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Article

Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia

1
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA
2
Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA
3
State University of New York Eye Institute, Brooklyn, NY 11203, USA
4
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Kings County Hospital Center, Brooklyn, NY 11203, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Michele Samaja
Int. J. Mol. Sci. 2021, 22(7), 3473; https://doi.org/10.3390/ijms22073473
Received: 11 February 2021 / Revised: 11 March 2021 / Accepted: 23 March 2021 / Published: 27 March 2021
(This article belongs to the Special Issue New Strategies of Neuroprotection and Repair in the Developing Brain)
(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine. View Full-Text
Keywords: apoptosis; caffeine; cerebral cortex; hyperoxia; mylenation; neonatal intermittent hypoxia; oxidative stress apoptosis; caffeine; cerebral cortex; hyperoxia; mylenation; neonatal intermittent hypoxia; oxidative stress
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MDPI and ACS Style

Soontarapornchai, K.; Cai, C.L.; Ahmad, T.; Aranda, J.V.; Hand, I.; Beharry, K.D. Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia. Int. J. Mol. Sci. 2021, 22, 3473. https://doi.org/10.3390/ijms22073473

AMA Style

Soontarapornchai K, Cai CL, Ahmad T, Aranda JV, Hand I, Beharry KD. Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia. International Journal of Molecular Sciences. 2021; 22(7):3473. https://doi.org/10.3390/ijms22073473

Chicago/Turabian Style

Soontarapornchai, Kutilda, Charles L. Cai, Taimur Ahmad, Jacob V. Aranda, Ivan Hand, and Kay D. Beharry 2021. "Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia" International Journal of Molecular Sciences 22, no. 7: 3473. https://doi.org/10.3390/ijms22073473

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