Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A₂ inhibitors

Abstract

In kainate-induced neurotoxicity, the stimulation of kainate receptors results in the activation of phospholipase A₂ and a rapid release of arachidonic acid from neural membrane glycerophospholipids. This process raises arachidonic acid levels and produces alterations in membrane fluidity and permeability. These result in calcium influx and stimulation of lipolysis and proteolysis, production of lipid peroxides, depletion of ATP, and loss of reduced glutathione. As well as the above neurochemical changes, stimulation of ornithine decarboxylase, altered activities of protein kinase C isozymes, and expression of immediate early genes, cytokines, growth factors, and heat shock proteins have also been reported. Kainate-induced stimulation of arachidonic acid release, calcium influx, accumulation of lipid peroxides and products of their decomposition, especially 4-hydroxynonenal (4-HNE), along with alterations in cellular redox state and ATP depletion may play important roles in kainate-induced cell death. Thus the consequences of altered glycerophospholipid metabolism in kainate-induced neurotoxicity can lead to cell death. Kainate-induced neurotoxicity initiates apoptotic as well as necrotic cell death depending upon the intensity of oxidative stress and abnormality in mitochondrial function. Other neurochemical changes may be related to synaptic reorganization following kainate-induced seizures and may be involved in recapitulation of hippocampal development and synaptogenesis.

Introduction

Neural membranes are composed of phospholipids, glycolipids, cholesterol, and proteins. The phospholipids include glycerophospholipids and sphingomyelin. The glycerophospholipids are enriched in polyunsaturated fatty acid residues at the sn-2 position of the glycerol backbone. Oxygen free radicals generated during oxidative stress can attack polyunsaturated fatty acids in the neural membrane bilayer. This makes neural membranes highly susceptible to oxidative damage. The glycerophospholipid bilayer is penetrated to varying degrees by receptors, enzymes, and ion channels that protrude differentially through the membrane or are localized predominantly on the intracellular or extracellular membrane surface. One of the important functions of neural membranes is the regulation of ion homeostasis. The interaction of an agonist (glutamate) with a glutamate receptor results in the enhancement of glycerophospholipid metabolism, which not only regulates the activities of membrane-bound enzymes and ion channels but also modulates many physicochemical properties such as phase transition temperature, fluidity, and permeability [39].

During the past decade, significant information has accumulated on the importance of excitatory amino acids and their receptors, especially glutamate receptors, in neural membrane glycerophospholipid catabolism [35], [36], [37], [66], [127]. Degradation of neural membrane glycerophospholipids, induced by the stimulation of excitatory amino acid receptors, results in the generation of second messengers that carry extracellular signals into the nerve cell. This process is closely associated with synaptogenesis, neuronal plasticity, neuronal survival, and learning and memory processes, whereas the overstimulation of these receptors causes neural cell injury and neurodegeneration [35]. Excitatory amino acids receptors are classified into N-methyl-d-aspartate (NMDA), kainate (KA), 2-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA), l-2-amino-4-phosphonobutanoic acid (L-AP4) and trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD) receptors [75], [81]. Within the above subclasses, multiple subunits have now been identified. These subunits may form heteromeric assemblies that play important roles in modulating the activity of excitatory amino acid receptors [18], [84], [85].

Current interest in excitatory amino acids is due to the involvement of excitatory amino acid receptors in neural cell injury in a variety of neurological disorders [35], [36], [37], [66], [127]. Glutamate- and NMDA-induced cell injury is accompanied by the accumulation of calcium, marked degradation of membrane glycerophospholipids, and accumulation of free fatty acids and lipid peroxides [36]. Less information is available on the molecular mechanism of KA-induced neurotoxicity [23]. We have reported that KA-induced neurotoxicity also involves the stimulation of phospholipase A₂, release of arachidonic acid from neural membrane phospholipids, accumulation of lipid peroxides, alterations in prostaglandins, decline in reduced glutathione (GSH) content, and accumulation of 4-hydroxynonenal, an especially neurotoxic end product of lipid peroxide decomposition [89], [90]. We have also observed that PLA₂ inhibitors protect neural cells from KA-induced neural cell injury [68], [69]. These processes along with alterations of the energy status and the redox status of neural cells may be responsible for injury in KA-induced neurotoxicity. The purpose of this review is (1) to integrate and evaluate studies on the pathophysiological consequences of KA-induced arachidonic acid release on neural cell integrity and (2) discuss the therapeutic effects of PLA₂ inhibitors on KA-induced neurotoxicity [68], [69]. It is hoped that this discussion will promote more studies on the molecular mechanism of KA-induced neuronal degeneration in brain tissue.