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Protective Effects of Methylxanthines on Hypoxia-Induced Apoptotic Neurodegeneration and Long-Term Cognitive Functions in the Developing Rat Brain

Aminophylline is widely used in the management of premature apnea. The methylxanthines aminophylline, theophylline and caffeine are nonspecific inhibitors of adenosine receptors. There are no proven effects of methylxanthines on acute brain injury and long-term cognitive functions. This study is aimed at investigating the effects of methylxanthines on brain injury and cognitive functions. Newborn rats were allocated to form four groups, which contained at least 21 pups: two groups were exposed to room air and two groups were exposed to intermittent hypoxia. Intraperitoneal aminophylline was administered to treatment groups during postnatal day 1 through postnatal day 7. All rats were sacrificed on postnatal day 8 via intraperitoneal pentobarbital and the effects of the administered drug on brain injury and adenosine receptor expression were determined. Cognitive functions of rats were evaluated via water maze test. Histopathological evaluation demonstrated that aminophylline significantly diminished the number of ‘apoptotic cells’ in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in the brain. Aminophylline treatment immediately after hypoxic insult significantly improved long-term neurobehavioral achievements. In conclusion, aminophylline administration immediately after neonatal hypoxic insult provides benefit over a prolonged period in the developing rat brain.