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It has been suggested that the bioactive lipid mediator oleoylethanolamide (OEA), a potent agonist of the peroxisome proliferator-activated receptor-alpha (PPAR-α) possesses anti-depressant-like effects in several preclinical models. We recently demonstrated that several of OEA's behavioural actions require the integrity of the brain histaminergic system, and that an intact histaminergic neurotransmission is specifically required for selective serotonin re-uptake inhibitors to exert their anti-depressant-like effect. The purpose of our study was to test if OEA requires the integrity of the histaminergic neurotransmission to exert its antidepressant-like effects. Immobility time in the tail suspension test was measured to assess OEA's potential (10 mg/kg i.p.) as an antidepressant drug in histidine decarboxylase null (HDC−/-) mice and HDC+/+ littermates, as well as in PPAR-α+/+ and PPAR-α−/− mice. CREB phosphorylation was evaluated using Western blot analysis in hippocampal and cortical homogenates, as pCREB is considered partially responsible for the efficacy of antidepressants. Serotonin release from ventral hippocampi of HDC+/+ and HDC−/- mice was measured with in-vivo microdialysis, following OEA administration. OEA decreased immobility time and increased brain pCREB levels in HDC+/+ mice, whereas it was ineffective in HDC−/- mice. Comparable results were obtained in PPAR-α+/+ and PPAR-α−/− mice. Microdialysis revealed a dysregulation of serotonin release induced by OEA in HDC−/- mice. Our observations corroborate our hypothesis that brain histamine and signals transmitted by OEA interact to elaborate appropriate behaviours and may be the basis for the efficacy of OEA as an antidepressant-like compound.

The satiety-promoting action of oleoylethanolamide (OEA) has been associated to the indirect activation of selected brain areas, such as the nucleus of the solitary tract (NST) in the brainstem and the tuberomammillary (TMN) and paraventricular (PVN) nuclei in the hypothalamus, where noradrenergic, histaminergic and oxytocinergic neurons play a necessary role. Visceral ascending fibers were hypothesized to mediate such effects. However, our previous findings demonstrated that the hypophagic action of peripherally administered OEA does not require intact vagal afferents and is associated to a strong activation of the area postrema (AP). Therefore, we hypothesized that OEA may exert its central effects through the direct activation of this circumventricular organ. To test this hypothesis, we subjected rats to the surgical ablation of the AP (APX rats) and evaluated the effects of OEA (10mgkg-1 i.p.) on food intake, Fos expression, hypothalamic oxytocin (OXY) immunoreactivity and on the expression of dopamine beta hydroxylase (DBH) in the brainstem and hypothalamus. We found that the AP lesion completely prevented OEA's behavioral and neurochemical effects in the brainstem and the hypothalamus. Moreover OEA increased DBH expression in AP and NST neurons of SHAM rats while the effect in the NST was absent in APX rats, thus suggesting the possible involvement of noradrenergic AP neurons. These results support the hypothesis of a necessary role of the AP in mediating OEA's central effects that sustain its pro-satiety action.

Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell (“frustration stress”). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg−1) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.

Brain fatty acid (FA) metabolism deserves a close attention not only for its energetic aspects but also because FAs and their metabolites/derivatives are able to influence many neural functions, contributing to brain pathologies or representing potential targets for pharmacological and/or nutritional interventions. Glucose is the preferred energy substrate for the brain, whereas the role of FAs is more marginal. In conditions of decreased glucose supply, ketone bodies, mainly formed by FA oxidation, are the alternative main energy source. Ketogenic diets or medium-chain fatty acid supplementations were shown to produce therapeutic effects in several brain pathologies. Moreover, the positive effects exerted on brain functions by short-chain FAs and the consideration that they can be produced by intestinal flora metabolism contributed to the better understanding of the link between "gut-health" and "brain-health". Finally, attention was paid also to the regulatory role of essential polyunsaturated FAs and their derivatives on brain homeostasis.

Multiple sclerosis (MS) is a central nervous demyelinating disease characterized by cyclic loss and repair of myelin sheaths associated with chronic inflammation and neuronal loss. This degenerative pathology is accompanied by modified levels of oxysterols (oxidative derivatives of cholesterol, implicated in cholesterol metabolism), highlighted in the brain, blood and cerebrospinal fluid of MS patients. The pathological accumulation of such derivatives is thought to participate in the onset and progression of the disease through their implication in inflammation, oxidative stress, demyelination and neurodegeneration. In this context, physical exercise is envisaged as a complementary resource to ameliorate therapeutic strategies. Indeed, physical activity exerts beneficial effects on neuronal plasticity, decreases inflammation and oxidative stress and improves blood-brain integrity in extents that could be beneficial for brain health. The present review attempts to summarize the available data on the positive effect of physical exercise to highlight possible links between physical activity and modulation of cholesterol/oxysterol homeostasis in MS.