arachidonyltrifluoromethane and Disease-Models--Animal

Although cardiovascular disease (CVD) is the leading cause of morbimortality worldwide, promising new drug candidates are lacking. We compared the arterial high-resolution proteome of patients with advanced versus early-stage CVD to predict, from a library of small bioactive molecules, drug candidates able to reverse this disease signature. Of the approximately 4000 identified proteins, 100 proteins were upregulated and 52 were downregulated in advanced-stage CVD. Arachidonyl trifluoromethyl ketone (AACOCF3), a cytosolic phospholipase A2 (cPLA2) inhibitor was predicted as the top drug able to reverse the advanced-stage CVD signature. Vascular cPLA2 expression was increased in patients with advanced-stage CVD. Treatment with AACOCF3 significantly reduced vascular calcification in a cholecalciferol-overload mouse model and inhibited osteoinductive signaling in vivo and in vitro in human aortic smooth muscle cells. In conclusion, using a systems biology approach, we have identified a potentially new compound that prevented typical vascular calcification in CVD in vivo. Apart from the clear effect of this approach in CVD, such strategy should also be able to generate novel drug candidates in other complex diseases.

Topics: Adult; Animals; Antigens, Human Platelet; Apolipoproteins E; Arachidonic Acids; Atherosclerosis; Cardiovascular Diseases; Cytosol; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocytes, Smooth Muscle; Systems Biology; Up-Regulation; Vascular Calcification

In the mammalian intestine, glutamine assimilation by the absorptive villus cells is mediated by Na-glutamine co-transport, specifically by B0AT1. In a rabbit model of chronic intestinal inflammation, B0AT1 is inhibited secondary to a decrease in the number of co-transporters in the brush border membrane (BBM). This inhibition can be reversed by treatment with a broad-spectrum immune modulator such as glucocorticoid suggesting that immune inflammatory mediators may regulate B0AT1 during chronic intestinal inflammation. Arachidonic acid (AA) metabolites (AAM) are increased during chronic intestinal inflammation. However, whether AAM may regulate B0AT1 during chronic intestinal inflammation is unknown. Treatment of rabbits with ATK, to prevent the release of AAM reversed the inhibition of B0AT1. AAM are products of cyclooxygenase (COX) and/or lipoxygenase (LOX) pathways. Inhibition of COX with piroxicam, therefore reduction of prostaglandin formation in the chronically inflamed intestine, reversed the inhibition of B0AT1 to its normal levels. In contrast, inhibition of LOX with MK886, thus reduction of leukotriene formation during chronic enteritis, did not affect the inhibition of B0AT1. Kinetic studies showed that the mechanism of restoration of B0AT1 by ATK or piroxicam was secondary to the restoration of BBM co-transporter numbers. Western Blot analysis also demonstrated restoration of BBM B0AT1 co-transporter numbers. In conclusion, this study demonstrates that Na-glutamine co-transport mediated by B0AT1 in villus cells is regulated by prostaglandins rather than leukotrienes in the chronically inflamed intestine.

Topics: Amino Acid Transport Systems, Neutral; Animals; Arachidonic Acid; Arachidonic Acids; Disease Models, Animal; Down-Regulation; Inflammatory Bowel Diseases; Leukotrienes; Lipoxygenase; Male; Microvilli; Piroxicam; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rabbits; Signal Transduction

Phospholipase A2 (PLA2)-derived proinflammatory lipid mediators such as prostaglandin E2 (PGE2), leukotrienes B4 (LTB4), lysophosphatidylcholine (LPC), and free fatty acids (FFA) are implicated in spinal cord injury (SCI) pathologies. Reducing the levels of these injurious bioactive lipid mediators is reported to ameliorate SCI. However, the specific role of the group IVA isoform of PLA2 cytosolic PLA2 (cPLA2) in lumbar spinal canal stenosis (LSS) due to cauda equina compression (CEC) injury is not clear. In this study, we investigated the role of cPLA2 in a rat model of CEC using a non-toxic cPLA2-preferential inhibitor, arachidonyl trifluoromethyl ketone (ATK).. LSS was induced in adult female rats by CEC procedure using silicone blocks within the epidural spaces of L4 to L6 vertebrae. cPLA2 inhibitor ATK (7.5 mg/kg) was administered by oral gavage at 2 h following the CEC. cPLA2-derived injurious lipid mediators and the expression/activity of cPLA2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were assessed. ATK-treated (CEC + ATK) were compared with vehicle-treated (CEC + VEH) animals in terms of myelin levels, pain threshold, and motor function.. ATK treatment of CEC animals reduced the phosphorylation of cPLA2 (pcPLA2) determined by Western blot, improved locomotor function evaluated by rotarod task, and reduced pain threshold evaluated by mechanical hyperalgesia method. Levels of FFA and LPC, along with PGE2 and LTB4, were reduced in CEC + ATK compared with CEC + VEH group. However, ATK treatment reduced neither the activity/expression of 5-LOX nor the expression of COX-2 in CEC + VEH animals. Increased cPLA2 activity in the spinal cord from CEC + VEH animals correlated well with decreased spinal cord as well as cauda equina fiber myelin levels, which were restored after ATK treatment.. The data indicate that cPLA2 activity plays a significant role in tissue injury and pain after LSS. Reducing the levels of proinflammatory and tissue damaging eicosanoids and the deleterious lipid mediator LPC shows therapeutic potential. ATK inhibits cPLA2 activity, thereby decreasing the levels of injurious lipid mediators, reducing pain, improving functional deficits, and conferring protection against LSS injury. Thus, it shows potential for preclinical evaluation in LSS.

