leukotriene-b4 and Brain-Ischemia

The cytosolic 85 kDa phospholipase A(2) (cPLA(2)) is a unique member of the phospholipase A(2) (PLA(2)) superfamily. Because PLA(2) activity and eicosanoid production are important in normal and pathophysiological states we and the laboratory of Shimizu created a mouse deficient in cPLA(2) (cPLA(2)(-/-) mouse). cPLA(2)(-/-) mice develop normally but the females have severe reproductive defects. cPLA(2)(-/-) mice suffer smaller infarcts and fewer neurological deficits after transient occlusion of the middle cerebral artery and have less injury after administration of a dopaminergic selective neurotoxin. cPLA(2)(-/-) mice have a more rapid recovery from allergen-induced bronchoconstriction and have no airway hyperresponsiveness. Peritoneal macrophages from cPLA(2)(-/-) mice fail to produce prostaglandins, leukotriene B(4) and cysteinyl leukotrienes after stimulation. Bone marrow-derived mast cells from cPLA(2)(-/-) mice fail to produce eicosanoids in either immediate or delayed phase responses. Thus the cPLA(2) knockout mouse has revealed important roles of cPLA(2) in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses. Furthermore the cPLA(2)(-/-) mouse reveals that the many other forms of PLA(2) cannot replace many functions of cPLA(2). The importance of cPLA(2) in inflammation and tissue injury suggests that pharmacological targeting of this enzyme may have important therapeutic benefits.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Airway Resistance; Anaphylaxis; Animals; Brain Injuries; Brain Ischemia; Bronchoconstriction; Cytosol; Female; Gene Deletion; Leukotriene B4; Leukotriene C4; Lipopolysaccharides; Litter Size; Macrophages, Peritoneal; Methacholine Chloride; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Cerebral Artery; Models, Animal; Ovalbumin; Phospholipases A; Pregnancy

Topics: Brain Ischemia; Epoprostenol; Humans; Leukotriene B4; SRS-A; Thromboxane A2

Topics: Animals; Arachidonic Acids; Brain; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Eicosanoic Acids; Epoprostenol; Fatty Acids, Unsaturated; Humans; Indomethacin; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Leukotriene B4; Lipid Peroxides; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandins; Thromboxanes

Brain ischemia due to a critical reduction in cerebral blood flow is a well recognized and common cause of irreversible brain damage. The observation that brain cells are more resistant to ischemia than was previously assumed on the basis of clinical experience has stimulated considerable investigative work designed to determine those factors responsible for irreversible ischemic cell damage. At this time, data from these investigations indicate that cellular acidosis and biochemical disturbances initiated by abnormal intracellular ion homeostasis may be especially important in determining the ultimate survival of nerve cells. This review examines the biochemical events initiated by ischemia and their potential role in determining the ultimate survival of brain cells.

Topics: Acid-Base Equilibrium; Animals; Blood-Brain Barrier; Brain; Brain Ischemia; Calcium; Energy Metabolism; Humans; Ischemic Attack, Transient; Leukotriene B4; Membrane Lipids; Oxygen; Phospholipids; Potassium; Prostaglandins; SRS-A; Thromboxanes

