosine kinase inhibitors can be significantly augmented when administered simultaneously with an adenosine deaminase inhibitor.
Pain 1998 Feb
PMID:Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. 952 Feb 38

Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions.
Pain 1999 Mar
PMID:Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain. 1020 15

Spinal administration of an adenosine kinase inhibitor, alone or in combination with an adenosine deaminase inhibitor, produces antinociception in inflammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) administration of 5'-amino-5'-deoxyadenosine (an adenosine kinase inhibitor), 2'-deoxycoformycin (an adenosine deaminase inhibitor), and combinations of both agents in the carrageenan-induced thermal hyperalgesia and paw oedema model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 micromol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinociceptive and anti-inflammatory effects was seen when 5'-amino-5'-deoxyadenosine and 2'-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of adenosine receptors, as indicated by blockade by an adenosine receptor antagonist. When administered into the contralateral paw, 1 micromol 5'-amino-5'-deoxyadenosine+1 micromol 2'-deoxycoformycin produced prominent antinociception, indicating a systemic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activity was locally mediated. Reversal of systemic effects on thermal thresholds by an intrathecal adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 micromol 5'-amino-5'-deoxyadenosine, but not 1 micromol 2'-deoxycoformycin, reduced carrageenan-induced c-Fos expression in the spinal dorsal horn, and this was further reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a predominantly peripheral anti-inflammatory effect produced by inhibitors of adenosine kinase and adenosine deaminase.
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PMID:Antinociceptive and anti-inflammatory properties of an adenosine kinase inhibitor and an adenosine deaminase inhibitor. 1061 32

A cDNA coding for a protein with significant similarity to adenosine deaminase (ADA) was found while randomly sequencing a cDNA library constructed from salivary gland extracts of adult female Culex quinquefasciatus. Prompted by this result, we found high ADA activities in two culicine mosquitoes, Culex quinquefasciatus and Aedes aegypti, but not in the anopheline Anopheles gambiae. Homogenates from Culex quinquefasciatus also have an AMP deaminase activity that is three times greater than the ADA activity, whereas in Aedes aegypti the AMP deaminase activity is less than 10% of the ADA activity. Evidence for secretion of ADA during blood feeding by Aedes aegypti includes the presence of ADA activity in warm solutions probed through a membrane by mosquitoes and in serotonin-induced saliva and a statistically significant reduction in the levels of the enzyme in Aedes aegypti following a blood meal. We could not demonstrate, however, that C. quinquefasciatus secrete ADA in their saliva. Male Aedes aegypti and C. quinquefasciatus, which do not feed on blood, have less than 3% of the levels of ADA found in females. We propose that ADA activity in A. aegypti may help blood feeding by removing adenosine, a molecule associated with both the initiation of pain perception and the induction of mast cell degranulation in vertebrates, and by producing inosine, a molecule that potently inhibits the production of inflammatory cytokines. The role of salivary ADA in Culex quinquefasciatus remains unclear.
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PMID:The salivary adenosine deaminase activity of the mosquitoes Culex quinquefasciatus and Aedes aegypti. 1144 Oct 41

We sometimes encounter difficulties in differentiating tuberculous peritonitis from other inflammatory disorders or ascites due to carcinomatous peritonitis. Acid-fast bacilli are very rarely detected in ascites. In this study, we reported a case of tuberculous peritonitis accompanied with active pulmonary tuberculosis in which acid-fast bacilli were detected in ascites. The patient was a 37-year-old single man who had been admitted to our hospital on February 28, 2000, because acid-fast bacilli were detected in sputum, faces and ascites by a direct smear. He had a lower abdominal distention and pain. His serum CA 125 level was high, 121 U/ml. Abdominal ultrasonography showed marked ascites in Douglas pouch. However adenosine deaminase level was not high in his ascites. During treatment by the combination chemotherapy with INH, RFP, EB, and PZA, serum CA 125 level was decreased.
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PMID:[A case of tuberculous peritonitis diagnosed by a direct smear of ascitic fluid complicated with an active pulmonary tuberculosis and intestinal tuberculosis]. 1149 28

Modulation of endogenous adenosine levels by inhibition of adenosine metabolism produces a peripheral antinociceptive effect in a neuropathic pain model. The present study used microdialysis to investigate the neuronal mechanisms modulating extracellular adenosine levels in the rat hind paw following tight ligation of the L5 and L6 spinal nerves. Subcutaneous injection of 50 microl saline into the nerve-injured paw induced a rapid and short-lasting increase in extracellular adenosine levels in the subcutaneous tissues of the rat hind paw ipsilateral to the nerve injury. Saline injection did not increase adenosine levels in sham-operated rats or non-treated rats. The adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine and the adenosine deaminase inhibitor 2'-deoxycoformycin, at doses producing a peripheral antinociceptive effect, did not further enhance subcutaneous adenosine levels in the nerve-injured paw. Systemic pretreatment with capsaicin, a neurotoxin selective for small-diameter sensory afferents, markedly reduced the saline-evoked release of adenosine in rat hind paw following spinal nerve ligation. Systemic pretreatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic afferent nerves, did not affect release. These results suggest that following nerve injury, peripheral capsaicin-sensitive primary sensory afferent nerve terminals are hypersensitive, and are able to release adenosine following a stimulus that does not normally evoke release in sham-operated or intact rats. Sympathetic postganglionic afferents do not appear to be involved in such release. The lack of effect on such release by the inhibitors of adenosine metabolism suggests an altered peripheral adenosine system following spinal nerve ligation.
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PMID:Enhanced release of adenosine in rat hind paw following spinal nerve ligation: involvement of capsaicin-sensitive sensory afferents. 1220 7

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
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PMID:Adenosine in the spinal cord and periphery: release and regulation of pain. 1278 73

Tuberculous spondylitis runs atypically with its acute onset, high fever, and violent pain in 20% of cases. This disease is characterized by a high specific activity of T lymphocytes, by high levels of antituberculous antibodies, by a higher activity of adenosine deaminase, by higher concentrations of IgA and IgE. The gradual onset and few-symptom course of hematogenous osteomyelitis were revealed in 15% of cases. In osteomyelitis, there was a low concentration of antituberculous antibodies, higher levels of low and medium molecular mass, and IgG.
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PMID:[Clinical and laboratory features in tuberculosis and osteomyelitis of the spine]. 1466 28


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