Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lesch-Nyhan syndrome involves disorders of both purine and dopamine metabolism. Neonatal lesioning of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) has been proposed as a rodent model of the dopamine deficiency in this childhood disorder. In the present studies, the functional interaction between purines and dopamine was examined in adult rats which received 6-OHDA lesions either as neonates or as adults. Even though dopamine levels were decreased by at least 92%, both neonatal- and adult-6-OHDA-lesioned rats had normal hypoxanthine-guanine phosphoribosyltransferase function and purine nucleotide levels (adenosine, ADP, ATP and AMP), indicating that hypoxanthine-guanine phosphoribosyltransferase is not localized only to dopaminergic neurons in striatum. However, the 6-OHDA-lesioned animals were supersensitive to the locomotor activating effects of the adenosine antagonist, theophylline, with the response being greater in adult-6-OHDA-lesioned rats. This effect was presynaptic to dopaminergic neurons as indicated by alpha-methyltyrosine blockade of the theophylline response and its reinstatement by L-dopa. The presynaptic nature of this action of theophylline was supported further by a lack of interaction between theophylline and the direct acting D1- and D2-dopamine agonists, SKF-38393 and LY-171555, respectively. After systemic administration of SKF-38393 or L-dopa, central microinjection of the adenosine agonists, 2-chloroadenosine or 5'-N-ethylcarboxamide adenosine, were effective in preventing self mutilation induced by these dopamine agonists in neonatally lesioned rats. Relative potencies of the adenosine agonists for A1 and A2-adenosine receptors suggested involvement of an A2-adenosine receptor in this action.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine. 312 93

Adenosine receptors modulate neuronal and synaptic function in a range of ways that may make them relevant to the occurrence, development and treatment of brain ischemic damage and degenerative disorders. A(1) adenosine receptors tend to suppress neural activity by a predominantly presynaptic action, while A(2A) adenosine receptors are more likely to promote transmitter release and postsynaptic depolarization. A variety of interactions have also been described in which adenosine A(1) or A(2) adenosine receptors can modify cellular responses to conventional neurotransmitters or receptor agonists such as glutamate, NMDA, nitric oxide and P2 purine receptors. Part of the role of adenosine receptors seems to be in the regulation of inflammatory processes that often occur in the aftermath of a major insult or disease process. All of the adenosine receptors can modulate the release of cytokines such as interleukins and tumor necrosis factor-alpha from immune-competent leukocytes and glia. When examined directly as modifiers of brain damage, A(1) adenosine receptor (AR) agonists, A(2A)AR agonists and antagonists, as well as A(3)AR antagonists, can protect against a range of insults, both in vitro and in vivo. Intriguingly, acute and chronic treatments with these ligands can often produce diametrically opposite effects on damage outcome, probably resulting from adaptational changes in receptor number or properties. In some cases molecular approaches have identified the involvement of ERK and GSK-3beta pathways in the protection from damage. Much evidence argues for a role of adenosine receptors in neurological disease. Receptor densities are altered in patients with Alzheimer's disease, while many studies have demonstrated effects of adenosine and its antagonists on synaptic plasticity in vitro, or on learning adequacy in vivo. The combined effects of adenosine on neuronal viability and inflammatory processes have also led to considerations of their roles in Lesch-Nyhan syndrome, Creutzfeldt-Jakob disease, Huntington's disease and multiple sclerosis, as well as the brain damage associated with stroke. In addition to the potential pathological relevance of adenosine receptors, there are earnest attempts in progress to generate ligands that will target adenosine receptors as therapeutic agents to treat some of these disorders.
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PMID:Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. 1963 93