Caffeine Protects Against Anticonvulsant-Induced Neurotoxicity in the Developing Rat Brain

Abstract

Phenobarbital is the most commonly used drug for the treatment of neonatal seizures but may induce neurodegeneration in the developing brain. Methylxanthine caffeine is used for the treatment of apnea in newborn infants and appears to be neuroprotective, as shown by antiapoptotic and anti-inflammatory effects in oxidative stress models in newborn rodents and reduced rates of cerebral palsy in human infants treated with caffeine. We hypothesized that caffeine may counteract the proapoptotic effects of phenobarbital in newborn rats. Postnatal day 4 (P4) rats received phenobarbital (50 mg/kg) +/- caffeine (10 mg/kg) for three consecutive days. Brains examined at 6, 12, and 24 h after last injection of phenobarbital showed a drastic increase of apoptotic cell death (TUNEL+), which was attenuated by co-treatment with caffeine at 6 and 24 h but not at 12 h. Phenobarbital also increased protein levels of apoptosis inducing factor (AIF) and cleaved caspase-3, which was reduced by caffeine co-administration at all time points investigated. RNA expression of the pro-inflammatory cytokines TNFα, IFNγ, and IL-1β, but not IL-18, was upregulated by phenobarbital. Co-treatment with caffeine significantly decreased these upregulations at all time points investigated, while caffeine without phenobarbital resulted in increased expression of TNFα, IL-1β, and IL-18, but not IFNγ at 6 h. Downregulation of the adenosine A1 and A2a receptors, both of which bind caffeine, by 24 h of phenobarbital exposure was partly antagonized by caffeine. These results raise the possibility that the phenobarbital-induced adverse effects could be reduced by a co-treatment with caffeine.

Prevention of Oxygen-Induced Inflammatory Lung Injury by Caffeine in Neonatal Rats

“…The snap-frozen lung tissue was chopped in a radioimmunoprecipitation assay buffer (RIPA; Thermo Fisher Scientific, Waltham, MA, USA), centrifuged at 3000× g for 10 min at 4°C, and the supernatant of homogenized lung tissue was obtained. Protein concentrations were determined using the Pierce BCA kit (Pierce/Thermo Fisher Scientific, Rockford, IL, USA) as described in [ 50 ].…”

Caffeine and seizures: A systematic review and quantitative analysis

“…Caffeine may also protect against neurotoxicity and downregulation of A1-and A2A receptors induced by the AED phenobarbital in the frontal cortex, retrosplenial cortex, hypothalamus, thalamus and the dentate gyrus. [65] In mice a physiological dose of caffeine (0.5 mg/kg) significantly reduced the incidence of seizure-induced respiratory arrest which may be involved in sudden death in epilepsy (SUDEP). [34] Overall, in animal models caffeine has beneficial effects on seizure susceptibility, especially in models of absence epilepsy, after early-life convulsions and traumatic brain injury.…”

Taurine, caffeine, and energy drinks: Reviewing the risks to the adolescent brain

“…Since caffeine is often used in the treatment of apnea in newborn infants, the research supports the view that caffeine is neuroprotective as shown by anti‐inflammatory effects in oxidative stress models in rodents. In one study, postnatal day 4 rats received phenobarbital (50 mg/kg) for 3 days with or without 10 mg/kg caffeine (Endesfelder et al, ). The phenobarbital‐induced adverse outcomes were partly antagonized by the caffeine.…”