Neuroinflammatory response contributes to early neurological deterioration (END) and unfavorable long-term functional outcome in patients with acute ischemic stroke (AIS) who recanalized successfully by endovascular thrombectomy (EVT), but there are no reliable biomarkers for their accurate prediction. Here, we sought to determine the temporal plasma profiles of the bioactive lipid mediators lipoxin A4 (LXA4), resolvin D1 (RvD1), and leukotriene B4 (LTB4) for their associations with clinical outcome.. We quantified levels of LXA4, RvD1, and LTB4 in blood samples retrospectively and longitudinally collected from consecutive AIS patients who underwent complete angiographic recanalization by EVT at admission (pre-EVT) and 24 hrs post-EVT. The primary outcome was unfavorable long-term functional outcome, defined as a 90-day modified Rankin Scale score of 3-6. Secondary outcome was END, defined as an increase in National Institutes of Health Stroke Scale (NIHSS) score ≥4 points at 24 hrs post-EVT.. Eighty-one consecutive AIS patients and 20 healthy subjects were recruited for this study. Plasma levels of LXA4, RvD1, and LTB4 were significantly increased in post-EVT samples from AIS patients, as compared to those of healthy controls. END occurred in 17 (20.99%) patients, and 38 (46.91%) had unfavorable 90-day functional outcome. Multiple logistic regression analyses demonstrated that post-EVT levels of LXA4 (adjusted odd ratio [OR] 0.992, 95% confidence interval [CI] 0.987-0.998), ΔLXA4 (adjusted OR 0.995, 95% CI 0.991-0.999), LTB4 (adjusted OR 1.003, 95% CI 1.001-1.005), ΔLTB4 (adjusted OR 1.004, 95% CI 1.002-1.006), and post-EVT LXA4/LTB4 (adjusted OR 0.023, 95% CI 0.001-0.433) and RvD1/LTB4 (adjusted OR 0.196, 95% CI 0.057-0.682) ratios independently predicted END, and post-EVT LXA4 levels (adjusted OR 0.995, 95% CI 0.992-0.999), ΔLXA4 levels (adjusted OR 0.996, 95% CI 0.993-0.999), and post-EVT LXA4/LTB4 ratio (adjusted OR 0.285, 95% CI 0.096-0.845) independently predicted unfavorable 90-day functional outcome. These were validated using receiver operating characteristic curve analyses.. Plasma lipid mediators measured 24 hrs post-EVT were independent predictors for early and long-term outcomes. Further studies are needed to determine their causal-effect relationship, and whether the imbalance between anti-inflammatory/pro-resolving and pro-inflammatory lipid mediators could be a potential adjunct therapeutic target.

Topics: Brain Ischemia; Endovascular Procedures; Humans; Ischemic Stroke; Leukotriene B4; Retrospective Studies; Stroke; Thrombectomy; Treatment Outcome

Ischemic stroke has become one of the main causes of death worldwide. MicroRNAs (miRNAs) have been implicated in cerebral ischemia-reperfusion (I/R) injury and could serve as therapeutic targets. 5-Lipoxygenase (5-LOX) is a key enzyme in the biosynthesis of leukotrienes and has been implicated in inflammatory central nerve system disorders. The objective of this study was to explore the neuroprotective effects of miR-193b-3p against focal cerebral I/R injury in rats by regulating 5-LOX expression.. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion injury. The level of miR-193b-3p expression was observed in the rat cortical peri-infarct region after focal cerebral I/R injury. Bioinformatics analysis was used to predict the binding sites of miR-193b-3p, and a dual-luciferase reporter gene assay was applied to verify the potential interaction between 5-LOX mRNA and miR-193b-3p. Then, rats were injected with a miR-193b-3p agomir (modified and enhanced mimic) or antagomir (modified and enhanced inhibitor) in the right lateral ventricle of the brain. Neurological deficit scores, infarct volumes, neuron damage and 5-LOX enzymatic activity and expression were measured. In an in vitro experiment, cultured PC12 cells were exposed to oxygen-glucose deprivation and reperfusion (OGD/R). OGD/R-induced cells were treated with a miR-193b-3p mimic or inhibitor and 5-LOX siRNA. Cell viability, lactate dehydrogenase release, apoptosis rate and 5-LOX expression were evaluated.. The level of miR-193b-3p expression was increased in the cortical peri-infarct region of rats with cerebral focal I/R injury. The results of the dual-luciferase reporter gene assay showed that a miR-193b-3p binding site was located in the 3' untranslated region (3'UTR) of 5-LOX mRNA. Neurological deficit scores, infarct volumes and neuronal injury were alleviated by miR-193b-3p agomir treatment but aggravated by miR-193b-3p antagomir. Furthermore, leukotriene B4, cysteinyl-leukotrienes and 5-LOX expression in the cortical peri-infarct region of rats with focal cerebral I/R injury were also downregulated by miR-193b-3p agomir treatment but upregulated by miR-193b-3p antagomir. In PC12 cells, miR-193b-3p mimic significantly decreased OGD/R-induced cell death and reduced lactate dehydrogenase release and 5-LOX expression. In contrast, miR-193b-3p inhibitor exacerbated OGD/R-induced injury in PC12 cells. Additionally, the in vitro effects of miR-193b-3p inhibitor on OGD/R-induced cell injury were partially reversed by 5-LOX siRNA treatment.. MiR-193b-3p has a potentially neuroprotective effect on focal cerebral I/R-induced injury by inhibiting 5-LOX expression.

