title: A1 adenosine receptor activation induces ventriculomegaly and white matter loss.
abstract: A1 adenosine receptors (A1ARs) are widely expressed in the brain during development. To examine whether A1AR activation can alter postnatal brain formation, neonatal rats from postnatal days 3 to 14 were treated with the A1AR agonist N6-cyclopentyladenosine (CPA) in the presence or absence of the peripheral A1AR antagonist 8-(p-sulfophenyl)-theophylline (8SPT). CPA or CPA + 8SPT treatment resulted in reductions in white matter volume, ventriculomegaly, and neuronal loss. Quantitative electron microscopy revealed reductions in total axon volume following A1AR agonist treatment. We also observed reduced expression of myelin basic protein in treated animals. Showing that functional A1ARs were present over the ranges of ages studies, high levels of specific [3H]CCPA binding were observed at PD 4, 7 and 14, and receptor-G protein coupling was present at each age. These observations show that activation of A1ARs with doses of CPA that mimic the effects of high adenosine levels results in damage to the developing brain.
authors.affiliation: Department of Pediatrics, P.O. 208081, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Turner
authors.forename: Henglin
authors.initials: H
authors.lastname: Yan
authors.forename: Michael
authors.initials: M
authors.lastname: Schwartz
authors.forename: Timothy
authors.initials: T
authors.lastname: Othman
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rivkees
mesh_terms: D000241:Adenosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D004338:Drug Combinations; D004347:Drug Interactions; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013687:Telencephalon / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; D004676:Myelin Basic Protein; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C048599:N(6)-cyclopentyladenosine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D019204:GTP-Binding Proteins; D000241:Adenosine