n-oleoylethanolamine and Nerve-Degeneration

Acylethanolamides are formed in the brain "on demand" from membrane phospholipids called N-acylated phosphatidylethanolamines. The acylethanolamides are signaling molecules of lipid nature, and this lipofilicity suggests an autocrine function. The acylethanolamides include palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and several other quantitative minor species including anandamide (= arachidonoylethanolamide). PEA and OEA can activate several different receptors and inhibit some ion channels, e.g., PPARalpha, vanilloid receptor, K(+) channels (Kv4.3, Kv1.5), and OEA can activate GPR119 and inhibit ceramidases. Targets for SEA are less clear, but it has some cannabimimetic actions in rats in vivo. All acylethanolamides accumulate during neuronal injury, and injected OEA has neuroprotective effects, and PEA has anti-inflammatory effects as studied in the peripheral system. Several of the pharmacological effects seem to be mediated via activation of PPARalpha. Recently, injected OEA has been found to consolidate memories in rats. Inhibitors of the acylethanolamide-degrading enzyme FAAH can increase levels of all acylethanolamides including annandamide, and some of the pharmacological effects caused by these inhibitors may be explained by increased cerebral levels of OEA and PEA, e.g., suppression of nicotine-induced activation of dopamine neurons. Furthermore, through activation of PPARalpha, OEA and PEA may stimulate neurosteroid synthesis, thereby modulating several biological functions mediated by GABA(A) receptors. The existence of acylethanolamides in the mammalian brain has been known for decades, but it is first within the last few years that the putative biological functions of the three most abundant acylethanolamides species are starting to emerge.

Topics: Amides; Animals; Arachidonic Acids; Brain; Cytoprotection; Endocannabinoids; Ethanolamines; Humans; Nerve Degeneration; Neurons; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Receptors, Cannabinoid

Oleoylethanolamide (OEA), agonist of nuclear PPAR-alpha receptors and antagonist of vanilloid TRPV1 receptors, has been reported to show cytoprotective properties. In this study, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. First, PPAR-alpha receptors were confirmed to be located in the nigrostriatal circuit, these receptors being expressed by dopamine neurons of the substantia nigra, and intrinsic neurons and fibers bundles of the dorsal striatum. In the substantia nigra, their location was confined to the ventral tier. The in vitro study showed that 1 microM OEA exerted a significantly neuroprotective effect on cultured nigral dopamine neurons, effects following U-shaped dose-response curves. Regarding the in vivo study, rats were locally injected with OEA into the right striatum and vehicle into the left striatum 30 min before 6-OHDA-induced striatal lesion. In the short term, signals of heme oxygenase-1 (oxidation marker, 24 and 48 h post-lesion) and OX6 (reactive microglia marker, 96 h post-lesion) were found to be significantly less intense in the striatum pretreated with 5 microM OEA. In the long term (1 month), reduction in striatal TH and synaptophysin was less intense whether the right striatum was pretreated with 5 microM OEA, and nigral TH+ neuron death was significantly reduced after pretreatment with 1 and 5 microM OEA. In vivo effects also followed U-shaped dose-response curves. In conclusion, OEA shows U-shaped partial and dose-dependent neuroprotective properties both in vitro and in vivo models of substantia nigra dopamine neuron degeneration. The occurrence of U-shaped dose-response relationships normally suggests toxicity due to high drug concentration or that opposing intracellular pathways are activated by different OEA doses.

Topics: Animals; Cell Survival; Cells, Cultured; Dopamine; Dose-Response Relationship, Drug; Endocannabinoids; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Oleic Acids; Oxidopamine; PPAR alpha; Rats; Rats, Wistar; Substantia Nigra; Synaptophysin

Amyloid-beta peptide (Abeta) accumulation in senile plaques, a pathological hallmark of Alzheimer's disease (AD), has been implicated in neuronal degeneration. We have recently demonstrated that Abeta induced oligodendrocyte (OLG) apoptosis, suggesting a role in white matter pathology in AD. Here, we explore the molecular mechanisms involved in Abeta-induced OLG death, examining the potential role of ceramide, a known apoptogenic mediator. Both Abeta and ceramide induced OLG death. In addition, Abeta activated neutral sphingomyelinase (nSMase), but not acidic sphingomyelinase, resulting in increased ceramide generation. Blocking ceramide degradation with N-oleoyl-ethanolamine exacerbated Abeta cytotoxicity; and addition of bacterial sphingomyelinase (mimicking cellular nSMase activity) induced OLG death. Furthermore, nSMase inhibition by 3-O-methyl-sphingomyelin or by gene knockdown using antisense oligonucleotides attenuated Abeta-induced OLG death. Glutathione (GSH) precursors inhibited Abeta activation of nSMase and prevented OLG death, whereas GSH depletors increased nSMase activity and Abeta-induced death. These results suggest that Abeta induces OLG death by activating the nSMase-ceramide cascade via an oxidative mechanism.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Death; Cells, Cultured; Ceramides; Endocannabinoids; Ethanolamines; Glutathione; Nerve Degeneration; Oleic Acids; Oligodendroglia; Oxidative Stress; Rats; Signal Transduction; Spheroids, Cellular; Sphingomyelin Phosphodiesterase; Sphingomyelins; Up-Regulation