arachidonic-acid-omega-9-hydroperoxide and baicalein

Increased matrix metalloproteinase 1 (MMP-1) expression is a feature of photo-aged skin. We investigated the effects of baicalein and sulphoraphane on ultraviolet B (UVB) irradiation-induced MMP-1 expression and apoptosis using human dermal fibroblasts. UVB irradiation not only increased MMP-1 expression, but also caused apoptosis. Both baicalein and sulphoraphane protected cells from UVB irradiation-induced apoptosis, but only baicalein inhibited MMP-1 expression. UVB irradiation activated 12-lipoxygenase, and its product, 12-hydroxyeicosatetraenoic acid, activated TRPV1 channels. The resulting UVB irradiation-induced Ca

Topics: Anthracenes; Antioxidants; Apoptosis; Arachidonate 12-Lipoxygenase; Calcium; Capsaicin; Cytosol; Dermis; Egtazic Acid; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Flavanones; Humans; Leukotrienes; Matrix Metalloproteinase 1; NF-E2-Related Factor 2; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Skin; Skin Aging; TRPV Cation Channels; Ultraviolet Rays

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3R-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5S-hexanediol (U75302), a leukotriene BLT receptor antagonist. Treatment with 15-hydroxyperoxyeicosatetranoic acid (HPETE) increased phase II formalin activity, but had no effect on tail-flick responses. 12-HPETE failed to produce an effect in either nociceptive test. In the second part of this study, chronic spinal morphine for 5 days produced progressive decline in morphine antinociception and loss in analgesic potency. These effects were attenuated by co-administration of morphine with selective and nonselective lipoxygenase inhibitors. These results suggest involvement of lipoxygenase metabolites in both pain modulation and induction of opioid tolerance at the spinal level.

Topics: Analgesics, Opioid; Animals; Benzoquinones; Dose-Response Relationship, Drug; Drug Tolerance; Flavanones; Formaldehyde; Hindlimb; Hyperalgesia; Injections, Spinal; Leukotriene B4; Leukotrienes; Lipid Peroxides; Lipoxygenase; Lipoxygenase Inhibitors; Male; Masoprocol; Morphine; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors

Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains of Parkinson's disease patients. However, data from animal models show that GSH depletion by itself is not sufficient to induce nigral degeneration. We have previously shown that non-toxic inhibition of GSH synthesis with l-buthionine-(S,R)-sulfoximine in primary midbrain cultures transforms a nitric oxide (NO) neurotrophic effect, selective for dopamine neurons, into a toxic effect with participation of guanylate cyclase (GC) and cGMP-dependent protein kinase (PKG) (Canals, S., Casarejos, M. J., de Bernardo, S., Rodríguez-Martín, E., and Mena, M. A. (2001) J. Neurochem. 79, 1183-1195). Here we demonstrate that arachidonic acid (AA) metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. LOX inhibitors (nordihydroguaiaretic acid and baicalein), but not cyclooxygenase (indomethacin) or epoxygenase (clotrimazole) ones, prevent cell death in the culture, even when added 10 h after NO treatment. Furthermore, the addition of AA to GSH-depleted cultures precipitates a cell death process that is indistinguishable from that initiated by NO in its morphology, time course, and 12-LOX, GC, and PKG dependence. The first AA metabolite through the 12-LOX enzyme, 12-hydroperoxyeicosatetraenoic acid, induces cell death in the culture, and its toxicity is greatly enhanced by GSH depletion. In addition we show that if GSH synthesis inhibition persists for up to 4 days without any additional treatment, it will induce a cell death process that also depends on 12-LOX, GC, and PKG activation. In this study, therefore, we show that the signaling pathway AA/12-LOX/12-HPETE/GC/PKG may be important in several pathologies in which GSH decrease has been documented, such as Parkinson's disease. The potentiating effect of NO over such a signaling pathway may be of relevance as part of the cascade of events leading to and sustaining nerve cell death.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 12-Lipoxygenase; Blotting, Western; Brain; Cell Membrane; Cell Survival; Cells, Cultured; Clotrimazole; Culture Media; Cyclic GMP-Dependent Protein Kinases; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavanones; Flavonoids; Free Radical Scavengers; Glutathione; Growth Inhibitors; Immunohistochemistry; Indomethacin; Inhibitory Concentration 50; Leukotrienes; Masoprocol; Mesencephalon; Microscopy, Fluorescence; Nitric Oxide; Platelet Aggregation Inhibitors; Protein Binding; Rats; Signal Transduction; Time Factors

Angiotensin II (AII) action on adrenal and smooth muscle cells is mediated via mechanisms that include changes in calcium flux and phosphoinositide hydrolysis. Phosphoinositide metabolism results in the release of arachidonic acid, a precursor of both the cyclooxygenase (CO) and lipoxygenase (LO) pathway. The effects of both LO and CO inhibitors on AII action were studied using both static incubations and perifusions of rat renal cortical slices. 12-Hydroperoxyeicosatetraenoic acid and its stable metabolite 12-hydroxyacid mimicked the inhibitory actions of AII on renin. A specific CO blocker did not alter AII inhibition of renin and a 5-LO blocker U60,257 was also ineffective, whereas the LO blockers BW755c, phenidone, and baicalein all eliminated or interfered with the action of AII on renin. All inhibition in the presence of a LO blocker was restored by adding nanomolar concentrations of 12-hydroperoxyeicosatetraenoic acid. LO inhibitors were specific for blocking AII, as they did not interfere with potassium (K+)-induced renin inhibition. These results imply that 12 and/or 15 products of the LO pathway are involved in AII action.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Angiotensin II; Animals; Arachidonate 12-Lipoxygenase; Arachidonate Lipoxygenases; Arachidonic Acids; Cyclooxygenase Inhibitors; Epoprostenol; Flavanones; Flavonoids; Hydroxyeicosatetraenoic Acids; Kidney Cortex; Leukotrienes; Lipoxygenase Inhibitors; Male; Meclofenamic Acid; Potassium; Pyrazoles; Rats; Rats, Inbred Strains; Renin