Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans.

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.

Bovine brain diacylglycerol lipase: substrate specificity and activation by cyclic AMP-dependent protein kinase.

Diacylglycerol lipase (EC 3.1.1.3) was purified from bovine brain microsomes using multiple column chromatographic techniques. The purified enzyme migrates as a single band on SDS-PAGE and has an apparent molecular weight of 27 kDa. Substrate specificity experiments using mixed molecular species of 1,2-diacyl-sn-glycerols indicate that low concentrations of Ca(2+) and Mg(2+) have no direct effect on enzymic activity and 1,2-diacyl-sn-glycerols are the preferred substrate over 1,3-diacyl-sn-glycerols. The enzyme hydrolyzes stearate in preference to palmitate from the sn-1 position of 1,2-diacyl-sn-glycerols. 1-O-Alkyl-2-acyl-sn-glycerols are not a substrate for the purified enzyme. The native enzyme had a V (max) value of 616 nmol/min mg protein. Phosphorylation by cAMP-dependent protein kinase resulted in a threefold increase in catalytic throughput (V (max) = 1,900 nmol/min mg protein). The substrate specificity and catalytic properties of the bovine brain diacylglycerol lipase suggest that diacylglycerol lipase may regulate protein kinase C activity and 2-arachidonoyl-sn-glycerol levels by rapidly altering the intracellular concentration of diacylglycerols.

Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders.

Three enzyme systems, cyclooxygenases that generate prostaglandins, lipoxygenases that form hydroxy derivatives and leukotrienes, and epoxygenases that give rise to epoxyeicosatrienoic products, metabolize arachidonic acid after its release from neural membrane phospholipids by the action of phospholipase A(2). Lysophospholipids, the other products of phospholipase A(2) reactions, are either reacylated or metabolized to platelet-activating factor. Under normal conditions, these metabolites play important roles in synaptic function, cerebral blood flow regulation, apoptosis, angiogenesis, and gene expression. Increased activities of cyclooxygenases, lipoxygenases, and epoxygenases under pathological situations such as ischemia, epilepsy, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease produce neuroinflammation involving vasodilation and vasoconstriction, platelet aggregation, leukocyte chemotaxis and release of cytokines, and oxidative stress. These are closely associated with the neural cell injury which occurs in these neurological conditions. The metabolic products of docosahexaenoic acid, through these enzymes, generate a new class of lipid mediators, namely docosatrienes and resolvins. These metabolites antagonize the effect of metabolites derived from arachidonic acid. Recent studies provide insight into how these arachidonic acid metabolites interact with each other and other bioactive mediators such as platelet-activating factor, endocannabinoids, and docosatrienes under normal and pathological conditions. Here, we review present knowledge of the functions of cyclooxygenases, lipoxygenases, and epoxygenases in brain and their association with neurodegenerative diseases.

Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly.

Phospholipase A2 (PLA2) generates arachidonic acid, docosahexaenoic acid, and lysophospholipids from neural membrane phospholipids. These metabolites have a variety of physiological effects by themselves and also are substrates for the synthesis of more potent lipid mediators such as eicosanoids, platelet activating factor, and 4-hydroxynonenal (4-HNE). At low concentrations, these mediators act as second messengers. They affect and modulate several cell functions, including signal transduction, gene expression, and cell proliferation, but at high concentrations, these lipid mediators cause neurotoxicity. Among the metabolites generated by PLA2, 4-HNE is the most cytotoxic metabolite and is associated with the apoptotic type of neural cell death. Levels of 4-HNE are markedly increased in neurological disorders such as Alzheimer disease, Parkinson disease, ischemia, spinal cord trauma, and head injury. The purpose of this review is to summarize and integrate the vast literature on metabolites generated by PLA2 for a wider audience. The authors hope that this discussion will jump-start more studies not only on the involvement of PLA2 in neurological disorders but also on the importance of PLA2-generated lipid mediators in physiological and pathological processes.

Ca2+-independent phospholipases A2 and production of arachidonic acid in nuclei of LA-N-1 cell cultures: a specific receptor activation mediated with retinoic acid.

