A1 adenosine receptor activation induces ventriculomegaly and white matter loss.
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.
Turner
Christopher P
CP
Department of Pediatrics, P.O. 208081, Yale University School of Medicine, New Haven, CT 06520, USA.
Yan
Henglin
H
Schwartz
Michael
M
Othman
Timothy
T
Rivkees
Scott A
SA
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
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