Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF-3845: A regional analysis of the contribution of endocannabinoid signaling machinery.

OBJECTIVE: Consumption of energy-dense palatable "comfort" food can alleviate stress and negative emotions, while abrupt withdrawal from a palatable diet can worsen these symptoms, causing difficulties with adherence to weight-loss diets. Currently, no pharmacological treatment is effective for obesity-related anxiety, so we investigated the endocannabinoid system (ECS), and specifically the fatty acid amide hydrolase (FAAH), as an interesting emerging target in this context because of its key role in the regulation of both energy homeostasis and emotional behavior. METHODS: Rats were subjected to exposure and subsequent abstinence from a palatable cafeteria diet. During abstinence period, rats were treated with the selective FAAH inhibitor PF-3845 (10 mg/kg; intraperitoneal administration every other day). RESULTS: Abstinent rats displayed an anxiogenic-like behavior and changes in the proteins of ECS signaling machinery in brain areas involved both in anxiety and food intake regulation. In particular, withdrawal caused a reduction of the expression of cannabinoid receptors in the nucleus accumbens and of enzymes diacylglycerol lipase alpha and monoacylglycerol lipase (MAGL) in the amygdala. Pharmacological inhibition of FAAH exerted an anxiolytic-like effect in abstinent animals and increased both MAGL expression in amygdala and CB2 expression in prefrontal cortex. DISCUSSION: Overall, our results suggest that emotional disturbances associated with dieting are coupled with region-specific alterations in the cerebral expression of the ECS and that the enhancement of the endocannabinoid signaling by FAAH inhibition might represent a novel pharmacological strategy for the treatment of anxiety related to abstinence from palatable food. PUBLIC SIGNIFICANCE: The present study focused on evaluating the role of the endocannabinoid system in modulating withdrawal from naturally rewarding activities that have an impact on mood, such as feeding. The variations observed in the emotional behavior of abstinent rats was linked to neuroadaptations of the ECS in specific brain areas.

PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimer's Disease.

In the present study, we used a mouse model of Alzheimer's disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aß and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone's involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.

Investigating the role of the central melanocortin system in stress and stress-related disorders.

The melanocortinergic neural circuit, known for its influence on energy expenditure and feeding behavior, also plays a role in stress and stress-induced psychiatric disorders, including anxiety and depression. The major contribution is given by the melanocortin-4 receptor (MC4R) subtype, highly expressed in brain regions involved in the control of stress responses. Furthermore, the MC4R appears to profoundly affect the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and it has been also highlighted a functional and anatomical interaction with the corticotropin-releasing factor (CRF), an important mediator of stress and stress-related behaviors. The MC4R agonists seem to exacerbate stress-inducing anxiety- and depressive-like behavior, while MC4R antagonists have been demonstrated to mitigate such disorders, as shown in several preclinical behavioral tests. The evidence collected in the present review suggests that the melanocortin system, through the MC4R, could possibly modulate behavioral responses to stress, suggesting the use of MC4R antagonists as a possible novel treatment for anxiety and depression induced by stress.

Therapeutic Potential of Targeting the Oxytocinergic System.

The nine amino acid neuropeptide oxytocin (OXT, Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2) is one of the most studied hormones of the body [...].

Brief daily access to cafeteria-style diet impairs hepatic metabolism even in the absence of excessive body weight gain in rats.

