leukotriene-c4 and Brain-Injuries

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

The leukotrienes belong to a family of biologically active lipids derived from arachidonate that are often involved in inflammatory responses. In the central nervous system, a group of leukotrienes, known as the cysteinyl leukotrienes, is generated in brain tissue in response to a variety of acute brain injuries. Although the exact clinical significance of this excess production remains unclear, the cysteinyl leukotrienes may contribute to injury-related disruption of the brain-blood barrier and exacerbate secondary injury processes. In the present study, the formation and role of cysteinyl leukotrienes was explored in the fluid percussion injury model of traumatic brain injury in rats. The results showed that levels of the cysteinyl leukotrienes were elevated after fluid percussion injury with a maximal formation 1 hour after the injury. Neutrophils contributed to cysteinyl leukotriene formation in the injured brain hemisphere, potentially through a transcellular biosynthetic mechanism. Furthermore, pharmacological reduction of cysteinyl leukotriene formation after the injury, using MK-886, resulted in reduction of brain lesion volumes, suggesting that the cysteinyl leukotrienes play an important role in traumatic brain injury.

Topics: Animals; Brain Injuries; Chromatography, Liquid; Cysteine; Disease Models, Animal; Enzyme Inhibitors; Indoles; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Male; Mass Spectrometry; Neutrophils; Rats; Rats, Sprague-Dawley

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

Regional concentrations of leukotriene C4 and extravasation of Evans blue were measured after lateral fluid-percussion brain injury in rats. Tissue levels of LTC4 were elevated in the injured cortex at 10 min, 30 min, and 1 h after injury; these levels returned to normal by 2 h after injury. Increases in the levels of LTC4 were also observed in the ipsilateral hippocampus after brain injury, and these elevations persisted for 2 h after injury. No significant increase in levels of LTC4 was observed in the contralateral cortex at any time after injury. A substantial extravasation of Evans blue was observed only in the ipsilateral cortex and hippocampus at 3 h and 6 h after brain injury. Although a temporal association between LTC4 and blood-brain barrier (BBB) breakdown is suggested by these data, no cause-and-effect relationship has been addressed in this study. However, it is possible that, as is true for cerebral ischemia, LTC4 may play a role as a mediator in the BBB breakdown associated with fluid-percussion brain injury in rats.

Topics: Animals; Blood-Brain Barrier; Brain Injuries; Evans Blue; Female; Leukotriene C4; Rats; Rats, Sprague-Dawley; Time Factors; Tissue Distribution; Wounds, Nonpenetrating