Pediatric drugs which are used as anesthetics, sedatives and antiepileptics in neonatal and pediatric medicine, can be harmful to the developing brain. They have been shown to cause widespread cell death, impair synaptic maturation and plasticity and inhibit neurogenesis (the birth of new nerve cells) in the brains of rodents and non-human primates (NHP). Studies in rodents and in NHPs have provided compelling evidence that early life exposure to these drugs also triggers behavioral toxicity, i.e. causes long term behavioral and cognitive deficits that persist when the animals mature. Furthermore, retrospective clinical studies raise serious concerns that exposure of human infants to these classes of drugs may lead to neurocognitive and behavioral disorders. Practicing medicine without anesthetics, sedatives and antiepileptics is impossible. These medications must be used during surgeries, prolonged sedation during critical illness, and for the treatment of seizures. Thus, the crucial question arises whether protective measures can be developed and applied in the clinical setting to avoid potential iatrogenic adverse effects of these classes of drugs on brain health and subsequent development in the most vulnerable age groups, specifically neonates and infants during the first year of life. Hypothermia is successfull applied in neonatal and pediatric medicine to minimize brain injury from perinatal asphyxia, cardiac surgery and neonatal stroke. We propose to investigate hypothermia as a potential protective treatment of the developing primate brain against histological, behavioral and neurocognitive toxicity of anesthetic, sedative and anticonvulsant drugs. Research will be conducted in NHP infants using clinically relevant drug combinations and durations of treatment. We plan to use sevoflurane (SEVO), which is becoming one of the most frequently used general anesthetics in pediatric medicine and the combination of phenobarbital and midazolam (Pb/M), a protocol commonly used for sedation or antiepileptic therapy in neonates and infants. We want to test the following three hypotheses: (1) Exposure of NHP infants to SEVO anesthesia for 5 hrs will cause death (apoptosis) of brain cells, and application of hypothermia throughout the duration of anesthesia and for 1 hr thereafter will prevent or reduce the severity of this injuy; (2) Application of hypothermia during and 12 hrs after exposure of NHP infants to a 24 hr long treatment with the antiepileptic/sedative drug combination phenobarbital/midazolam (Pb/M) will prevent or mitigate the acute cell death (apoptosis) response caused by the drugs; (3) Exposure of NHP infants to the drug combination Pb/M for 24 hours will cause long- term neurobehavioral impairment (NBI), and application of hypothermia throughout the duration of Pb/M treatment and for 12 hrs thereafter (the period during which the drugs are still present at toxic concentrations n the brain) will prevent or mitigate the long-term NBI. These questions cannot be answered by research on human subjects, but can be successfully addressed and answered by research using non-human primates.
A multidisciplinary team of researchers from two universities will collaborate in a study aimed at determining whether hypothermia can protect the non-human primate brain from histological, behavioral and neurocognitive toxicity of common drugs used for anesthesia, prolonged sedation or antiepileptic therapy in human neonates and infants. Human research cannot provide timely and definitive answers to this important question, but translationally reliable answers can be obtained by research on NHP subjects, as is proposed in this study. If positive, this project would help identify a safe, effective and FDA approved neuroprotective treatment from which millions of infants would be expected to benefit every year worldwide.
| Noguchi, Kevin K; Johnson, Stephen A; Manzella, Francesca M et al. (2018) Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain. Sci Rep 8:5302 |
| O'Connor, Shawn David; Cabrera, Omar Hoseá; Dougherty, Joseph D et al. (2017) Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum. J Matern Fetal Neonatal Med 30:2156-2162 |