Topics: Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Brain Ischemia; Cell Survival; Leukotriene B4; Lipoxygenase Inhibitors; Male; MicroRNAs; Neurons; PC12 Cells; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Lipoxin A(4) (LXA(4)), a biologically active eicosanoid with anti-inflammatory and pro-resolution properties, was recently found to have neuroprotective effects in brain ischemia. As 5-lipoxygenase (5-LOX) and leukotrienes are generally considered to aggravate cerebral ischemia/reperfusion (I/R) injury, we investigated their effects on LXA(4)-mediated neuroprotection by studying middle cerebral artery occlusion (MCAO)/reperfusion in rats and oxygen-glucose deprivation (OGD)/recovery in neonatal rat astrocyte primary cultures. LXA(4) effectively reduced infarct volumes and brain edema, and improved neurological scores in the MCAO/reperfusion experiments; this effect was partially blocked by butoxycarbonyl-Phe-Leu-Phe-Leu-Phe (Boc2), a specific antagonist of the LXA(4) receptor (ALXR). Total 5-LOX expression did not change, regardless of treatment, but LXA(4) could inhibit nuclear translocation induced by MCAO or OGD. We also found that LXA(4) inhibits the upregulation of both leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) and the phosphorylation of extracellular signal-regulated kinase (ERK) induced by MCAO or OGD. The phosphorylation of the 38-kDa protein kinase (p38) and c-Jun N-terminal kinase (JNK) was not altered throughout the experiment. These results suggest that the neuroprotective effects of LXA(4) are probably achieved by anti-inflammatory mechanisms that are partly mediated by ALXR and through an ERK signal transduction pathway.

Topics: Animals; Animals, Newborn; Arachidonate 5-Lipoxygenase; Astrocytes; Brain Edema; Brain Ischemia; Disease Models, Animal; Enzyme Inhibitors; Flavonoids; Glucose; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipoxins; Male; MAP Kinase Signaling System; Neuroprotective Agents; Oxygen; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

Despite accumulating evidence supporting the association between variants of the ALOX5AP gene and atherosclerotic vascular events, the precise mechanism is still unclear. No variants in the coding sequence that lead to amino acid substitution have been found. We investigated genetic variants in the promoter region of the ALOX5AP gene and the association with ischemic stroke in a north Chinese Han population.. 505 cases of ischemic stroke and 500 age- and gender-matched controls of the north Chinese Han population were enrolled. Genetic variants in the promoter region of the ALOX5AP gene were identified by polymerase chain reaction and DNA sequencing. 40 cases and 40 controls were randomly selected and compared for serum leukotriene B(4) (LTB(4)) concentration. The effect on ischemic stroke was evaluated by logistic regression.. Three genetic variants were identified, including a mutation (-519 G > A), an insertion and deletion polymorphisms (-581_582 Ins A) and a single nuclear polymorphisms (-946 A > G). Association study showed that the II genotype of -581_582 Ins A was significantly associated with ischemic stroke of a large artery atherosclerosis (OR = 3.50, 95% CI = 1.93-6.36, p = 0.0002) and undetermined etiology (OR = 3.66, 95% CI = 1.92-6.94, p = 0.0006). No significant association was found between the -519 GA genotype (OR = 0.35, 95% CI = 0.02-5.88, p = 0.46), -946 AG genotype (OR = 1.35, 95% CI = 0.85-2.16, p = 0.21) and ischemic stroke. There was no significant difference in serum LTB(4) concentration between cases (n = 40) and controls (n = 40) (log serum LTB(4) of cases vs. controls: 2.67 ± 0.14 vs. 2.73 ± 0.18 pg/ml, p = 0.10). However, the serum LTB(4) concentration was significantly higher in participants with the II genotype of -581_582 Ins A (n = 12) than that of participants with the DD genotype (n = 68) (log serum LTB(4) of participants with II genotype vs. DD genotype: 2.82 ± 0.18 vs. 2.68 ± 0.15 pg/ml, p = 0.01).. The -581_582 Ins A polymorphism might be a novel genetic risk factor for ischemic stroke in a north Chinese Han population. Further studies on molecular mechanism are warranted.

