12‐Lipoxygenase Products Attenuate the Glutamate Release and Ca²⁺ Accumulation Evoked by Depolarization of Hippocampal Mossy Fiber Nerve Endings

Abstract

Presynaptic correlates of evoked neurotransmitter release include a rise in cytosolic free calcium level and the calcium-dependent liberation of unesterified arachidonic acid. It has been proposed that lipoxygenase metabolites produced from arachidonic acid may constitute an endogenous feedback system for the modulation of neurotransmitter release. The results of the present study are in agreement with this hypothesis. It was demonstrated that membrane depolarization evoked the release of endogenous glutamate from hippocampal mossy fiber synaptosomes, as well as the accumulation of intraterminal free calcium. The presence of 12-lipoxygenase products attenuated both the induced release of glutamate and the increase in calcium content, whereas 5- or 15-lipoxygenase metabolites were ineffective. A role for lipoxygenase products in the negative modulation of mossy fiber secretion processes was further indicated by the observations that low concentrations of the lipoxygenase inhibitor nordihydroguaiaretic acid (0.1-10 microM) potentiated the glutamate release and calcium accumulation induced by membrane depolarization. Therefore, we suggest that 12-lipoxygenase metabolites provide a presynaptic inhibitory signal that limits neurotransmitter release from hippocampal mossy fiber terminals.

Expression of Arachidonate 12-Lipoxygenase in Rat Tissues: A Possible Role in Glucagon Secretion

“…It is of interest that the 12-lipoxygenase metabolites might act as a second messenger in Aplysia neurons (Piomelli et al 1987;Buttner et al 1989). Moreover, 12-lipoxygenase was shown to modulate glutamate release in hippocampal mossy fiber terminals (Freeman et al 1991;Dorman et al 1992). Our recent experiments demonstrated that the 12-lipoxygenase and/or its metabolites upregulated membrane excitability by targeting K ϩ channels in NG108-15 cells (Takahashi et al 1999).…”

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

“…45 Indeed, LOX metabolites were found to be synthesized in both neurons and glial cells. 21,[46][47][48] Some of them, such as 5-and 12-hydroxyeicosatetraenoic acids, have been reported to exert various actions on neurons, including modulation of Na-K ATPase activity, 49 neurotransmitter release 50 or alteration of membrane potential. 51,52 LOXs also act as regulators of cell proliferation and death, and have been implied in the mediation of apoptosis induced by various physical or chemical agents such as UV light, oxidative stress or receptor ligands 25,26 In contrast, only a small number of studies investigated the involvement of LOXs in the various signaling pathways leading to neurodegeneration.…”

Modification by Arachidonic Acid of Extracellular Adenosine Metabolism and Neuromodulatory Action in the Rat Hippocampus

“…Several effects exerted by eicosanoids in the hippocampus are mediated by cyclooxygenase or lipoxygenase metabolites of AA (22,23). Indeed, AA was metabolized by hippocampal nerve terminals with the formation mainly of lypoxygenase products but also cyclooxygenase products (see dashed line in Fig.…”