Topics: Administration, Oral; Analysis of Variance; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Enzyme Inhibitors; Fatty Acids; Female; Hyperalgesia; Leukotriene B4; Locomotion; Lysophosphatidylcholines; Nociception; Polyradiculopathy; Rats; Rats, Sprague-Dawley

The aim of this study is to determine if the mannose-induced protein (MIP-133) from Acanthamoeba castellanii trophozoites induces apoptosis of corneal epithelial cells through a cytosolic phospholipase A2α (cPLA2α)-mediated pathway. The efficacy of cPLA2α inhibitors to provide protection against Acanthamoeba keratitis was examined in vivo. Chinese hamster corneal epithelial (HCORN) cells were incubated with or without MIP-133. MIP-133 induces significant increase in cPLA2α and macrophage inflammatory protein-2 (MIP-2/CXCL2) levels from corneal cells. Moreover, cPLA2α inhibitors, MAFP (Methyl-arachidonyl fluorophosphonate) and AACOCF3 (Arachidonyl trifluoromethyl ketone), significantly reduce cPLA2α and CXCL2 from these cells (P < 0.05). Additionally, cPLA2α inhibitors significantly inhibit MIP-133-induced apoptosis in HCORN cells (P < 0.05). Subconjunctival injection of purified MIP-133 in Chinese hamster eyes induced cytopathic effects resulting in corneal ulceration. Animals infected with A. castellanii-laden contact lenses and treated with AACOCF3 and CAY10650, showed significantly less severe keratitis as compared with control animals. Collectively, the results indicate that cPLA2α is involved in MIP-133 induced apoptosis of corneal epithelial cells, polymorphonuclear neutrophil infiltration, and production of CXCL2. Moreover, cPLA2α inhibitors can be used as a therapeutic target in Acanthamoeba keratitis.

Topics: Acanthamoeba castellanii; Acanthamoeba Keratitis; Animals; Apoptosis; Arachidonic Acids; Blotting, Western; Cells, Cultured; Chemokine CXCL2; Chromatography, High Pressure Liquid; Conjunctiva; Cricetinae; Cricetulus; Disease Models, Animal; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Epithelium, Corneal; Mannose; Organophosphonates; Phospholipases A2, Cytosolic; Protozoan Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

It is postulated that inhibition of cytosolic phospholipase A(2) alpha (cPLA(2)α) can reduce severity of stroke injury. This is supported by the finding that cPLA(2)α-deficient mice are partially protected from transient, focal cerebral ischemia. The object of this study was to determine the effect of cPLA(2)α inhibition with arachidonyl trifluoromethyl ketone (ATK) on stroke injury in mice. Male C57BL/6 mice were subjected to 1h of focal cerebral ischemia followed by 24 or 72 h of reperfusion. Mice were treated with ATK or vehicle by intermittent intraperitoneal injection or continuous infusion via an implanted infusion pump. ATK injections 1h before and then 1 and 6h after the start of reperfusion significantly reduced infarction volumes in striatum and hemisphere after 24h of reperfusion. ATK did not reduce injury if it was not administered before onset of ischemia or was not administered after 6h of reperfusion. Intermittent doses of ATK failed to reduce infarct volume after 72 h of reperfusion. Continuous infusion with ATK throughout 72h of reperfusion significantly reduced cortical and whole hemispheric infarct volume compared to vehicle treatment. Following ischemia and reperfusion, ATK treatment significantly reduced brain PLA(2) activity. These results are the first to demonstrate a therapeutic effect of cPLA(2)α inhibition on ischemia and reperfusion injury and define a therapeutic time window. cPLA(2)α activity augments injury in the acute and delayed phases of cerebral ischemia and reperfusion injury. We conclude that cPLA(2)α inhibition may be clinically useful if started before initiation of cerebral ischemia.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Body Temperature; Brain Infarction; Brain Injuries; Cyclooxygenase 2; Disease Models, Animal; Functional Laterality; Group IV Phospholipases A2; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrobenzenes; Reperfusion; Reperfusion Injury; Sulfonamides; Time Factors

