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Detection of Apoptosis in the Developing Primate Brain

NIH 5P51OD011106-53
Wisconsin National Primate Research Center Pilot Award, University of Wisconsin
PI: Chris Ikonomidou, MD, PhD
1/1/2015 - 4/30/2017

The goal of this pilot project is to develop ways to image apoptosis in the nonhuman primate brain exposed to anesthetic drugs using MRI and ultrasound.

SUMMARY: Pediatric drugs which are used as sedatives/anesthetics (SADs) and antiepileptics (AEDs) 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 in the brains of rodent 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.

Millions of human fetuses and infants are exposed every year to SADs and/or AEDs at doses that have been shown to induce apoptotic injury in the developing animal brain.  Currently, we are at an impasse in dealing with this potentially serious dilemma. The human epidemiological evidence, although generated by highly competent researchers, is considered inconclusive, so it remains debatable whether the developing human brain is susceptible to apoptotic injury induced by SADs and AEDs. Methods used in animal research to document the brain damaging properties of SADs and AEDs are invasive and cannot be used in human research.  We need new research approaches that are reliable and can non-invasively address and answer the human susceptibility and related questions.

Here we propose to use diffusion weighted MRI and high frequency ultrasound, two modalities which non-invasively detect apoptosis in cancer, to study apoptotic cell death in the brains of infant NHPs exposed to sevoflurane (SEVO) anesthesia.

Aim 1:  Using a P6 infant NHP model in which SAD exposure [sevoflurane (SEVO) x 5 hrs] is expected to cause acute apoptotic brain injury, test the hypothesis that the brains of SEVO-exposed infant NHPs will display changes that can be diagnosed non-invasively by diffusion weighted MRI.

Aim 2:  In this same infant NHP model, test the hypothesis that the brains of SEVO-exposed infant NHPs will display changes that can be diagnosed non-invasively by high frequency ultrasound.

If successful, this project would provide the first data to help develop non-invasive methodology that would allow us explore the phenomenon of drug-induced developmental neuro- and oligoapoptosis in humans and would also provide us with tools that allow to individually monitor treatment safety.

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.

Methods to Study Chemotherapy-Related Neurotoxicity in Children

ICTR UWMF Pilot
10/1/2015-9/30/2016

The goal of this pilot project is to measure blood and CSF markers for neuronal and glial injury in 20 children with B-cell ALL while they are undergoing chemotherapy. There is no overlap with the proposed project as these 20 subjects will be studied in addition to the 40 subjects we propose to enrol in the current application.

SUMMARY: Survival rates of children with cancer are steadily increasing and this urges attention to neurocognitive and psychiatric outcomes, as these markedly influence quality of life in these children. Neurobehavioral morbidity in childhood cancer survivors affects diverse aspects of cognitive function, attention, memory, processing speed, intellect (IQ), academic achievement and emotional health. Reasons for neurobehavioral morbidity are multiple with one major contributor being chemotherapy (Chemo)-induced central nervous system (CNS) toxicity. Preclinical studies have provided compelling evidence that medications used for cancer Chemo are potent neuro- and gliotoxins in vitro and in vivo and cause brain injury via excitotoxic and apoptotic mechanisms. Furthermore, Chemo triggers DNA damage directly or through increased oxidative stress, shortens telomeres and accelerates cell aging, causes cytokine deregulation, inhibits hippocampal neurogenesis and reduces brain vascularization and blood flow. These mechanisms, when allowed to operate on the developing human brain, have high potential to not only cause brain injury, but also alter crucial developmental events, such as myelination, synaptogenesis, neurogenesis, cortical thinning and formation of neuronal networks. Clinical studies investigating the effects of Chemo and radiation on CNS in children with cancer have reported causative associations with the development of leukoencephalopathies as well as smaller regional grey and white matter volumes, and these were found to correlate with neurocognitive deficits. The great majority of these findings are based on retrospective or cross sectional studies in children with CNS tumors or acute lymphoblastic leukemia (ALL). Problems with these pediatric studies are that (i) in the majority of them, Chemo was accompanied by radiation and (ii) many were performed in patients with CNS tumors, where it is difficult if not impossible to separate and characterize toxicity related to Chemo versus surgery or the cancer itself. Furthermore, because most studies were performed after treatment had been completed, they allow very limited insight into timely evolution and potential pathomechanisms of neuro- and gliotoxicity of Chemo in children, and this information is crucial for development of preventive measures.

The goal of this project is to prospectively characterize the evolution of biochemical features of Chemo-induced CNS toxicity in children. We will prospectively enroll children undergoing systemic and CNS directed Chemo without irradiation for low, average and high risk B-cell-ALL. Children 2-12 years of age (n=20) will be enrolled. Testing will be performed at diagnosis and at 1- 6 months. Goal is to explore and characterize changes in neurochemical biomarkers indicative of apoptotic and excitotoxic cell death of neurons and glia in blood and cerebrospinal fluid (CSF) in children during Chemo for ALL.

We expect that the proposed study will identify early biochemical biomarkers of Chemo-induced CNS toxicity in children undergoing treatment for ALL. These biomarkers can then be used to monitor and help develop strategies to prevent CNS injury in response to Chemo.

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