20-Hydroxyeicosatetraenoic Acid Inhibition by HET0016 Offers Neuroprotection, Decreases Edema, and Increases Cortical Cerebral Blood Flow in a Pediatric Asphyxial Cardiac Arrest Model in Rats

Abstract

Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets.

Cerebral Hemodynamics and Metabolism During Cardiac Arrest and Cardiopulmonary Resuscitation Using Hyperspectral Near Infrared Spectroscopy

“…We also observed that there was a larger decrease in Cyt-ox in the brain compared to muscle during untreated VF, which may represent higher concentrations of Cyt-ox in the brain 35 or the brain's vulnerability to hypoxia.…”

“…Interestingly, we also observed an increase in cerebral total Hb of ~200 s after VF induction (which was not observed in the muscle); this is consistent with a previous study by Shaik et al who showed increased vasodilator eicosanoids in the cerebral cortex during CA in rats. 35 Increased cerebral total Hb only in the cerebral tissue during untreated VF may represent the cerebral autoregulation through cerebral vasodilation.…”

Cerebral blood flow is decoupled from blood pressure and linked to EEG bursting after resuscitation from cardiac arrest

“…Previous studies have not been able to identify the exact time and magnitude of the hyperemic peak and stabilized hypoperfusion post-ROSC due to the relatively poor temporal resolution (~5-30min) [7,10,23]. Interestingly, in a pediatric model of asphyxial CA, Manole et al [9] and Shaik et al [24] both did not observe a hyperemic peak in cortical CBF using MRI and LSI, respectively. Their results suggest that post-ROSC cerebral hemodynamics vary between adults and children.…”

Molecular mechanisms in differentiated thyroid cancer

“…CSD has recently been reported to be associated with an increase in 20-HETE synthesis and reduced CBF in rat model. Administration of 20-HETE inhibitor ameliorated the reduction in CBF, decreased edema and afforded neuroprotection (282, 283). …”