Inhibition of phospholipase A(2) (PLA(2)) has recently been found to attenuate the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis (MS). However, the protective mechanisms that underlie PLA(2) inhibition are still not well understood. In this study, we found that cytosolic PLA(2) (cPLA(2)) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA(2) is also expressed in spinal cord neurons and oligodendrocytes, there were no differences observed in these cell types between EAE and control animals. Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA(2) inhibitor, significantly reduced the clinical symptoms and inhibited the body weight loss typically found in EAE mice. AACOCF3 also attenuated the loss of mature, myelin producing, oligodendrocytes, and axonal damage in the spinal cord white matter. Nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was dramatically increased in EAE mice and attenuated by treatment with AACOCF3. These protective effects were not evident when AA861, an inhibitor of lipoxygenase, was used. In primary cultures of microglia, lipopolysaccharide (LPS) induced an upregulation of cPLA(2), inducible nitric oxide synthase (iNOS) and components of the NADPH oxidase complex, p47phox and p67phox. AACOCF3 significantly attenuated iNOS induction, nitric oxide production and the generation of reactive oxygen species in reactive microglia. Similar to the decomposition catalyst of peroxynitrite, AACOCF3 also blocked oligodendrocyte toxicity induced by reactive microglia. These results suggest that AACOCF3 may prevent oligodendrocyte loss in EAE by attenuating peroxynitrite formation in the spinal cord white matter.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Mice; Mice, Inbred C57BL; Oligodendroglia; Peroxynitrous Acid; Phospholipases A2, Cytosolic; Rats; Rats, Sprague-Dawley; Spinal Cord

Lungs of cystic fibrosis (CF) patients are chronically infected with Pseudomonas aeruginosa. Increased airway constriction has been reported in CF patients but underplaying mechanisms have not been elucidated.. To examine the effect of P. aeruginosa LPS on airway constriction in CF mice and the implication in this process of cytosolic phospholipase A2alpha (cPLA2alpha), an enzyme involved in arachidonic acid (AA) release.. Mice were instilled intra-nasally with LPS. Airway constriction was assessed using barometric plethysmograph. MIP-2, prostaglandin E2 (PGE2), leukotrienes and AA concentrations were measured in BALF using standard kits and gas chromatography.. LPS induced enhanced airway constriction and AA release in BALF of CF compared to littermate mice. This was accompanied by increased levels of PGE2, but not those of leukotrienes. However, airway neutrophil influx and MIP-2 production remained similar in both mouse strains. The cPLA2alpha inhibitor arachidonyl trifluoro-methyl-ketone (ATK), but not aspirin which inhibit PGE2 synthesis, reduced LPS-induced airway constriction. LPS induced lower airway constriction and PGE2 production in cPLA2alpha -/- mice compared to corresponding littermates. Neither aspirin nor ATK interfered with LPS-induced airway neutrophil influx or MIP-2 production.. CF mice develop enhanced airway constriction through a cPLA2alpha-dependent mechanism. Airway inflammation is dissociated from airway constriction in this model. cPLA2alpha may represent a suitable target for therapeutic intervention in CF. Attenuation of airway constriction by cPLA2alpha inhibitors may help to ameliorate the clinical status of CF patients.

Topics: Administration, Intranasal; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chemokine CXCL2; Cyclooxygenase Inhibitors; Cystic Fibrosis; Dinoprostone; Disease Models, Animal; Enzyme Inhibitors; Group IV Phospholipases A2; Leukotrienes; Lipopolysaccharides; Lung; Mice; Mice, Inbred CFTR; Mice, Knockout; Neutrophil Infiltration; Pneumonia; Pseudomonas aeruginosa; Time Factors

