Millions of infants, children and young adults are living with disabilities resulting from traumatic brain injury (TBI) in childhood. Following the intial insult, a cascade of secondary events produces progressive neurodegeneration. The developing brain may be uniquely vulnerable to some of these secondary insults, due to maturational features. In the very young, the injury may interfere with the execution of the developmental program later in life, leading to learning, attention, and social behavior abnormalities. Currently, treatment is limited to supportive care. Here, we will investigate novel emerging pathways involving cell signaling by 20- HETE, a cytochrome P450 metabolite of arachidonic acid. We find that specific cytochrome P450s known to synthesize 20-HETE are expressed in neurons and microglia and that 20-HETE can induce phosphorylation of NMDA receptors and Na,K-ATPase. Based on our previous work showing that a 20-HETE inhibitor is neuroprotective in models of neonatal hypoxia-ischemia and adult ischemic and hemorrhagic stroke, we began to study its effect in the controlled cortical impact model in postnatal day 10 rats. Preliminary data show large reductions in lesion volume, improved long-term sensorimotor function, attenuated morphological changes in microglia, and a reduction of pro-inflammatory cytokines. The 20-HETE inhibitor also attenuated the response to lipopolysaccharide in microglia cultures. The goal of this project is to investigate the role of 20-HETE in males and females in a model of pediatric TBI.
In Aim 1, we will determine the optimal duration of 20-HETE inhibitor administration and the maximum delay that provides efficacy so as to inform when 20-HETE signaling is exerting adverse effects after TBI.
In Aim 2, we will determine the effects of 20-HETE inhibition after TBI on NADPH oxidase and the consequent downstream effects on key caspase-dependent and independent cell death pathways.
In Aim 3, we will determine the effects of 20-HETE inhibition after TBI on microglia morphology and the cytokine profile. By targeting both cell death and inflammatory pathways with a single drug in the very immature brain, this work has great potential for improving outcome from TBI in infants and toddlers who often have the poorest prognosis in pediatric TBI. Moreover, emerging evidence with cerebral ischemia indicates sex differences in cell death mechanisms and inflammation in both immature and mature brain, yet sex differences have been understudied in pediatric TBI models. Thus, the proposed work also is innovative in that it will begin to reveal whether sex differences in response to neuroprotective therapies are operative after TBI in the immature brain. Finally, elucidation of new pathways of 20-HETE in neurons and microglia could have an important bearing beyond TBI for other neurodegenerative disorders involving excitotoxicity and neuroinflammation and, hence, may stimulate new areas of investigation.
Traumatic brain injury is the leading cause of long-term disability in children and young adults in the United States, making it a significant public health problem. This study will investigate the role of the arachidonic pathway metabolite, 20-HETE, in recovery after pediatric head injury, using a clinically relevant animal model in immature rats. We will use a translational platform of outcome tests to study optimal drug dosing, and response in both male and female rats, and will study the effects of 20-HETE on neuronal cell death pathways and neuroinflammation.
| Shin, Samuel S; Krishnan, Vijai; Stokes, William et al. (2018) Transcranial magnetic stimulation and environmental enrichment enhances cortical excitability and functional outcomes after traumatic brain injury. Brain Stimul 11:1306-1313 |
