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.