leukotriene-c4 and Brain-Edema

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

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 post-traumatic changes of leukotrienes LTC4, LTD4, LTE4, and LTB4 in cerebrospinal fluid of rats from 10 min to 7 days were investigated after controlled cortical impact in relation to brain edema and cellular inflammatory response. LTC4 increased five-fold at 4 h, normalized at 24 h, and showed another four-fold increase at 7 days. The same pattern was observed for LTD4 and LTE4. LTB4 however, behaved differently: concentrations were lower and levels peaked two-fold at 24 h. Edema in the injured hemisphere increased continuously up to 24 h without change contralaterally. Leukocyte infiltration, macrophage presence and microglia activation were most prominent at 24 h, 7 days and 24 h respectively. Leukotriene changes in CSF seem to reflect those in the affected tissue, with a time delay and in lower concentrations, and were not linearly correlated to brain edema. The initially high leukotriene levels are rather likely to contribute to the cytotoxic edema than to enhance a vasogenic edema component. The profile of LTB4 was parallel to the time course of leukocyte infiltration, indicating initiation of infiltration as well as prolonged production by leukocytes themselves. The second leukotriene peak at 7 days is likely to follow a different pathway and might be related to a production in macrophages or activated glia.

Topics: Animals; Brain Edema; Brain Injuries; Leukocytes; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Rats; Rats, Sprague-Dawley; Water

Accumulation of arachidonic acid (AA) is greatest in brain regions most sensitive to transient ischemia. Free AA released after ischemia is either: 1) reincorporated into the membrane phospholipids, or 2) oxidized during reperfusion by lipoxygenases and cyclooxygenases, producing leukotrienes (LT), prostaglandins, thromboxanes and oxygen radicals. AA, its metabolite LTC4 and lipid peroxides (generated during AA metabolism) have been implicated in the blood-brain barrier (BBB) dysfunction, edema and neuronal death after ischemia/reperfusion. This report describes the time course of AA release, LTC4 accumulation and association with the physiological outcome during transient cerebral ischemia of gerbils. Significant amount of AA was detected immediately after 10 min ischemia (0 min reperfusion) which returned to sham levels within 30 min reperfusion. A later release of AA occurred after 1 d. LTC4 levels were elevated at 0-6 h and 1 d after ischemia. Increased lipid peroxidation due to AA metabolism was observed between 2-6 h. BBB dysfunction occurred at 6 h. Significant edema developed at 1 and 2 d after ischemia and reached maximum at 3 d. Ischemia resulted in approximately 80% neuronal death in the CA1 hippocampal region. Pretreatment with a 5-lipoxygenase inhibitor, AA861 resulted in significant attenuation of LTC4 levels (Baskaya et al. 1996. J. Neurosurg. 85: 112-116) and CA1 neuronal death. Accumulation of AA and LTC4, together with highly reactive oxygen radicals and lipid peroxides, may alter membrane permeability, resulting in BBB dysfunction, edema and ultimately to neuronal death.

Topics: Animals; Arachidonic Acid; Blood-Brain Barrier; Brain Edema; Gerbillinae; Ischemic Attack, Transient; Leukotriene C4; Lipid Peroxidation; Male

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

The role of leukotrienes as mediator of brain edema is still controversial. Recently, the ability of gamma-GTP to act as enzymatic barrier and to inactivate leukotrienes in normal brain capillaries was pointed out. A hypothesis tested in our experiments was that Leukotriene C4 (LTC4) increases permeability of a cerebral capillary endothelial monolayer which lacks gamma-GTP activity. Brain capillary endothelial cells were obtained of 10 rats from cerebral cortex by an enzymatic isolation procedure. The cells have an intact function, however, lack gamma-GTP activity. The endothelial cells were cultured on an optically clear collagen membrane mounted on a plastic frame. Effects of bradykinin (1 x 10(-5) M) and LTC4 (1 x 10(-7) M, 1 x 10(-6) M, 5 x 10(-6) M, 1 x 10(-5) M) were tested on permeability of the endothelial cell monolayer by measuring leakage of 14C-sucrose. The effect of LTC4 and bradykinin on intracellular calcium was studied by laser scanning confocal microscopy. LTC4 did not increase permeability of the brain capillary endothelial cell monolayer which lacked gamma-GTP activity. LTC4 did neither increase the concentration of intracellular calcium. Differences of LTC4 receptor function in normal brain capillaries and tumor capillaries remain to be studied.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Calcium; Capillary Permeability; Cerebral Cortex; Culture Techniques; Endothelium, Vascular; gamma-Glutamyltransferase; Intracellular Fluid; Leukotriene C4; Rats

The products resulting from arachidonic acid metabolism of the both cyclo-oxygenase and lipoxygenase pathways possess strong physiological activities, such as vasoconstriction and the enhancement of vascular permeability. Therefore, it is likely that these metabolites are involved in cerebral circulatory disturbance and the formation of brain edema in cerebral ischemia. It is reported that intracerebral injection of leukotriene B4, C4, and E4 increased blood-brain barrier permeability. Thus, it is suggested that leukotrienes may induce vasogenic cerebral edema. We examined role of the products resulting from arachidonic acid of the cyclo-oxygenase and lipoxygenase pathways on the formation of ischemic cerebral edema in rats with focal cerebral ischemia. Focal cerebral ischemia was induced by the occlusion of right middle cerebral artery. Acyclo-oxygenase inhibitor, indomethacin (4mg/kg), was given intravenously 30 minutes before the occlusion of the middle cerebral artery. Also, azerastine hydrochloride (8mg/kg), which has an inhibitory effect on the production and release of leukotrienes from human neutrophil as well as an antagonistic action on leukotrienes and another inhibitory effect on the production of superoxide anion, was given intravenously 5 minutes prior to occlusion. Concentrations of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene C4 (LTC4) measured by radioimmunoassay. The percent water content of a cerebral hemisphere was determined by the wet-dry weight method. In the occluded hemisphere, PGE2, 6-keto-PGF1 alpha, TxB2 and LTC4 significantly increased at 2, 6, 12 hours respectively, following the MCA occlusion as compared to the control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Brain Edema; Brain Ischemia; Cerebral Arteries; Constriction; Dinoprostone; Leukotriene C4; Male; Rats; Rats, Wistar; Thromboxane B2