The LA-N-1 cell nucleus contains Ca2+-independent phospholipase A2 (PLA2) activity hydrolyzing plasmenylethanolamine (PlsEtn) and 1,2-diacyl-sn-glycero-3-phosphoethanolamine (PtdEtn). These enzymes hydrolyze glycerophospholipids to produce arachidonic acid and lysoglycerophospholipids. The treatment of LA-N-1 cell cultures with all-trans retinoic acid (atRA) results in time- and dose-dependent stimulation of PlsEtn-PLA2 and PtdEtn-PLA2 activities in the nuclear fraction. PLA2 activities in the non-nuclear fraction (microsomes) are not affected by atRA, whilst the pan retinoic acid receptor (RAR) antagonist, BMS493, blocks the PLA2 activities in the nuclear fraction. This indicates that the stimulation of PLA2 activities is a receptor-mediated process. Treatment of LA-N-1 cell cultures with cycloheximide has no effect on basal PLA2 activities. However, atRA-mediated stimulation of PLA2 activities in LA-N-1 cell nuclei is partially inhibited by cycloheximide indicating that this decrease in PLA2 activity is due to a general decreased protein synthesis. Our results also support earlier studies in which atRA induces morphologic differentiation through the stimulation of PLA2-generated second messengers such as arachidonic acid and eicosanoids.

Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function.

The central nervous system has the second highest concentration of lipids after adipose tissue. Long chain fatty acids, particularly arachidonic acid and docosahexaenoic acid, are integral components of neural membrane phospholipids. Alterations in neural membrane phospholipid components cannot only influence crucial intracellular and intercellular signaling but also alter many membrane physical properties such as fluidity, phase transition temperature, bilayer thickness, and lateral domains. A deficiency of docosahexaenoic acid markedly affects neurotransmission, membrane-bound enzyme and ion channel activities, gene expression, intensity of inflammation, and immunity and synaptic plasticity. Docosahexaenoic acid deficiency is associated with normal aging, Alzheimer disease, hyperactivity, schizophrenia, and peroxisomal disorders. Although the molecular mechanism of docosahexaenoic acid involvement in the disorders remains unknown, the supplementation of docosahexaenoic acid in the diet restores gene expression and modulates neurotransmission. Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease.

Brain phospholipases A2: a perspective on the history.

The phospholipases A2 (PLA2) belong to a large family of enzymes involved in the generation of several second messengers that play an important role in signal transduction processes associated with normal brain function. The phospholipase A2 family includes secretory phospholipase A2, cytosolic phospholipase A2, calcium-independent phospholipase A2, plasmalogen-selective phospholipase A2 and many other enzymes with phospholipase A2 activity that have not been classified. Few attempts have been made purify and characterize the multiple forms of PLA2 and none have been fully characterized and cloned from brain tissue. A tight regulation of phospholipase A2 isozymes is necessary for maintaining physiological levels of free fatty acids including arachidonic acid and its metabolites in the various types of neural cells. Under normal conditions, phospholipase A2 isozymes may be involved in neurotransmitter release, long-term potentiation, growth and differentiation, and membrane repair. Under pathological conditions, high levels of lipid metabolites generated by phospholipase A2 are involved in neuroinflammation, oxidative stress, and neural cell injury.

Neuroprotection abilities of cytosolic phospholipase A2 inhibitors in kainic acid-induced neurodegeneration.

Phospholipases A2 (PLA2) belong to a super-family of enzymes that hydrolyze membrane phospholipids at the sn-2 position to liberate free fatty acids and lysophospholipids. Different forms of PLA2 are involved in inflammation, neurodegeneration, and intracellular and intercellular signaling related to neurotransmitter release, axonal growth and gene expression. The action of cytosolic PLA2 (cPLA2) on phospholipid containing arachidonic acid at sn-2 position releases arachidonic acid and lysophospholipids, precursors for various proinflammatory lipid mediators including prostaglandins, leukotrienes, thromboxanes, and platelet activating factor. During hypoxic/ischemic insults, alterations in calcium homeostasis and induction of cytokines results in stimulation of cPLA2 and increased production of prostaglandins, leukotrienes, thromboxanes, and platelet activating factor. These metabolites cause atherosclerotic plaque development in cerebrovascular and coronary artery diseases in arterial walls and neuronal cell injury in brain tissue. Our studies on kainic acid-induced neurodegeneration in rat brain indicate that the stimulation of cPLA2 increased generation of proinflammatory lipid mediators, and accumulation of 4-hydroxynonenal, a toxic aldehyde with neurodegenerative properties. Treatment of rat brain hippocampal slices with antimalarial drugs (non-specific cPLA2 inhibitors) not only inhibits cPLA2 activity but also blocks neurodegeneration suggesting that cPLA2 inhibitors can be used as neuroprotective and anti-inflammatory agents in neurodegenerative diseases.

