Cyclooxygenase- and cytochrome P450-derived eicosanoids in stroke

Abstract

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX) and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in cardiovascular diseases and stroke. Evidence has demonstrated the important functions of these eicosanoids in regulating cerebral vascular tone, cerebral blood flow, and autoregulation of cerebral circulation. Although COX-2 inhibitors have been suggested as potential treatments for stroke, adverse events, including an increased risk of stroke, occur following long-term use of coxibs. It is important to note that prolonged treatment with rofecoxib increased circulating levels of 20-hydroxyeicosatetraenoic acid (20-HETE), and 20-HETE blockade is a possible strategy to prevent coxib-induced stroke events. It appears that 20-HETE has detrimental effects in the brain, and that its blockade exerts cerebroprotection against ischemic stroke and subarachnoid hemorrhage (SAH). There is clear evidence that activation of EP2 and EP4 receptors exerts cerebroprotection against ischemic stroke. Several elegant studies have contributed to defining the importance of stabilizing the levels of epoxyeicosatrienoic acids (EETs), by inhibiting or deleting soluble epoxide hydrolase (sEH), in stroke research. These reports support the notion that sEH blockade is cerebroprotective against ischemic stroke and SAH. Here, we summarize recent findings implicating these eicosanoid pathways in cerebral vascular function and stroke. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of ischemic stroke and SAH.

The Brain Oxylipin Profile Is Resistant to Modulation by Dietary n‐6 and n‐3 Polyunsaturated Fatty Acids in Male and Female Rats

“…For example, a lipoxin A 4 analog is neuroprotective and reduces inflammation in a rat model of cerebral ischemic reperfusion injury (Ye et al, ),15‐deoxy‐PGJ2 has antipyretic effects associated with reduction in LPS‐induced COX2 expression in the hypothalamus (Mouihate et al, ), 8,9‐ and 11,12‐EpETrE from astrocytes have angiogenic and mitogenic effects in cultured cerebral capillary endothelial cells (Zhang and Harder, ), 11,12‐EpETrE attenuates interleukin‐1β (IL‐1β)‐induced fever in the anterior hypothalamus (Nakashima et al, ), 11,12‐ and 14,15‐EpETrE have vasodilatory effects in the cerebral microcirculation (Alkayed et al, ) and astrocyte 14,15‐EpETrE enhances cell viability in oxidation‐induced ischemic injury (Terashvili et al, ; Yuan et al, ). On the other hand, abnormal levels of ARA oxylipins are also associated with brain dysfunction, such as PGE 2 , thromboxane B 2 , and leukotriene B 4 , which increase production of Aβ peptides that contributes to the formation of amyloid plaques, a hallmark of Alzheimer's disease (Amtul et al, ), 12‐HETE, a marker of brain injury (Farias et al, ), and 20‐HETE, which contributes to vasoconstriction and vasospasm in brain, which has detrimental effects in ischemic stroke (Huang et al, ).…”

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

“…However, the published reports on the role of 20-HETE on cerebral autoregulation in ischemic stroke is still not elucidated, and further investigation is needed. 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).…”

“…Therefore, results from these studies can only explain the role of 20-HETE on progression of outcomes of ischemic stroke. It has to be mentioned, tissue plasminogen activator (r-tPA), the only FDA-approved drug treatment for ischemic stroke patients, and COX inhibitors commonly used for acute ischemic stroke treatment, all could reduce CBF, along with other confounders such as antihypertensive drugs and vasodilators (Fan et al, 2013; Huang et al, 2016; Jordan and Powers, 2012). In fact, our recent studies using Dahl salt sensitive (SS) rats that have decreased 20-HETE production demonstrated that there is impaired autoregulation of CBF, BBB leakage, and neurodegeneration after induction of hypertension (Fan et al, 2018).…”

CYP3A4 and CYP11A1 variants are risk factors for ischemic stroke: a case control study

“…To the best of our knowledge, this is the first study to demonstrate the association of these polymorphisms in CYP3A4 and CYP11A1 with IS risk in Chinese population. CYP genes encode monooxygenases responsible for arachidonic acid metabolism, which is involved in cardiovascular diseases and stroke [17]. Numerous studies have suggested an association between genetic variants of CYP pathway genes and the risk of IS [18].…”