Molecular Characterization of an Arachidonic Acid Epoxygenase in Rat Brain Astrocytes

Alkayed, Nabil J.; Narayanan, Jayashree; Gebremedhin, Debebe; Medhora, Meetha; Roman, Richard J.; Harder, David R.

doi:10.1161/01.str.27.5.971

Cited by 176 publications

(211 citation statements)

References 22 publications

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“…Epoxyeicosatrienoic acids are formed by the catalytic conversion of arachidonic acid (AA) via cytochrome P450 (CYP)2C11 enzymes in rat astrocytes (Alkayed et al, 1996) and by CYP4X1 in rat brain (Bylund et al, 2002). Four regioisomers of EETs are formed from AA,namely,5,8,11,and 14, All regioisoforms are capable of supporting angiogenesis; however, our previous findings suggest that 8,9-and 11,12-EET are the most potent .…”

Section: Introductionmentioning

confidence: 99%

Antiangiogenic Effect of Inhibitors of Cytochrome P450 on Rats with Glioblastoma Multiforme

Zagorac

Jakovcevic

Gebremedhin

et al. 2008

J Cereb Blood Flow Metab

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Cytochrome P450 epoxygenase catalyzes 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) from arachidonic acid (AA). In 1996, our group identified the expression of the cytochrome P450 2C11 epoxygenase (CYP epoxygenase) gene in astrocytes. Because of our finding an array of physiological functions have been attributed to EETs in the brain, one of the actions of EETs involves a predominant role in brain angiogenesis. Blockade of EETs formation with different epoxygenase inhibitors decreases endothelial tube formation in cocultures of astrocytes and capillary endothelial cells. The intent of this investigation was to determine if pharmacologic inhibition of formation of EETs is effective in reducing capillary formation in glioblastoma multiforme with a concomitant reduction in tumor volume and increase in animal survival time. Two mechanistically different inhibitors of CYP epoxygenase, 17-octadecynoic acid (17-ODYA) and miconazole, significantly reduced capillary formation and tumor size in glial tumors formed by injection of rat glioma 2 (RG2) cells, also resulting in an increased animal survival time. However, we observed that 17-ODYA and miconazole did not inhibit the formation of EETs in tumor tissue. This implies that 17-ODYA and miconazole appear to exert their antitumorogenic function by a different mechanism that needs to be explored.

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Section: Introductionmentioning

confidence: 99%

Antiangiogenic Effect of Inhibitors of Cytochrome P450 on Rats with Glioblastoma Multiforme

Zagorac

Jakovcevic

Gebremedhin

et al. 2008

J Cereb Blood Flow Metab

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“…More recently, we reported that miconazole and MS-PPOH reduce the CBF response to whisker stimulation (Peng et al, 2002). EETs can dilate cerebral arteries (Ellis et al, 1990;Gebremedhin et al, 1992;Leffler and Fedinec, 1997) by a mechanism involving the opening of K Ca channels (Alkayed et al, 1996b;Gebremedhin et al, 1992). In cortical brain slices, afferent stimulation leads to increases in astrocyte calcium and subsequent arteriolar dilation by a mechanism dependent on activation of metabotropic glutamate receptors (Zonta et al, 2003).…”

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confidence: 99%

“…EETs are synthesized from arachidonic acid by specific cytochrome P450 (CYP) enzymes possessing epoxygenase activity (Roman, 2002). One such epoxygenase, CYP2C11, has been identified in cultured rat astrocytes (Alkayed et al, 1996b). Application of glutamate to cultured astrocytes increases EETs in the astrocytes and media, and the increase is inhibited by the epoxygenase inhibitor miconazole (Alkayed et al, 1997).…”

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confidence: 99%

Dependency of Cortical Functional Hyperemia to Forepaw Stimulation on Epoxygenase and Nitric Oxide Synthase Activities in Rats

