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A1 adenosine receptor activation induces ventriculomegaly and white matter loss
Christopher P Turner1, Henglin Yan, Michael Schwartz
1Department of Pediatrics, P.O. 208081, Yale University School of Medicine, New Haven, CT 06520, USA.
Insights
Activation of A1 adenosine receptors (A1ARs) in neonatal rats damages the developing brain. This leads to reduced white matter volume, neuronal loss, and impaired axon growth.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- A1 adenosine receptors (A1ARs) are crucial in brain development.
- Understanding A1ARs' role in postnatal brain formation is essential.
Purpose of the Study:
- To investigate the effects of A1AR activation on postnatal brain development.
- To determine if A1AR stimulation can alter brain formation processes.
Main Methods:
- Neonatal rats (postnatal days 3-14) were treated with an A1AR agonist (CPA).
- Peripheral A1AR antagonist (8SPT) was used to confirm central effects.
- Quantitative electron microscopy and myelin basic protein expression were analyzed.
Main Results:
- A1AR agonist treatment reduced white matter volume, caused ventriculomegaly, and led to neuronal loss.
- Reduced total axon volume and myelin basic protein expression were observed.
- Functional A1ARs were confirmed through binding and receptor-G protein coupling assays.
Conclusions:
- Activation of A1 adenosine receptors during early development causes significant brain damage.
- High adenosine levels mimicking CPA effects can harm the developing brain.
- A1ARs are critical targets for understanding and potentially protecting the developing brain.
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.