Numerous nutritional approaches aimed at reducing body weight have been developed as a strategy to reduce obesity. Most of these interventions rely on reducing caloric intake or limiting calories access to a few hours per day. In this work, we analyzed the effects of the extended (24 hours/day) or restricted (1 hour/day) access to a cafeteria-style (CAF) diet, on rat body weight and hepatic lipid metabolism, with respect to control rats (CTR) fed with a standard chow diet. The body weight gain of restricted-fed rats was not different from CTR, despite the slightly higher total caloric intake, but resulted significantly lower than extended-fed rats, which showed a CAF diet-induced obesity and a dramatically higher total caloric intake. However, both CAF-fed groups of rats showed, compared to CTR, unhealthy serum and hepatic parameters such as higher serum glucose level, lower HDL values, and increased hepatic triacylglycerol and cholesterol amount. The hepatic expression and activity of key enzymes of fatty acid synthesis, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was similarly reduced in both CAF-fed groups of rats with respect to CTR. Anyway, while in extended-fed rats this reduction was associated to a long-term mechanism involving sterol regulatory element-binding protein-1 (SREBP-1), in restricted-fed animals a short-term mechanism based on PKA and AMPK activation occurred in the liver. Furthermore, hepatic fatty acid oxidation (FAO) and oxidative stress resulted significantly increased in extended, but not in restricted-fed rats, as compared to CTR. Overall, these results demonstrate that although limiting the total caloric intake might successfully fight obesity development, the nutritional content of the diet is the major determinant for the health status.

Targeting the Oxytocinergic System: A Possible Pharmacological Strategy for the Treatment of Inflammation Occurring in Different Chronic Diseases.

Unresolved inflammation represents a central feature of different human pathologies including neuropsychiatric, cardiovascular, and metabolic diseases. The epidemiologic relevance of such disorders justifies the increasing interest in further understanding the mechanisms underpinning the inflammatory process occurring in such chronic diseases to provide potential novel pharmacological approaches. The most common and effective therapies for controlling inflammation are glucocorticoids; however, a variety of other molecules have been demonstrated to have an anti-inflammatory potential, including neuropeptides. In recent years, the oxytocinergic system has seen an explosion of scientific studies, demonstrating its potential to contribute to a variety of physiological processes including inflammation. Therefore, the aim of the present review was to understand the role of oxytocin in the modulation of inflammation occurring in different chronic diseases. The criterion we used to select the diseases was based on the emerging literature showing a putative involvement of the oxytocinergic system in inflammatory processes in a variety of pathologies including neurological, gastrointestinal and cardiovascular disorders, diabetes and obesity. The evidence reviewed here supports a beneficial role of oxytocin in the control of both peripheral and central inflammatory response happening in the aforementioned pathologies. Although future studies are necessary to elucidate the mechanistic details underlying such regulation, this review supports the idea that the modulation of the endogenous oxytocinergic system might represent a new potential pharmacological approach for the treatment of inflammation.

Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders?

Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.

Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

It is widely accepted that chronic stress may alter the homeostatic mechanisms of body weight control. In this study, we followed the metabolic changes occurring in mice when chronic stress caused by psychosocial defeat (CPD) is associated with ad libitum exposure to a palatable high-fat diet (HFD). In this model, CPD mice consumed more HFD than unstressed (Un) mice without gaining body weight. We focused on metabolic processes involved in weight control, such as de novo lipogenesis (DNL), fatty acid ß-oxidation (FAO), and thermogenesis. The activity and expression of DNL enzymes were reduced in the liver and white adipose tissue of mice consuming the HFD. Such effects were particularly evident in stressed mice. In both CPD and Un mice, HFD consumption increased the hepatic expression of the mitochondrial FAO enzyme carnitine palmitoyltransferase-1. In the liver of mice consuming the HFD, stress exposure prevented accumulation of triacylglycerols; however, accumulation of triacylglycerols was observed in Un mice under the same dietary regimen. In brown adipose tissue, stress increased the expression of uncoupling protein-1, which is involved in energy dissipation, both in HFD and control diet-fed mice. We consider increased FAO and energy dissipation responsible for the antiobesity effect seen in CPD/HFD mice. However, CPD associated with HFD induced hepatic oxidative stress.-Giudetti, A. M., Testini, M., Vergara, D., Priore, P., Damiano, F., Gallelli, C. A., Romano, A., Villani, R., Cassano, T., Siculella, L., Gnoni, G. V., Moles, A., Coccurello, R., Gaetani, S. Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.