The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases.

Reactive oxygen species (ROS) are produced in mammalian cells through enzymic and non-enzymic mechanisms. Although some ROS production pathways are needed for specific physiological functions, excessive production is detrimental and is regarded as the basis of numerous neurodegenerative diseases. Among enzymes producing superoxide anions, NADPH oxidase is widespread in mammalian cells and is an important source of ROS in mediating physiological and pathological processes in the cardiovascular and the CNS. ROS production is linked to the alteration of intracellular calcium homeostasis, activation of Ca(2+)-dependent enzymes, alteration of cytoskeletal proteins, and degradation of membrane glycerophospholipids. There is evolving evidence that ROS produced by NADPH oxidase regulate neuronal functions and degrade membrane phospholipids through activation of phospholipases A(2) (PLA(2)). This review is intended to cover recent studies describing ROS generation from NADPH oxidase in the CNS and its downstream activation of PLA(2), namely, the group IV cytosolic cPLA(2) and the group II secretory sPLA(2). A major focus is to elaborate the dual role of NADPH oxidase and PLA(2) in mediating the oxidative and inflammatory responses in neurodegenerative diseases, including cerebral ischemia and Alzheimer's disease. Elucidation of the signaling pathways linking NADPH oxidase with the multiple forms of PLA(2) will be important in understanding the oxidative and degradative mechanisms that underline neuronal damage and glial activation and will facilitate development of therapeutic intervention for prevention and treatment of these and other neurodegenerative diseases.

Modulation of inflammation in brain: a matter of fat.

Neuroinflammation is a host defense mechanism associated with neutralization of an insult and restoration of normal structure and function of brain. Neuroinflammation is a hallmark of all major CNS diseases. The main mediators of neuroinflammation are microglial cells. These cells are activated during a CNS injury. Microglial cells initiate a rapid response that involves cell migration, proliferation, release of cytokines/chemokines and trophic and/or toxic effects. Cytokines/chemokines stimulate phospholipases A2 and cyclooxygenases. This results in breakdown of membrane glycerophospholipids with the release of arachidonic acid (AA) and docosahexaenoic acid (DHA). Oxidation of AA produces pro-inflammatory prostaglandins, leukotrienes, and thromboxanes. One of the lyso-glycerophospholipids, the other products of reactions catalyzed by phospholipase A2, is used for the synthesis of pro-inflammatory platelet-activating factor. These pro-inflammatory mediators intensify neuroinflammation. Lipoxin, an oxidized product of AA through 5-lipoxygenase, is involved in the resolution of inflammation and is anti-inflammatory. Docosahexaenoic acid is metabolized to resolvins and neuroprotectins. These lipid mediators inhibit the generation of prostaglandins, leukotrienes, and thromboxanes. Levels of prostaglandins, leukotrienes, and thromboxanes are markedly increased in acute neural trauma and neurodegenerative diseases. Docosahexaenoic acid and its lipid mediators prevent neuroinflammation by inhibiting transcription factor NFkappaB, preventing cytokine secretion, blocking the synthesis of prostaglandins, leukotrienes, and thromboxanes, and modulating leukocyte trafficking. Depending on its timing and magnitude in brain tissue, inflammation serves multiple purposes. It is involved in the protection of uninjured neurons and removal of degenerating neuronal debris and also in assisting repair and recovery processes. The dietary ratio of AA to DHA may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases. The dietary intake of docosahexaenoic acid offers the possibility of counter-balancing the harmful effects of high levels of AA-derived pro-inflammatory lipid mediators.

Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide.

The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.

Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders.

