Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is well established that in the CNS, endogenous adenosine plays a pivotal role in neurodegeneration. A low, nanomolar concentration of adenosine is normally present in the extracellular fluid, but it increases dramatically during enhanced nerve activity, hypoxia or ischemia. In these pathological conditions, adenosinergic transmission-potentiating agents, which elevate adenosine level by either inhibiting its degradation (adenosine deaminase and kinase inhibitors) or preventing its transport, offer protection against ischemic or excitotoxic neuronal damage. The directly acting adenosine A1 receptor agonists are known to mediate neuroprotection, mostly by the blockade of Ca2+ influx, which results in the inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. More recent data have shown that antagonists of adenosine A2A receptors markedly reduce cerebral ischemic damage in animal models of focal and global ischemia. Moreover, these compounds attenuate the neuronal loss induced by excitatory amino acids (EAA). A neuroprotective effect of adenosine A2A receptor antagonists was also shown in animal models of Parkinson's disease (MPTP, 6-OHDA, methamphetamine). Hence, it might be suggested that adenosine A2A receptor antagonists may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events, since they not only reverse motor impairment but can act as neuroprotective compunds by promoting cell survival.
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PMID:Neuroprotective role of adenosine in the CNS. 1252 85

Hypoxia and reoxygenation, ischemia and reperfusion, catecholamine infusion, ouabain, sodium pentobarbital and caffeine, can all be used experimentally to induce ventricular arrhythmias. According to the Lambeth Convention guidelines our experimentally-induced ventricular arrhythmias include but are not limited to: ventricular premature beats (VPB), ventricular salvos (VS), ventricular bigeminy (VB), nonsustained ventricular tachycardia (VTn), sustained ventricular tachycardia (VTs) and ventricular fibrillation (VF, or if the heart is not defibrillated, sudden cardiac death). We have studied these arrhythmias in the absence and presence of adenosine deaminase, methyl xanthines, and more recently, acetaminophen. Our laboratory was the first to discover the anti-arrhythmic properties of acetaminophen an analgesic used in Western medicine for more than 100 years before our publication. We have also identified other cardioprotective properties of acetaminophen, and have begun to work out some of the cellular/molecular mechanisms. For example, we know that acetaminophen protects hypoxic/ischemic cardiac mitochondria, in part, by sustaining function of the mitochondrial permeability transition pore (MPTP, a protein involved in regulating mitochondrial pH). Acetaminophen also attenuates the actions of matrix metalloproteinases that can be harmful to myocardial contractile proteins. Of course, like all science, more work is needed to expand on these and related topics.
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PMID:Experimentally-induced ventricular arrhythmias. 2934 97

Neuroinflammation is one of the driving forces of progressive neurodegeneration in Parkinson's disease (PD). The metabolomics approach has been proved highly useful in identifying potential therapeutic targets. Here, to identify inflammation-relevant treatment targets for PD, mass spectrometry-based untargeted metabolomics was applied to characterize metabolic changes in the striatum of mice with double-hit PD induced by lipopolysaccharide plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Seven days after the final MPTP administration, metabolites from the purine metabolism pathway, including adenosine, 1-methyladenosine, adenine, inosine, hypoxanthine, xanthine, xanthosine, and guanosine, were found to be significantly dysregulated. The metabolite-protein interaction network and changes in the concentration ratio of these metabolites indicated that adenosine and adenosine deaminase (ADA; EC 3.5.4.4) were the most promising therapeutic targets and adenosine augmentation might be a rational approach to slow PD progression. These findings were then verified in a subacute MPTP-induced PD mouse model treated with ADA inhibition alone or in conjunction with antagonism of adenosine A2A receptors (A2A R). Behavioral, biochemical, and immunohistochemical analysis demonstrated that ADA inhibition significantly ameliorated the MPTP-mediated motor disabilities, dopamine depletion, and dopaminergic cell death. Significantly enhanced neuroprotective effects were further observed when the ADA inhibitor was utilized in conjunction with an A2A R antagonist. Together, our study indicated for the first time that ADA inhibitors protected against neurodegeneration induced by the neurotoxin MPTP, and ADA inhibitors in combination with A2A R antagonists showed additive antiparkinsonian effects.
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PMID:Metabolomics-driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease. 3112 Oct 68