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Hypothermia To Prevent Neurotoxic Side Effects of Pediatric Drugs

NIH R01HD083001-01A1
PI: Chris Ikonomidou
1/1/2016 - 12/30/2019

The goal of this project is to study whether hypothermia protects the nonhuman primate brain from histological and behavioral toxicity of anesthetics, sedatives and antiepileptics.

SUMMARY: 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 successfully 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.

IN SITU PROTEIN VISUALIZATION AND CHARACTERIZATION IN THE MAMMALIAN BRAIN

NIH R56MH110215-01A1
MPI: Lingjun Li, PhD, School of Pharmacy (corresponding); Chris Ikonomidou, MD PhD
The aim of this project is to create next generation of MALDI mass spectrometry imaging (MSI) technology that enables simultaneous mapping and quantifying in situ protein expression patterns in biological tissues from animal models of diseases
1/1/2017 - 12/31/2018