The phospholipase A(2) family includes secretory phospholipase A(2), cytosolic phospholipase A(2), plasmalogen-selective phospholipase A(2), and calcium-independent phospholipase A(2). It is generally thought that the release of arachidonic acid by cytosolic phospholipase A(2) is the rate-limiting step in the generation of eicosanoids and platelet activating factor. These lipid mediators play critical roles in the initiation and modulation of inflammation and oxidative stress. Neurological disorders, such as ischemia, spinal cord injury, Alzheimer's disease, multiple sclerosis, prion diseases, and epilepsy are characterized by inflammatory reactions, oxidative stress, altered phospholipid metabolism, accumulation of lipid peroxides, and increased phospholipase A(2) activity. Increased activities of phospholipases A(2) and generation of lipid mediators may be involved in oxidative stress and neuroinflammation associated with the above neurological disorders. Several phospholipase A(2) inhibitors have been recently discovered and used for the treatment of ischemia and other neurological diseases in cell culture and animal models. At this time very little is known about in vivo neurochemical effects, mechanism of action, or toxicity of phospholipase A(2) inhibitors in human or animal models of neurological disorders. In kainic acid-mediated neurotoxicity, the activities of phospholipase A(2) isoforms and their immunoreactivities are markedly increased and phospholipase A(2) inhibitors, quinacrine and chloroquine, arachidonyl trifluoromethyl ketone, bromoenol lactone, cytidine 5-diphosphoamines, and vitamin E, not only inhibit phospholipase A(2) activity and immunoreactivity but also prevent neurodegeneration, suggesting that phospholipase A(2) is involved in the neurodegenerative process. This also suggests that phospholipase A(2) inhibitors can be used as neuroprotectants and anti-inflammatory agents against neurodegenerative processes in neurodegenerative diseases.

Signaling and interplay mediated by phospholipases A2, C, and D in LA-N-1 cell nuclei.

Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in phospholipid metabolism occur during cellular differentiation, proliferation, and apoptosis, but the molecular mechanism involved in the above processes remains unknown. We propose that the coordinated expression of different genes responsible for the expression of transcription factors, neurotrophins, and cytokines, along with lipid mediators generated by the action of phospholipases A2, C, and D (PLA2, PLC, and PLD), play a very important role in differentiation, proliferation, and apoptosis. The purpose of this minireview is to discuss recent developments in PLA2, PLC, and PLD-mediated signaling in the nucleus of LA-N-1 neuroblastoma cell cultures. In brain tissue, arachidonic acid is mainly released by the action of PLA2 and phospholipase C/diacylglycerol lipase (PLC/DAG-lipase) pathways. We have used LA-N-1 cell cultures to study activities of PLA2, C, and D during retinoic acid (RA)-mediated differentiation. The treatment of LA-N-1 cells with RA produces an increase in PLA2 activity in the nuclear fraction. This increase in PLA2 activity can be prevented with BMS493, a pan retinoic acid receptor antagonist, suggesting that RA-induced stimulation of PLA2 activity is a RA receptor-mediated process. The treatment of LA-N-1 cells with 12-O-tetradecanoyl-phorbol-13 acetate (TPA) and RA increases diacylglycerol (DAG) levels indicating the stimulation of PLC activity. This stimulation is blocked by D609, tricyclodecan-9-yl potassium xanthate, a competitive PtdCho-specific PLC inhibitor. LA-N-1 cells also contain DAG-and monoacylglycerol (MAG) lipase activities. Two isoforms of PLD, oleate-dependent and TPA-dependent, are also present in LA-N-1 cell homogenates. RA stimulates the oleate-dependent isoform of PLD, whereas RA does not stimulate the TPA-dependent isoform. Our studies have indicated that lipid mediators generated by the action of PLA2, PLC, and PLD on nuclear phospholipids markedly affect neuritic outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that RA receptors coupled with PLA2, PLC, and PLD activities in the nucleus may play an important role in the redistribution of arachidonic acid and its metabolites and DAG in nuclear and non-nuclear neuronal membranes during differentiation and growth suppression.

Biochemical aspects of neurodegeneration in human brain: involvement of neural membrane phospholipids and phospholipases A2.

Neural membrane phospholipids are hydrolyzed by a group of enzymes known as phospholipases. This process results in the generation of second messengers such as arachidonic acid, eicosanoids, platelet activating factor, and diacylglycerols. High levels of these metabolites are neurotoxic and are associated with neurodegeneration. The collective evidence from many studies suggests that neural membrane phospholipid metabolism is disturbed in neural trauma and neurodegenerative diseases. This disturbance is caused by the stimulation of phospholipases A2. Stimulation of these enzymes produces changes in membrane permeability, fluidity, and alteration in ion homeostasis. Low calcium influx produces mild oxidative stress and results in neurodegeneration promoted by apoptosis, whereas a calcium overload generates high oxidative stress and causes neurodegeneration associated with necrosis. Alterations in phospholipid metabolism along with the accumulation of lipid peroxides and compromised energy metabolism may be responsible for neurodegeneration in ischemia, spinal cord trauma, head injury, and Alzheimer disease. The synthesis of phospholipases A2 inhibitors that cross the blood-brain barrier without harm may be useful for the treatment of acute neural trauma and neurodegenerative diseases.