PURPOSE: Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress. METHODS: In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression. RESULTS: CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFD-fed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD. CONCLUSIONS: CPD appears to uncouple the intake of HFD from energy homeostasis causing higher HFD intake, larger iBAT accumulation, increased energy expenditure and lipid oxidation, and lower body weight. Overall, the present study confirms the notion that the chronic activation of the stress response can be associated with metabolic disorders, altered energy homeostasis, and changes of orexigenic and anorexigenic signaling. These changes might be relevant to better understand the etiology of stress-induced obesity and eating disorders and might represent a valid therapeutic approach for the development of new therapies in this field.

Role of the area postrema in the hypophagic effects of oleoylethanolamide.

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.

Estrogenic suppression of binge-like eating elicited by cyclic food restriction and frustrative-nonreward stress in female rats.

Because binge eating and emotional eating vary through the menstrual cycle in human females, we investigated cyclic changes in binge-like eating in female rats and their control by estrogens. Binge-like eating was elicited by three cycles of 4 days of food restriction and 4 days of free feeding followed by a single frustrative nonreward-stress episode (15 min visual and olfactory exposure to a familiar palatable food) immediately before presentation of the palatable food. Intact rats showed binge-like eating during the diestrous and proestrous phases of the ovarian cycle, but not during the estrous (periovulatory) phase. Ovariectomized (OVX) rats not treated with estradiol (E2) displayed binge-like eating, whereas E2-treated OVX rats did not. The procedure did not increase signs of anxiety in an open-field test. OVX rats not treated with E2 that were subjected to food restriction and sacrificed immediately after frustrative nonreward had increased numbers of cells expressing phosphorylated extracellular signal-regulated kinases (ERK) in the central nucleus of the amygdala (CeA), paraventricular nucleus of hypothalamus (PVN), and dorsal and ventral bed nuclei of the stria terminalis (BNST) compared with nonrestricted or E2-treated rats. These data suggest that this female rat model is appropriate for mechanistic studies of some aspects of menstrual-cycle effects on emotional and binge eating in human females, that anxiety is not a sufficient cause of binge-like eating, and that the PVN, CeA, and BNST may contribute to information processing underlying binge-like eating.

Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake.

Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.

Eating disorders: from bench to bedside and back.

The central nervous system and viscera constitute a functional ensemble, the gut-brain axis, that allows bidirectional information flow that contributes to the control of feeding behavior based not only on the homeostatic, but also on the hedonic aspects of food intake. The prevalence of eating disorders, such as anorexia nervosa, binge eating and obesity, poses an enormous clinical burden, and involves an ever-growing percentage of the population worldwide. Clinical and preclinical research is constantly adding new information to the field and orienting further studies with the aim of providing a foundation for developing more specific and effective treatment approaches to pathological conditions. A recent symposium at the XVI Congress of the Societá Italiana di Neuroscienze (SINS, 2015) 'Eating disorders: from bench to bedside and back' brought together basic scientists and clinicians with the objective of presenting novel perspectives in the neurobiology of eating disorders. Clinical studies presented by V. Ricca illustrated some genetic aspects of the psychopathology of anorexia nervosa. Preclinical studies addressed different issues ranging from the description of animal models that mimic human pathologies such as anorexia nervosa, diet-induced obesity, and binge eating disorders (T. Lutz), to novel interactions between peripheral signals and central circuits that govern food intake, mood and stress (A. Romano and G. Provensi). The gut-brain axis has received increasing attention in the recent years as preclinical studies are demonstrating that the brain and visceral organs such as the liver and guts, but also the microbiota are constantly engaged in processes of reciprocal communication, with unexpected physiological and pathological implications. Eating is controlled by a plethora of factors; genetic predisposition, early life adverse conditions, peripheral gastrointestinal hormones that act directly or indirectly on the central nervous system, all are receiving attention as they presumably contribute to the development of eating disorders.

Epigenetic regulation of nociceptin/orphanin FQ and corticotropin-releasing factor system genes in frustration stress-induced binge-like palatable food consumption.

