6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2h-pyran-2-one and palmitoyl-trifluoromethyl-ketone

Phospholipase A(2) (PLA(2)) is a family of enzymes that cleave membrane phospholipids generating important lipid mediators in signal transduction. In rat hippocampal slices, both intracellular cytosolic Ca(2+)-dependent PLA(2) (cPLA(2)) and Ca(2+)-independent PLA(2) (iPLA(2)) have been implicated in mechanisms of synaptic plasticity underlying memory processes. In mice, intraperitoneal injections of a selective iPLA(2) inhibitor impaired spatial learning. Accordingly, reduced cPLA(2) and iPLA(2) activities were found in postmortem hippocampus of patients with Alzheimer's disease.. This study investigates the effects of injections of PLA(2) inhibitors directly into rat hippocampus on the acquisition of short-term (STM) and long-term memory (LTM) of a one-trial step-down inhibitory avoidance (IA) task.. Wistar rats were bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus. After surgery, the rats received bilateral injections of a vehicle, or of dual cPLA(2) and iPLA(2) inhibitors (MAFP or PACOCF(3)), or a selective iPLA(2) inhibitor (bromoenol lactone) before training in IA. The animals were tested 1.5 h (for STM) and 24 h (for LTM) after training.. Significant inhibition of iPLA(2) activity in rat hippocampus impaired acquisition of STM and LTM. Memory impairment did not result from neuronal death after iPLA(2) inhibition. Moreover, IA training per se increased significantly hippocampal PLA(2) activity.. The present results suggest a functional effect of hippocampal PLA(2) on the neurochemistry of memory acquisition and support the hypothesis that reduced PLA(2) activity may contribute to memory impairment in Alzheimer's disease.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Exploratory Behavior; Group VI Phospholipases A2; Hippocampus; Ketones; Male; Memory, Short-Term; Motor Activity; Naphthalenes; Organophosphonates; Phospholipases A; Phospholipases A2; Pyrones; Rats; Rats, Wistar; Retention, Psychology

The calcium-independent form of phospholipase A2 (iPLA2), an enzyme known to generate arachidonic acid (AA), was recently identified as the predominant constitutive phospholipase in the hippocampus. The present study shows that the iPLA2 inhibitor bromoenol lactone, when introduced into hippocampal CA1 pyramidal cells through a patch pipette, generated a dose-dependent increase in the amplitude of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs). The iPLA2 inhibitor by itself interfered with neither paired pulse facilitation nor N-methyl-D-aspartate (NMDA) receptor-mediated EPSCs, suggesting that its influence on synaptic transmission is postsynaptic in origin and specific to the AMPA subtype of glutamate receptors. Comparable results were obtained with palmitoyl trifluoromethyl ketone, a second structurally distinct iPLA2 inhibitor. The ability of iPLA2 inhibitors to increase AMPA receptor-mediated currents was also reproduced by MK-866, an inhibitor recognized to interfere with the generation of 5-lipoxygenase by-products of AA. At the biochemical level, we found that AMPA, but not NMDA glutamate receptor subunits, were upregulated in rat brain sections pre-incubated with the iPLA2 inhibitors. Collectively, these results provide the first experimental evidence that constitutive iPLA2 and/or its metabolites play an important role in the postsynaptic modulation of neurotransmission in CA1 pyramidal cells of the hippocampus.

Topics: Animals; Arachidonic Acid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Group VI Phospholipases A2; Hippocampus; In Vitro Techniques; Ketones; Naphthalenes; Phospholipases A; Phospholipases A2; Pyramidal Cells; Pyrones; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Membranes; Synaptic Transmission; Up-Regulation

Topics: Animals; Arachidonic Acid; Caproates; Enzyme Inhibitors; Group VI Phospholipases A2; Isoenzymes; Ketones; Leukemia P388; Macrophages; Mice; Naphthalenes; Neoplasm Proteins; Phospholipases A; Phospholipases A2; Pyrones