Topics: 5-Lipoxygenase-Activating Proteins; Aged; Analysis of Variance; Base Sequence; Biomarkers; Brain Ischemia; Case-Control Studies; Chi-Square Distribution; China; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Leukotriene B4; Linkage Disequilibrium; Logistic Models; Male; Middle Aged; Molecular Sequence Data; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Assessment; Risk Factors; Stroke

The aim of the present study is to investigate the role of nordihydroguaiaretic acid (NDGA) on inflammatory cells accumulation after focal cerebral ischemia and the underlying mechanism. Focal cerebral ischemia was induced by 30 min of middle cerebral artery occlusion (MCAO) followed by 72 h of reperfusion. NDGA (5 and 10 mg/kg) was administered intraperitoneally 30 min, 2, 24, 48 h after reperfusion, respectively. The brain injuries were observed by neurological and histological examination. Endogenous IgG exudation, neutrophils and macrophages/microglia accumulation, and intercellular adhesion molecule-1 (ICAM-1) protein expression were determined by immunohistochemistry 72 h after reperfusion. ICAM-1 mRNA was determined by RT-PCR 72 h after reperfusion. The catalysates of 5-lipoxygenase (5-LOX), leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs), were evaluated by ELISA 3 h after reperfusion. The results showed that NDGA ameliorated neurological dysfunction, decreased infarct volume, and inhibited endogenous IgG exudation, neutrophils infiltration, ICAM-1 mRNA and protein expression 72 h after reperfusion. Moreover, NDGA reduced the levels of LTB4 and CysLTs 3 h after reperfusion. However, NDGA did not reduce the accumulation of macrophages/microglia 72 h after reperfusion. These results suggest that NDGA decreases neutrophil infiltration in the subacute phase of focal cerebral ischemia via inhibiting 5-LOX activation.

Topics: Animals; Arachidonate 5-Lipoxygenase; Brain Ischemia; Immunoglobulin G; Inflammation; Intercellular Adhesion Molecule-1; Leukotriene B4; Lipoxygenase Inhibitors; Male; Masoprocol; Neutrophils; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

Arachidonic acid (AA) and its vasoactive metabolites have been implicated in the pathogenesis of brain damage induced by cerebral ischemia. The membrane AA concentrations can be reduced by changes in dietary fatty acid intake. The purpose of the present study was to investigate the effects of chronic ethyl docosahexaenoate (E-DHA) administration on the generation of eicosanoids of AA metabolism during the period of reperfusion after ischemia in gerbils. Weanling male gerbils were orally pretreated with either E-DHA (100, 200 mg/kg) or vehicle, once a day, for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 10 min. E-DHA (200 mg/kg) pretreatment significantly decreased the content of brain lipid AA at the termination of treatment, prevented postischemic impaired regional cerebral blood flow (rCBF) and reduced the levels of brain prostaglandin (PG) PGF(2alpha) and 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), as well as leukotriene (LT) LTB(4) and LTC(4) at 30 and 60 min of reperfusion compared with the vehicle, which was well associated with the attenuated cerebral edema in the E-DHA-treated brain after 48 h of reperfusion. These data suggest that the E-DHA (200 mg/kg) pretreatment reduces the postischemic eicosanoid productions, which may be due to its reduction of the brain lipid AA content.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebrovascular Circulation; Dinoprost; Docosahexaenoic Acids; Eicosanoids; Fatty Acids; Gerbillinae; Leukotriene B4; Leukotriene C4; Lipids; Male; Reperfusion; Thromboxane B2

