The inhibitor of 20‐HETE synthesis, TS‐011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice

Abstract

BACKGROUND AND PURPOSE 20‐Hydroxyeicosatetraenoic acid is a potent vasoconstrictor that contributes to cerebral ischaemia. An inhibitor of 20‐Hydroxyeicosatetraenoic acid synthesis, TS‐011, reduces infarct volume and improves neurological deficits in animal stroke models. However, little is known about how TS‐011 affects the microvessels in ischaemic brain. Here, we investigated the effect of TS‐011 on microvessels after cerebral ischaemia. EXPERIMENTAL APPROACH TS‐011 (0.3 mg·kg−1) or a vehicle was infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri‐infarct microvessels were measured using in vivo two‐photon imaging. KEY RESULTS The cerebral blood flow velocities in the peri‐infarct microvessels decreased at 1 and 7 h after reperfusion, followed by an increase at 24 h after reperfusion in the vehicle‐treated mice. We found that TS‐011 significantly inhibited both the decrease and the increase in the blood flow velocities in the peri‐infarct microvessels seen in the vehicle‐treated mice after reperfusion. In addition, TS‐011 significantly inhibited the reduction in the microvascular perfusion area after reperfusion, compared with the vehicle‐treated group. Moreover, TS‐011 significantly reduced the infarct volume by 40% at 72 h after middle cerebral artery occlusion. CONCLUSIONS AND IMPLICATIONS These findings demonstrated that infusion of TS‐011 improved defects in the autoregulation of peri‐infarct microcirculation and reduced the infarct volume. Our results could be relevant to the treatment of cerebral ischaemia.

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

“…For example, treatment with 20-HETE inhibitors improved CBF and reduced lesion volume after focal ischemia. 26,31 In other studies, 20-HETE inhibition reduced lesion volume and neurodegeneration independent of CBF, suggesting a direct neuroprotective effect of 20-HETE inhibition. 17,18,32 In a global cerebral ischemia model in immature piglets similar in some ways to our model, Yang et al 17 showed direct neuroprotection after CA in piglets treated with HET0016.…”

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…After acute ischemic injury, cerebral blood flow (CBF) is decreased at 1–2 h after reperfusion, and there is a second fall at 7 h after reperfusion (Huang et al, 2016). Administration 20-HETE synthesis inhibitors in MCAO rodents reduced infarct sizes, had no effect on the fall of CBF during the ischemic period and up to 2 h after reperfusion, but delayed or ameliorated the 2 nd fall (Dunn et al, 2008; Marumo et al, 2010; Poloyac et al, 2006; Renic et al, 2009). However, these data are not definitive to conclude that there is impaired autoregulation of CBF, since the perfusion pressure in cerebral vessels is below the autoregulatory range in acute ischemic status and when the vessels remain occluded during reperfusion.…”

“…However, these data are not definitive to conclude that there is impaired autoregulation of CBF, since the perfusion pressure in cerebral vessels is below the autoregulatory range in acute ischemic status and when the vessels remain occluded during reperfusion. Importantly, these experiments were performed in C57BL/6J mice, Sprague-Dawley, Wistar and Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and spontaneously hypertensive strokeprone rats (SHRSP) that have normal or elevated endogenous 20-HETE levels (Dunn et al, 2008; Marumo et al, 2010; Misir et al, 2017; Poloyac et al, 2006; Renic et al, 2009). Therefore, results from these studies can only explain the role of 20-HETE on progression of outcomes of ischemic stroke.…”

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

“…20-Hydroxyeicosatetraenoic acid has also been reported to induce the formation of oxygen radicals by interacting with nicotinamide adenine dinucleotide phosphate-oxidase and nitric oxide synthase (Wang et al, 2006;Cheng et al, 2008;Medhora et al, 2008). Previously, we reported that brain and plasma 20-HETE levels were significantly increased in the rat transient middle cerebral artery occlusion (tMCAO) model (Tanaka et al, 2007), and inhibition of 20-HETE synthesis by N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011), a selective inhibitor of CYP4s, improved the autoregulatory dysfunction in the peri-infarct microcirculation and the neurologic outcomes in rat and monkey stroke models by reducing the infarct volume of the brain after ischemia (Miyata et al, 2005;Omura et al, 2006;Tanaka et al, 2007;Marumo et al, 2010). However, 20-HETE is also known to be involved in the angiogenesis induced by vascular endothelial growth factor, which is known to be upregulated in the ischemic brain after stroke for a repair process (Kovács et al, 1996;Plate et al, 1999;Zhang et al, 2002).…”