Evidence suggests that binge eating may be caused by a unique interaction between dieting and stress. We developed a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after a 15-minute exposure to the sight of the palatable food (frustration stress). The aim of the present study was to investigate the regulation of the stress neurohormone corticotropin-releasing factor (CRF) system and of the nociceptin/orphanin FQ (N/OFQ) system genes in selective rat brain regions, using our animal model. Food restriction by itself seems to be responsible in the hypothalamus for the downregulation on messenger RNA levels of CRF-1 receptor, N/OFQ and its receptor (NOP). For the latter, this alteration might be due to selective histone modification changes. Instead, CRF gene appears to be upregulated in the hypothalamus as well as in the ventral tegmental area only when rats are food restricted and exposed to frustration stress, and, of relevance, these changes appear to be due to a reduction in DNA methylation at gene promoters. Moreover, also CRF-1 receptor gene resulted to be differentially regulated in these two brain regions. Epigenetic changes may be viewed as adaptive mechanisms to environmental perturbations concurring to facilitate food consumption in adverse conditions, that is, in this study, under food restriction and stressful conditions. Our data on N/OFQ and CRF signaling provide insight on the use of this binge-eating model for the study of epigenetic modifications in controlled genetic and environmental backgrounds.

Role of bed nucleus of the stria terminalis corticotrophin-releasing factor receptors in frustration stress-induced binge-like palatable food consumption in female rats with a history of food restriction.

We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders.

Inhibition of anandamide hydrolysis enhances noradrenergic and GABAergic transmission in the prefrontal cortex and basolateral amygdala of rats subjected to acute swim stress.

Limbic forebrain endocannabinoid (eCB) signaling is critically involved in stress integration by modulating neurotransmitters release. The purpose of this study was to examine, by brain microdialysis, the effects of fatty acid amide hydrolase (FAAH) inhibition on noradrenergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the prefrontal cortex (PFC) and basolateral amygdala (BLA) of rats subjected to a 20-min swim stress. Microdialysis started on stress- and drug-naïve rats that were treated with the FAAH inhibitor URB597 (0.1 or 0.3 mg/kg) 30 min before undergoing the stress procedure. Dialysate samples were collected every 20 min from the beginning of the experiment. Concentrations of noradrenaline (NA) and GABA were determined by HPLC coupled to electrochemical and fluorescence detection, respectively. We found that neither URB597 treatment nor 20 min of swim stress exposure per se altered NA and GABA extracellular levels in PFC or BLA. Interestingly, rats treated with 0.1 mg/kg of URB597 followed by 20 min of stress showed significantly higher NA and GABA levels in PFC and BLA. These effects were absent in rats treated with 0.3 mg/kg URB597, indicating a dose-specific effect. Moreover, we found that the pretreatment with the CB1 receptor antagonist rimonabant blocked the URB597 effects on NA and GABA release in PFC and BLA of animals subjected to forced swimming. The present study might provide an important first step toward understanding the mechanisms through which URB597 modulates stress-induced neuroendocrine secretion and behavioral coping strategies.

5-S-cysteinyldopamine neurotoxicity: Influence on the expression of α-synuclein and ERp57 in cellular and animal models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is still unclear in spite of extensive investigations. It has been hypothesized that 5-S-cysteinyldopamine (CysDA), a catechol-thioether metabolite of dopamine (DA), could be an endogenous parkinsonian neurotoxin. To gain further insight into its role in the neurodegenerative process, both CD1 mice and SH-SY5Y neuroblastoma cells were treated with CysDA, and the data were compared with those obtained by the use of 6-hydroxydopamine, a well-known parkinsonian mimetic. Intrastriatal injection of CysDA in CD1 mice caused a long-lasting depletion of DA, providing evidence of in vivo neurotoxicity of CysDA. Both in mice and in SH-SY5Y cells, CysDA treatment induced extensive oxidative stress, as evidenced by protein carbonylation and glutathione depletion, and affected the expression of two proteins, α-synuclein (α-Syn) and ERp57, whose levels are modulated by oxidative insult. Real-time PCR experiments support these findings, indicating an upregulation of both ERp57 and α-Syn expression. α-Syn aggregation was also found to be modulated by CysDA treatment. The present work provides a solid background sustaining the hypothesis that CysDA is involved in parkinsonian neurodegeneration by inducing extensive oxidative stress and protein aggregation.

