Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric
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BMC Neuroscience Open Access
Neurologic effects of short‑term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine Caitlin E. O’Brien1* , Polan T. Santos1, Ewa Kulikowicz1, Jennifer K. Lee1,3, Raymond C. Koehler1† and Lee J. Martin2,3†
Abstract Background: Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3–4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors. Results: Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits. Conclusion: Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets. Keywords: Neuroprotection, TPPU, Brain damage, Basal ganglia, Cell death, Piglet, Cardiac arrest Background Cardiac arrest is the most common cause of acute neurologic injury in children [1]. Although survival has improved over the past 2 decades [2], 40–60% of survivors have moderate-to-severe neurologic impairment at 1 year of recovery [3–5]. Furthermore, 25% of patients *Correspondence: [email protected] † Raymond C. Koehler and Lee J. Martin are co-senior authors 1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 1800 Orleans Street, Bloomberg Children’s Center Suite 6302, Baltimore, MD 21287, USA Full list of author information is available at the end of the article
classified as a having a favorable neurologic outcome by traditional assessment have significant cognitive impairment on neuropsychological testing at 1 year recovery [6], suggesting that more subtle and pernicious impairments are common and possibly overlooked on routine evaluations. Currently, no targeted clinical therapies exist to protect the develop
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