The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture.. We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, alpha-actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B4 and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell-rich areas was larger in symptomatic compared with asymptomatic patients (25+/-6% versus 8+/-4%, P<0.0001, and 74+/-17 versus 18+/-4 cell/mm2, P<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24+/-4% versus 6+/-3%, P<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27+/-4% versus 7+/-3%, P<0.0001, and 29+/-5% versus 8+/-2%, P<0.0001) and activity and with decreased collagen content (6.9+/-2.4% versus 17.8+/-3.1%, P<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB4 production (18.15+/-3.56 versus 11.27+/-3.04 ng/g tissue, P<0.0001).. The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB4, subsequent MMP biosynthesis, and plaque rupture.

Topics: Acute Disease; Aged; Arachidonate 5-Lipoxygenase; Brain Ischemia; Carotid Artery Diseases; Cells, Cultured; Collagen; Female; Humans; Leukotriene B4; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rupture; Signal Transduction; Vasculitis, Central Nervous System

It has been postulated that leukotriene B4 is involved in the pathogenesis of postischaemic cerebral oedema. We set out to determine if a relationship exists between jugular bulb leukotriene B4 and other indicators of cerebral ischaemia. No association could be demonstrated for either intracranial pressure, jugular bulb blood oxygen saturation or lactate oxygen index. Our results provide insufficient evidence to suggest that measurement of leukotriene B4 has any place in the management of head-injured patients.

Topics: Adolescent; Adult; Aged; Biomarkers; Brain Ischemia; Craniocerebral Trauma; Female; Humans; Intracranial Pressure; Jugular Veins; Lactates; Lactic Acid; Leukotriene B4; Male; Middle Aged; Oxygen

LTC4, which enhances vascular permeability and promotes tissue edema, and LTB4, which is a potent chemotactic and activating factor for leukocytes, were measured in rat brain after ischemia and several time periods of reperfusion. Forebrain ischemia was induced by 4-vessel occlusion. LTC4/LTB4 in the brain were measured by RIA. We also studied the effects of a 5-lipoxygenase inhibitor, AA-861 and a PAF antagonist, CV-3988 on LTC4/LTB4 concentrations. LTC4 in brain tissue increased during 30 min forebrain ischemia (p < 0.001). After reperfusion, LTC4 increased further, but at 15 min reperfusion LTC4 returned to the control level. Tissue levels of LTB4 in the brain increased during 30 min ischemia and remained high until 5 min after reperfusion (p < 0.01) returning at 15 min reperfusion to the control level. AA-861 inhibited elevation of LTC4/LTB4 in the reperfusion phase, but was not effective during ischemia. CV-3988 had a similar effect. LTC4 and LTB4 may be involved in the pathogenesis of ischemia brain edema and leukocyte infiltration. Further, PAF and LTs have many similarities of their pathophysiological properties, and may interact therefore in pathologic process.

Topics: Animals; Benzoquinones; Brain Edema; Brain Ischemia; Injections, Intraperitoneal; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Male; Phospholipid Ethers; Platelet Activating Factor; Premedication; Prosencephalon; Rats; Rats, Wistar; Reperfusion Injury