Vagal afferents are not necessary for the satiety effect of the gut lipid messenger oleoylethanolamide.

The endogenous lipid messenger oleoylethanolamide (OEA) inhibits eating and modulates fat metabolism supposedly through the activation of peroxisome proliferator-activated receptor-α (PPARα) and vagal sensory fibers. We tested in adult male rats whether OEA stimulates fatty acid oxidation (FAO) and ketogenesis and whether it increases plasma levels of the satiating gut peptides glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). We also explored whether OEA still inhibits eating after subdiaphragmatic vagal deafferentation (SDA). We found that intraperitoneally injected OEA (10 mg/kg body wt) reduced (P < 0.05) food intake mainly by increasing meal latency and that this effect was stronger in rats fed a 60% high-fat diet (HFD) than in chow-fed rats. OEA increased (P < 0.05) postprandial plasma nonesterified fatty acids and ß-hydroxybutyrate (BHB) in the hepatic portal vein (HPV) and vena cava (VC) 30 min after injection, which was more pronounced in HFD- than in chow-fed rats. OEA also increased the protein expression of the key ketogenetic enzyme, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, in the jejunum of HFD-fed rats, but not in the liver or duodenum of either diet group. Furthermore, OEA decreased GLP-1 and PYY concentrations (P < 0.05) in the HPV and VC 30 min after administration. Finally, OEA reduced food intake in SDA and sham-operated rats similarly. Our findings indicate that neither intact abdominal vagal afferents nor prandial increases in GLP-1 or

Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease.

BACKGROUND: Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models. METHODS: 18-month-old 3×Tg-AD male mice and their wild-type male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K(+)-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines. RESULTS: Aged 3×Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3×Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3×Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3×Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K(+) stimulation. Such alterations occur with obvious local amyloid-ß and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase. CONCLUSIONS: These results suggest that 3×Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression.

Autophagy and inflammation an intricate affair in the management of obesity and metabolic disorders: evidence for novel pharmacological strategies?

Unhealthy lifestyle habits including a sedentary life, the lack of physical activity, and wrong dietary habits are the major ones responsible for the constant increase of obesity and metabolic disorders prevalence worldwide; therefore, the scientific community pays significant attention to the pharmacotherapy of such diseases, beyond lifestyle interventions, the use of medical devices, and surgical approaches. The intricate interplay between autophagy and inflammation appears crucial to orchestrate fundamental aspects of cellular and organismal responses to challenging stimuli, including metabolic insults; hence, when these two processes are dysregulated (enhanced or suppressed) they produce pathologic effects. The present review summarizes the existing literature reporting the intricate affair between autophagy and inflammation in the context of metabolic disorders, including obesity, diabetes, and liver metabolic diseases (non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)). The evidence collected so far suggests that an alteration of autophagy might lead to maladaptive metabolic and inflammatory responses thus exacerbating the severity of the disease, and the most prominent conclusion underlies that autophagy might exert a protective function by contributing to balance inflammation. However, the complex nature of obesity and metabolic disorders might represent a limit of the studies; indeed, although many pharmacological treatments, producing positive metabolic effects, are also able to modulate autophagic flux and inflammation, it is not clear if the final beneficial effect might occur only by their mechanism of action, rather than because of additionally involved pathways. Finally, although future studies are needed, the observation that anti-obesity and antidiabetic drugs already on the market, including incretin mimetic agents, facilitate autophagy by dampening inflammation, strongly contributes to the idea that autophagy might represent a druggable system for the development of novel pharmacological tools that might represent an attractive strategy for the treatment of obesity and metabolic disorders.