In vascular endothelial cells, low doses of ionizing radiation trigger the immediate activation of cytosolic phospholipase A2 (cPLA2). This event initiates prosurvival signaling that could be responsible for radioresistance of tumor vasculature. Thus, the development of radiosensitizers targeting these survival pathways may enhance tumor response to radiation therapy. Arachidonyltrifluoromethyl Ketone (AACOCF3), a specific cPLA2 inhibitor, was studied as a potential radiosensitizer.. Vascular endothelial cells (3B11 and MPMEC) and lung tumor cells (LLC and H460) were treated with 1 micromol/L AACOCF3 for 30 minutes prior to irradiation. Treatment response was evaluated by clonogenic survival, activation of extracellular signal-regulated kinase 1/2 (ERK1/2), tubule formation, and migration assays. For in vivo experiments, mice with LLC or H460 tumors in the hind limbs were treated for 5 consecutive days with 10 mg/kg AACOCF3 administered daily 30 minutes prior to irradiation. Treatment response was assessed by tumor growth delay, Power Doppler Sonography, and immunohistochemistry.. In cell culture experiments, inhibition of cPLA2 with AACOCF3 prevented radiation-induced activation of ERK1/2 and decreased clonogenic survival of irradiated vascular endothelial cells but not the lung tumor cells. Treatment with AACOCF3 also attenuated tubule formation and migration in irradiated vascular endothelial cells. In both tumor mouse models, treatment with AACOCF3 prior to irradiation significantly suppressed tumor growth and decreased overall tumor blood flow and vascularity. Increased apoptosis in both tumor cells and tumor vascular endothelium was determined as a possible mechanism of the observed effect.. These findings identify cPLA2 as a novel molecular target for tumor sensitization to radiation therapy through the tumor vasculature.

Topics: Animals; Apoptosis; Arachidonic Acids; Blood Flow Velocity; Blotting, Western; Carcinoma, Large Cell; Carcinoma, Lewis Lung; Cell Movement; Collagen; Disease Models, Animal; Drug Combinations; Endothelium, Vascular; Enzyme Inhibitors; Laminin; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neovascularization, Pathologic; Phospholipases A2, Cytosolic; Phosphorylation; Proteoglycans; Proto-Oncogene Proteins c-akt; Radiation Dosage; Tumor Stem Cell Assay

Neuronal expression of familial Alzheimer's disease-mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A(2) (GIVA-PLA(2)). The levels of activated GIVA-PLA(2) in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Abeta caused a dose-dependent increase in GIVA-PLA(2) phosphorylation in neuronal cultures. Inhibition of GIVA-PLA(2) diminished Abeta-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA(2) protected hAPP mice against Abeta-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA(2) may be beneficial in the treatment and prevention of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Arachidonic Acids; Behavior, Animal; Brain; Case-Control Studies; Cell Death; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors; Fatty Acids; Female; Group IV Phospholipases A2; Humans; In Vitro Techniques; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Peptide Fragments; Rats; Receptors, AMPA

We previously reported that the cytosolic phospholipase A(2) (cPLA2) pathway is involved in ventilator-induced lung injury (VILI) produced by high peak inflation pressures (PIP) (J Appl Physiol 98: 1264-1271, 2005), but the relative contributions of the various downstream products of cPLA2 on the acute permeability response were not determined. Therefore, we investigated the role of cPLA2 and the downstream products of arachidonic acid metabolism in the high-PIP ventilation-induced increase in vascular permeability. We perfused isolated mouse lungs and measured the capillary filtration coefficient (K(fc)) after 30 min of ventilation with 9, 25, and 35 cmH2O PIP. In high-PIP-ventilated lungs, K(fc) increased significantly, 2.7-fold, after ventilation with 35 cmH2O PIP compared with paired baseline values and low-PIP-ventilated lungs. Also, increased phosphorylation of lung cPLA2 suggested enzyme activation after high-PIP ventilation. However, treatment with 40 mg/kg arachidonyl trifluoromethyl ketone (an inhibitor of cPLA2) or a combination of 30 microM ibuprofen [a cyclooxygenase (COX) inhibitor], 100 microM nordihydroguaiaretic acid [a lipoxygenase (LOX) inhibitor], and 10 microM 17-octadecynoic acid (a cytochrome P-450 epoxygenase inhibitor) prevented the high-PIP-induced increase in K(fc). Combinations of the inhibitors of COX, LOX, or cytochrome P-450 epoxygenase did not prevent significant increases in K(fc), even though bronchoalveolar lavage levels of the COX or LOX products were significantly reduced. These results suggest that multiple mediators from each pathway contribute to the acute ventilator-induced permeability increase in isolated mouse lungs by mutual potentiation.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Capillary Permeability; Cyclooxygenase Inhibitors; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Ibuprofen; In Vitro Techniques; Lipoxygenase Inhibitors; Lung; Lung Diseases; Male; Masoprocol; Mice; Mice, Inbred C57BL; Microcirculation; Phospholipases A2, Cytosolic; Phosphorylation; Pulmonary Circulation; Respiration, Artificial; Signal Transduction; Vascular Resistance