Peng

Zhang

Alkayed

et al. 2004

J Cereb Blood Flow Metab

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Summary: Individual inhibition of nitric oxide (NO) synthase and cytochrome P450 (CYP) epoxygenase activity attenuates cortical functional hyperemia evoked by whisker stimulation. The objectives of the present study were to determine (1) if administration of epoxygenase inhibitors attenuates cortical functional hyperemia by using a different modality of sensory activation (i.e., electrical stimulation of the rat forepaw), (2) if epoxygenase inhibition has an additive effect with NO synthase inhibition on the flow response, and (3) the cellular localization of the epoxygenase CYP2C11 in cerebral cortex. In six groups of anesthetized rats, the cortical surface was superfused for 90 minutes with (1) -methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH), a substrate inhibitor of P450 epoxygenase; (4) MS-PPOH plus L-NNA; (5) 20-mol/L miconazole, a reversible inhibitor at the heme site of P450 epoxygenase; and (6) miconazole plus L-NNA. The percent increases in laser-Doppler perfusion over primary sensory cortex during 20-second forepaw stimulation were reduced by 44% to 64% in all drugtreated groups. The addition of L-NNA to MS-PPOH produced no additional reduction (64%) compared with MS-PPOH alone (64%) or L-NNA alone (60%). The addition of L-NNA to miconazole also produced no additional reduction in the flow response. In situ hybridization of CYP2C11 mRNA showed localization in astrocytes, including those adjacent to blood vessels. Thus, activity of both epoxygenase, presumably localized in astrocytes, and NO synthase is required for generating a complete cortical hyperemic response evoked by electrical forepaw stimulation. The lack of additional blood flow attenuation with the combination of the NO synthase and the distinct epoxygenase inhibitors suggests that the signaling pathways do not act in a simple parallel fashion and that other mediators may be involved in coupling cortical blood flow to neuronal activation.

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“…Reports from the Ellis group, which have been confirmed in our laboratory, demonstrate that EETs are the predominant AA metabolite formed by astrocytes. 2,22,26,27 There are no consistent reports that glutamate stimulates the formation of cyclooxygenase products, whereas EET formation is significantly enhanced in the presence of glutamate. 22,27 Pharmacological inhibition of P450 epoxygenase significantly blunts the transient increase in nutritive laser-Doppler blood flow in response to glutamate infusion (Fig 6).…”

Section: Glutamate-induced Release Of Eets May Mediate Functional Hypmentioning

confidence: 99%

“…22 EETs released from astrocytes potently dilate cerebral microvessels by enhancing outward K ϩ current and hyperpolarizing cerebral and other arterial muscle cells. 2,4,21,24 Thus, a hypothesis emerges which states that release of glutamate during normal neuronal activity can bind to glutamate receptors on astrocytes to increase AA turnover and release EETs from astrocytes that quickly and potently dilate the cerebral microcirculation to "shunt" flow to those areas surrounding metabolically active neurons. This hypothesis is depicted in Fig 5. Binding of glutamate can activate phospholipases to release AA from the membrane of astrocytes, and free AA can be metabolized by P450 epoxygenases to EETs, which can diffuse out of astrocytic foot processes and hyperpolarize cerebral arterial vascular smooth muscle and induce dilation.…”

Section: Glutamate-induced Release Of Eets May Mediate Functional Hypmentioning

confidence: 99%

Differences in Stroke Between White, Hispanic, and Native American Patients

Frey

Jahnke

Bulfinch

1998

Stroke

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Background-Cerebral blood flow is tightly coupled to neuronal metabolic activity, a phenomenon referred to as functional hyperemia. The mechanisms underlying functional hyperemia in the brain have been extensively studied, but the link between neuronal activation and nutritive blood flow has yet to be defined. Recent investigations by our laboratory and others have identified a potential role for astrocytes as an intermediary cell type in this process. Summary of Review-This short review will develop the hypothesis that cytochrome P450 epoxygenase activity in astrocytes catalyzes formation of epoxyeicosatrienoic acids (EETs), which act as potent dilators of cerebral vessels and are released in response to glutamate receptor activation within astrocytes. Neuronal activity stimulates release of arachidonic acid from the phospholipid pool of astrocytic membranes. We provide evidence that the arachidonic acid released on stimulation of glutamate receptors within astrocytes is metabolized by cytochrome P450 2C11 cDNA enzymes into EETs. Conclusions-TheEETs thus formed will be released and activate K ϩ channels, increase outward K ϩ current, and hyperpolarize the plasma membrane. The resulting membrane hyperpolarization inhibits voltage-gated Ca 2ϩ channels and leads to arteriolar dilation, thereby increasing regional nutritive blood flow in response to neuronal activity. (Stroke. 1998;28:229-234.)

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Molecular Characterization of an Arachidonic Acid Epoxygenase in Rat Brain Astrocytes

Cited by 176 publications

References 22 publications

Antiangiogenic Effect of Inhibitors of Cytochrome P450 on Rats with Glioblastoma Multiforme

Antiangiogenic Effect of Inhibitors of Cytochrome P450 on Rats with Glioblastoma Multiforme

Dependency of Cortical Functional Hyperemia to Forepaw Stimulation on Epoxygenase and Nitric Oxide Synthase Activities in Rats

Differences in Stroke Between White, Hispanic, and Native American Patients

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