Measurement of free fatty acids in cerebrospinal fluid from patients with hemorrhagic and ischemic stroke

Pilitsis, Julie G.; Coplin, William M.; O’Regan, Michael H.; Wellwood, Jody; Díaz, Fernando G.; Fairfax, Marilynn R.; Michael, D.B.; Phillis, John W.

doi:10.1016/s0006-8993(03)03044-0

Cited by 50 publications

(43 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study also examined the potential of TS-011 on minimizing infarct size following transient occlusion of the MCA since previous studies have indicated that there is release of fatty acids including AA following ischemic stroke (Pilitsis et al, 2003). The results indicate that administration of 0.01 or 0.1 mg/kg of TS-011 significantly reduced infarct volume in rats following transient occlusion of the MCA by 35%.…”

Section: Discussionmentioning

confidence: 75%

“…There are no approved agents to increase collateral flow following ischemic stroke. Since the level of arachidonic acid (AA) in the CSF was high during ischemic stroke (Pilitsis et al, 2003), it is possible that the production of 20-HETE in cerebral arteries increases and that this might contribute to brain injury by opposing the recruitment of collateral flow. 20-HETE also activates several signal transduction pathways (Muthalif et al, 1998;Sun et al, 1999;Randriambozvonjy et al, 2003) involved in apoptosis and cell death.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-NЈ-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC 50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC 50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 M. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.Each year, 750,000 strokes occur in the United States. Approximately 80% of the strokes are ischemic, and 20% are hemorrhagic. Hemorrhagic stroke commonly occurs after rupture of aneurysms or head trauma. There is an initial period of cerebral ischemia lasting several hours due to a rise in cerebral spinal fluid (CSF) pressure and acute cerebral vasospasm. One-half of the patients that survive later develop delayed vasospasm. The mortality in the 1st month hovers around 50%. The majority of deaths (Ͼ60%) occur during the first 2 days and is associated with ischemic brain injury (Broderick et al., 1994). The factors that contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) remain uncertain.Ischemic strokes are caused by blockage of cerebral arteries. In the ischemic neuronal tissue, there is depletion of

show abstract

Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…However, in studies of Alzheimer (33) and Parkinson (34) diseases, neither free nor acyl-carnitine levels significantly correlate with disease. Free fatty acids were shown to increase in patients with traumatic brain injury (35), stroke (36), and subarachnoid hemorrhage (37), yet a decrease in fatty acid concentrations was demonstrated in multiple sclerosis (38) and Alzheimer disease (39).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

Wikoff¹,

Pendyala²,

Siuzdak³

et al. 2008

J. Clin. Invest.

127

113

View full text Add to dashboard Cite

HIV infiltrates the CNS soon after an individual has become infected with the virus, and can cause dementia and encephalitis in late-stage disease. Here, a global metabolomics approach was used to find and identify metabolites differentially regulated in the cerebrospinal fluid (CSF) of rhesus macaques with SIV-induced CNS disease, as we hypothesized that this might provide biomarkers of virus-induced CNS damage. The screening platform used a non-targeted, mass-based metabolomics approach beginning with capillary reverse phase chromatography and electrospray ionization with accurate mass determination, followed by novel, nonlinear data alignment and online database screening to identify metabolites. CSF was compared before and after viral infection. Significant changes in the metabolome specific to SIV-induced encephalitis were observed. Metabolites that were increased during infection-induced encephalitis included carnitine, acyl-carnitines, fatty acids, and phospholipid molecules. The elevation in free fatty acids and lysophospholipids correlated with increased expression of specific phospholipases in the brains of animals with encephalitis. One of these, a phospholipase A2 isoenzyme, is capable of releasing a number of the fatty acids identified. It was expressed in different areas of the brain in conjunction with glial activation, rather than linked to regions of SIV infection and inflammation, indicating widespread alterations in infected brains. The identification of specific metabolites as well as mechanisms of their increase illustrates the potential of mass-based metabolomics to address problems in CNS biochemistry and neurovirology, as well as neurodegenerative diseases.

show abstract

“…Both polymorphonuclear leukocytes and cerebral arteries produce 20-HETE, 5,27 and there is massive release of AA during cerebral ischemia. 3 Thus, it is likely that the local production of 20-HETE in cerebral arteries increase during ischemic stroke. We also obtained evidence for upregulation of the expression of CYP4A protein in neurons and vascular endothelial cells 24 hours after ischemia reperfusion injury in rats.…”

Section: Discussionmentioning

confidence: 99%

“…2 Recent studies have indicated that arachidonic acid (AA) is released in cerebrospinal fluid (CSF) after cerebral ischemia. 3 AA can be metabolized by cytochrome P450 (CYP) enzymes in cerebral arteries to the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid . 4 20-HETE plays an important role in the regulation of cerebral vascular tone by regulating the open state probability of K ϩ channels.…”

mentioning

confidence: 99%

Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury

Omura

Tanaka²,

Miyata³

et al. 2006

Stroke

View full text Add to dashboard Cite

Background and Purpose-Arachidonic acid that is released following cerebral ischemia can be metabolized to . 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys. Methods-Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery. Results-Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys. Conclusion-These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.

show abstract

Measurement of free fatty acids in cerebrospinal fluid from patients with hemorrhagic and ischemic stroke

Cited by 50 publications

References 15 publications

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

Effect of a New Inhibitor of the Synthesis of 20-HETE on Cerebral Ischemia Reperfusion Injury

Contact Info

Product

Resources

About