Arachidonic acid metabolites and platelet-activating factor (PAF) are potentially involved in ischemia-reperfusion (IR) lung injury. A key enzyme regulating their metabolism is cytosolic phospholipase A2 (cPLA2). Arachidonyl trifluoromethyl ketone (AACOCF3) is reported to be a potent cPLA2 inhibitor. In the present study, we hypothesized that pharmacological inhibition of cPLA2 might ameliorate IR lung injury.. To test the hypothesis, we examined the effects of AACOCF3 in an isolated rat lung model. Three groups were defined (n=6, each): in the vehicle group, lungs were perfused for 2 hours without an ischemic period. In the ischemic groups, 20 mg/kg of AACOCF3 (AACOCF3 group) or saline (control group) was i.v. administered 15 min before lung harvest. Lungs were flushed with LPD solution, cold-stored 18 hours, and reperfused for 2 hours.. IR increased cPLA2 activity mainly via alveolar macrophages, sPLA2 activity, thromboxane and leukotriene formation, and the expression of PAF receptor, whereas AACOCF3 treatment significantly reduced all of these. Compared to the vehicle group, the wet-to-dry ratio, proteins in BAL, and MPO activity increased significantly by twofold, fourfold, and threefold, respectively. Furthermore, the PO2 dropped from 615.7+/-31.2 to 452.1+/-30.9 mmHg at the end of reperfusion (P<0.001). AACOCF3 treatment maintained the PO2 at a level similar to the vehicle group throughout reperfusion and reduced significantly the alveolar-capillary leakage, edema formation, and neutrophil extravasation.. Pharmacological inhibition of the cPLA2 cascade decreases bioactive lipid formation and attenuates IR-induced lung injury.

Topics: Animals; Arachidonic Acids; Disease Models, Animal; Eicosanoids; Group IV Phospholipases A2; Group VI Phospholipases A2; In Vitro Techniques; Lung; Lung Transplantation; Male; Neutrophils; Phospholipases A; Phospholipases A2; Phosphorylation; Platelet Membrane Glycoproteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Reperfusion Injury

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that results in motor and sensory deficits. Although MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are thought to be T cell-mediated diseases, the mechanisms underlying the lesions in the CNS are not fully understood. We propose that a strong candidate as a central mediator in evoking the complex pathological changes seen in MS and EAE is the enzyme cytosolic phospholipase A2 (cPLA2). One of the metabolic products of this enzyme is pro-inflammatory, while the other induces myelin breakdown, demyelination, and chemokine/cytokine expression. We provide evidence that cPLA2 is highly expressed in EAE lesions and show that blocking this enzyme leads to a remarkable reduction in the onset and progression of EAE.

Topics: Animals; Arachidonic Acids; Axons; Blotting, Western; CD4-Positive T-Lymphocytes; Cell Count; Chemokines; Cyclooxygenase 2; Cytokinins; Cytosol; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Female; Gene Expression; Immunohistochemistry; Inflammation; Isoenzymes; Macrophages; Mice; Mice, Inbred C57BL; Microscopy, Electron; Multiple Sclerosis; Oligonucleotide Array Sequence Analysis; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Random Allocation; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Time Factors

This study was performed to investigate whether 85 kDa cytosolic phospholipase A2 (cPLA2) functions in eicosanoid generation in rat corpora lutea (CL) using its specific inhibitor, arachidonyl trifluoromethyl ketone (ATK). In both immature and adult pseudopregnant rats, PLA2 activity in the cytosol of CL, measured by the liposome-vesicle assay, increased from day 6 of pseudopregnancy (PSP6) to PSP12. 10 microM ATK potently inhibited all of these activities to 10-20% and the rate of the inhibition by ATK was much higher on PSP12. ATK also reduced arachidonic acid (AA) release from luteal cells of PSP12 prelabelled with 3H-AA. Furthermore, the production of prostaglandin E2 by cultured luteal cells was mostly suppressed by the drug. These results suggest the augmentation of cPLA2 activity with the luteal age of pseudopregnant rats and its principal role in eicosanoid generation in CL.

Topics: Aging; Animals; Arachidonic Acids; Corpus Luteum; Cytosol; Dinoprostone; Disease Models, Animal; Enzyme Inhibitors; Female; Phospholipases A; Phospholipases A2; Pseudopregnancy; Rats; Rats, Wistar