Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine

Abstract

Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects.

Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity

“…Ethanol, which possesses both GABA agonist and NMDA antagonist properties, is a potent enhancer of Ca 2+ [21] and causes a particularly devastating apoptotic reaction in fetal and neonatal brain. Importantly, the addition of CAF to ethanol-exposed neurons potentiates both intracellular Ca 2+ [21] and neuroapoptosis [8,21]. Furthermore, ketamine [22] and propofol [23] raise Ca 2+ in immature neurons with a concomitant decrease in cell viability.…”

“…Since our aim was to study acute neurotoxicity, we used a single 80 mg/kg dose of CAF (Sigma-Aldrich, St. Louis, MO) to model the bolus phase of this regimen. Prior studies have established that this dose produces blood levels of 38 μg/ml in infant mice [8], which is well within the therapeutic range of 5 to 50 μg/ml for apnea of prematurity in preterm infants [11]. …”

“…Brain regions maximally affected by neuroapoptogens include subiculum and hippocampal formation, caudate putamen, retrosplenial cortex, thalamus, superior and inferior colliculi, and all major divisions of neocortex [8]. Serial sectioning yielded 3 to 4 sections per animal encompassing these regions, which were outlined as a single structure using Stereo Investigator software (MicroBrightField, Inc., Colchester, VT) on a Pentium III PC connected to a Prior Optiscan motorized stage (ES103 XYZ system, Prior Scientific Inc., Rockland, MA) with a Nikon Labophot-2 microscope.…”

“…Black and colleagues [7] reported increased cell death in postnatal day (PND) 7 rat pups challenged with a moderate dose of CAF and morphine. In a series of studies, Yuede et al [8] administered PND4 mouse pups CAF in conjunction with various drugs known to cause apoptotic neurotoxicity: ethanol, PCP, ketamine, diazepam, or isoflurane. Importantly, pairing CAF with each of these agents caused more neurotoxicity than CAF or the apoptogen alone.…”

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

“…The resident-intruder paradigm, as described previously (86), was used as a direct social interaction test. Only males were used in this experiment.…”