Increase of 20-HETE Synthase after Brain Ischemia in Rats Revealed by PET Study with ¹¹C-Labeled 20-HETE Synthase-Specific Inhibitor

Abstract

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a 11 C-labeled specific 20-HETE synthase inhibitor, N 0 (4-dimethylaminohexyloxy)phenyl imidazole ([ 11 C]TROA). Autoradiographic study showed that [ 11 C]TROA has highspecific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [ 11 C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [ 11 C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [ 11 C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.

Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen–Glucose Deprivation in Cortical Neurons

“…1). This finding is consistent with previous reports in newborn piglets (Yang et al 2012), adult rats (Kawasaki et al 2012), and cultured rat hippocampal slices (Renic et al 2012). Moreover, expression of CYP4A protein was preserved in cultured cortical neurons (Fig.…”

“…Granule and pyramidal cells in hippocampal slice culture (Renic et al 2012) and cortical and striatal neurons in rat and piglet brain (Omura et al 2006; Yang et al 2012; Kawasaki et al 2012) all exhibit positive CYP4A immuno-signals. Although 20-HETE levels in the brain parenchyma increase early after brain ischemia (Tanaka et al 2007), neuronal CYP4A immuno-signals do not confirm that neurons are the source of 20-HETE production because only mouse Cyp4a12 can metabolize arachidonic acid into 20-HETE and CYP4A antibody cannot distinguish different CYP4A isoforms.…”

“…A recent study revealed that cultured rat astrocytes express Cyp4A protein and produce 20-HETE after mGluR agonist RS-3,5-dihydroxyphenylglycine treatment (Gebremedhin et al 2016). Others have reported that microglia express CYP4A and may serve as the main cellular source of 20-HETE in rat brains 7 days after transient middle cerebral artery occlusion (Kawasaki et al 2012). Therefore, in the present study, we examined (1) which CYP4A isoforms are expressed in primary cultures of mouse cortical neurons; (2) whether CYP4A isoform expression is upregulated after OGD, and (3) whether synthesized 20-HETE can contribute to neuronal death after OGD.…”

Molecular mechanisms in differentiated thyroid cancer

“…The levels of 20-HETE are elevated in cerebral tissue in rat (123, 320) and in the plasma of patients (321) and rats (50) following ischemic stroke. Administration of 20-HETE synthesis inhibitors markedly reduces infarct size and improves neurological outcomes following focal cerebral ischemia in rats (50, 116, 158, 168, 322, 323).…”

Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice

“…Its concentration together with that of ARA is elevated by brain ischemia [46, 47]. 20-HETE influences neurovascular and cardiovascular function and can activate NF-κB to produce inflammatory changes [37–40, 48, 49].…”