Neutrophils are critically involved with ischemia and reperfusion injury in many tissues but have not been studied under conditions of reperfusion after focal cerebral ischemia. The present studies were conducted to confirm our previous observations quantifying neutrophils in rat permanent focal stroke using a myeloperoxidase activity assay and to extend them to transient ischemia with reperfusion. In addition, leukotriene B4 receptor binding in ischemic tissue was evaluated as a potential marker for inflammatory cell infiltration.. Histological, enzymatic, and receptor binding techniques were used to evaluate neutrophil infiltration and receptor binding in infarcted cortical tissue 24 hours after permanent middle cerebral artery occlusion (n = 25) or temporary occlusion for 80 (n = 12) or 160 (n = 22) minutes followed by reperfusion for 24 hours in spontaneously hypertensive rats.. Sham surgery (n = 26) produced no changes in any parameter measured. After permanent middle cerebral artery occlusion, neutrophil accumulation was observed histologically, but the infiltration was moderate and typically within and adjacent to blood vessels bordering the infarcted cortex. After temporary middle cerebral artery occlusion with reperfusion, marked neutrophil infiltration was observed throughout the infarcted cortex. Myeloperoxidase activity was increased (p less than 0.05) after permanent occlusion and to a greater extent after temporary occlusion with reperfusion. Myeloperoxidase activity (units per gram wet weight) in ischemic cortex was increased over that in nonischemic (control) cortex 32.2-fold, 54.6-fold, and 92.1-fold for permanent occlusion and 80 and 160 minutes of temporary occlusion with reperfusion, respectively (p less than 0.05). Sham surgery produced no changes in myeloperoxidase activity. Leukotriene B4 receptor binding also was increased (p less than 0.05) after focal ischemia and paralleled the increases in myeloperoxidase activity. Ischemic cortex-specific receptor binding (femtomoles per milligram protein) was 3.87 +/- 0.63 in sham-operated rats and 4.57 +/- 0.98, 8.98 +/- 1.11, and 11.12 +/- 1.63 for rats subjected to permanent occlusion and 80 and 160 minutes of temporary occlusion with reperfusion, respectively (all p less than 0.05 different from sham-operated). Cortical myeloperoxidase activity was significantly correlated with the degree of cortical leukotriene B4 receptor binding (r = 0.66 and r = 0.79 in two different studies, p less than 0.01).. These data indicate that neutrophils are involved in focal ischemia and that there is a dramatic accumulation of neutrophils in infarcted tissue during reperfusion that can be quantified using the myeloperoxidase activity assay. Leukotriene B4 receptor binding increases in infarcted tissue in a parallel manner, which suggests that the increased leukotriene B4 binding is to receptors located on the accumulating neutrophils.

Topics: Animals; Brain; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Eosine Yellowish-(YS); Hematoxylin; Leukotriene B4; Male; Neutrophils; Rats; Rats, Inbred SHR; Receptors, Immunologic; Receptors, Leukotriene B4; Reperfusion; Staining and Labeling; Tetrazolium Salts

This study examined the changes in cerebral blood flow, water content, and lipoxygenase metabolites (leukotrienes) following bilateral carotid artery occlusion (BCO) and reperfusion in the gerbil. The effect of inhibiting lipoxygenase with nordihydroguaretic acid (NDGA) was also examined. BCO caused cerebral blood flow (measured using H2 clearance) to decline from 23.5 +/- 1.9 to 4.5 +/- 1.9 ml/min/100 gm. Reperfusion increased flow to 27.9 +/- 4 ml/min/100 gm at 10 min, which declined to 13.7 +/- 1.3 ml/min/100 gm at 50 min. Concomitant oedema measurement revealed brain specific gravity decreasing to 1.0402 +/- 0.0014 at 10 min and to 1.0325 +/- 0.0006 at 50 min reperfusion (nonoccluded controls). Leukotriene B4 (LTB4) increased from 26.8 +/- 4.6 to 33.5 +/- 2.1 pg/mg protein 10 min after reperfusion (p less than 0.05), but declined to 21.8 +/- pg/mg protein by 100 min (vs nonischaemic control = 21.3 +/- 2.9 pg/mg protein). Activation of arachidonate metabolism was confirmed by significantly increased 6 keto PGF1 alpha. Pretreatment of the animals with NDGA did not alter CBF, but increased specific gravity above saline-treated controls at 50 min of reperfusion (NDGA = 1.0370 +/- 0.002 vs control = 1.0325 +/- 0.0006, p less than 0.05). Similarly, NDGA blunted the increase in LTB4 formation 10 min after reperfusion (control = 26.8 +/- 4.6 pg/mg protein vs NDGA = 29.7 +/- 2.9 pg/mg protein, p = N.S.). These findings indicate that LTB4 production is stimulated by BCO and reperfusion in the gerbil, and that this stimulation occurs early on in the reperfusion. Further, we observe that the lipoxygenase inhibitor NDGA limits the formation of ischaemic cerebral oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Brain Chemistry; Brain Edema; Brain Ischemia; Gerbillinae; Leukotriene B4; Lipoxygenase; Regional Blood Flow