Retinoic acid-mediated phospholipase A2 signaling in the nucleus.

Retinoic acid modulates a wide variety of biological processes including proliferation, differentiation, and apoptosis. It interacts with specific receptors in the nucleus, the retinoic acid receptors (RARs). The molecular mechanism by which retinoic acid mediates cellular differentiation and growth suppression in neural cells remains unknown. However, retinoic acid-induced release of arachidonic acid and its metabolites may play an important role in cell proliferation, differentiation, and apoptosis. In brain tissue, arachidonic acid is mainly released by the action of phospholipase A2 (PLA2) and phospholipase C (PLC)/diacylglycerol lipase pathways. We have used the model of differentiation in LA-N-1 cells induced by retinoic acid. The treatment of LA-N-1 cells with retinoic acid produces an increase in phospholipase A2 activity in the nuclear fraction. The pan retinoic acid receptor antagonist, BMS493, can prevent this increase in phospholipase A2 activity. This suggests that retinoic acid-induced stimulation of phospholipase A2 activity is a retinoic acid receptor-mediated process. LA-N-1 cell nuclei also have phospholipase C and phospholipase D (PLD) activities that are stimulated by retinoic acid. Selective phospholipase C and phospholipase D inhibitors block the stimulation of phospholipase C and phospholipase D activities. Thus, both direct and indirect mechanisms of arachidonic acid release exist in LA-N-1 cell nuclei. Arachidonic acid and its metabolites markedly affect the neurite outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that retinoic acid receptors coupled with phospholipases A2, C and D in the nuclear membrane play an important role in the redistribution of arachidonic acid in neuronal and non-nuclear neuronal membranes during differentiation and growth suppression. Abnormal retinoid metabolism may be involved in the downstream transcriptional regulation of phospholipase A2-mediated signal transduction in schizophrenia and Alzheimer disease (AD). The development of new retinoid analogs with diminished toxicity that can cross the blood-brain barrier without harm and can normalize phospholipase A2-mediated signaling will be important in developing pharmacological interventions for these neurological disorders.

Induction of astrocytic cytoplasmic phospholipase A2 and neuronal death after intracerebroventricular carrageenan injection, and neuroprotective effects of quinacrine.

Glial reaction is often associated with nervous tissue injury, but thus far, few studies have examined whether it can be a cause of neuronal injury. We now study the effect of intracerebroventricular injection of a carrageenan on cytoplasmic phospholipase A(2) (cPLA(2)) expression and neuronal injury in the hippocampus. The enzyme cPLA(2) hydrolyzes neural membrane glycerophospholipids and generates precursors for proinflammatory mediators. An induction of cPLA(2) in astrocytes and death of neurons in the hippocampus were observed following glial reaction induced by intracerebroventricular injections of carrageenan. cPLA(2) levels and neuronal death were modulated by daily intraperitoneal injections of quinacrine, an inhibitor of phospholipase A(2) that can cross the blood brain barrier. These observations support a role for astrocytic cPLA(2) in mediating neuronal death.

Quinacrine abolishes increases in cytoplasmic phospholipase A2 mRNA levels in the rat hippocampus after kainate-induced neuronal injury.

The present investigation was carried out to study the possible effects of quinacrine in modulating cytoplasmic phospholipase A(2) (cPLA(2)) mRNA levels in rat hippocampus after kainate treatment. Injections of kainate into the right lateral ventricle resulted in significant increases in cPLA(2) mRNA levels in the hippocampus, at 3 days and 7 days after injection. The elevation in cPLA(2) mRNA levels is consistent with previous observations of increased cPLA(2) immunoreactivity in degenerating neurons and astrocytes at these times. Rats that received once daily intraperitoneal injections of quinacrine (5 mg/kg) after the intracerebroventricular kainate injections showed almost complete attenuation of increased cPLA(2) expression, at both 3 and 7 days after kainate injection. These results show that in addition to its well-known effect of inhibition of PLA(2) activity, quinacrine could also inhibit cPLA(2) expression, and further supports a role for PLA(2) in kainate-induced neuronal injury.