Publications by authors named "Juan Decara"

43 Publications

Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity.

Nutrients 2021 Jul 28;13(8). Epub 2021 Jul 28.

Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain.

Obesity is currently a major epidemic in the developed world. However, we lack a wide range of effective pharmacological treatments and therapies against obesity, and those approved are not devoid of adverse effects. Dietary components such as palmitoleic acid have been proposed to improve metabolic disbalance in obesity, although the mechanisms involved are not well understood. Both palmitoleic acid (POA) and oleic acid (OA) can be transformed in N-acylethanolamines (NAEs), mediating the effects of dietary POA and OA. To test this hypothesis, here, we study the effects on food intake and body weight gain of palmitoleylethanolamide (POEA) and the OA-derived NAE analogue, oleoylethanolamide (OEA), in Sprague-Dawley rats with a hypercaloric cafeteria diet (HFD). Plasma biochemical metabolites, inflammatory mediators, and lipogenesis-associated liver protein expression were also measured. The results indicate that POEA is able to improve health status in diet-induced obesity, decreasing weight, liver steatosis, inflammation, and dyslipemia. The action of POEA was found to be almost identical to that of OEA, which is an activator of the nuclear peroxisome proliferator receptor alpha (PPARα), and it is structurally related to POEA. These results suggest that the dietary administration of either POA or POEA might be considered as nutritional intervention as complementary treatment for complicated obesity in humans.
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http://dx.doi.org/10.3390/nu13082589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400335PMC
July 2021

Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol.

Nutrients 2021 Jun 30;13(7). Epub 2021 Jun 30.

Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010 Málaga, Spain.

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.
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http://dx.doi.org/10.3390/nu13072268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308282PMC
June 2021

Immunomodulatory, Antioxidant Activity and Cytotoxic Effect of Sulfated Polysaccharides from (S.F.Gray) Nägeli.

Biomolecules 2021 03 24;11(4). Epub 2021 Mar 24.

Instituto de Biotecnología y Desarrollo Azul (IBYDA), Departamento de Ecología y Geología, Facultad de Ciencias, Universidad de Málaga, Facultad de Ciencias, 29071 Málaga, Spain.

is a unicellular microalga that can synthesize and secrete to the culture medium-high amounts of polysaccharides. In this study, the immunomodulatory, cytotoxic effect and antioxidant activity of the sulfated polysaccharides (PcSPs) were determinate. The PcSPs were precipitated with 2% Cetylpyridinium bromide hydrate and ethanol and purified by dialysis. The extract was lyophilized for its characterization by Fourier transform-Infrared (FT-IR) spectroscopy and gas chromatography-mass spectrometry (GC-MS). The antioxidant activity of PcSPs were examined with assay 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) and compared with that of the biomass, observing significant differences between the results obtained from the PcSPs and biomass. To determine their ability to induce cytokine production Tumor Necrosis Factor alpha (TNF-α) and interleukina-6 (IL-6), the immunomodulatory activity of the PcSPs has been evaluated. In the mouse macrophage cell line (RAW 264.7), PcSPs are potent inducers of IL-6 cytokines but mainly of TNF-α. The cytotoxic capacity of PcSPs was measured by the MTT colorimetric assay in colorectal carcinoma (HTC-116), human leukemia (U-937 and HL-60), breast cancer (MCF-7), lung cancer (NCI-H460) and human gingival fibroblasts (HGF-1) cell lines. The IC value of 2311.20 µg mL, 1676.74 µg mL, 1089.63 µg mL, 5498.14 µg mL and 2861.49 µg mL respectively in the tumor lines and 5022.55 µg mL in gingival fibroblasts were obtained. Our study suggested that PcSPs from have a moderate immunomodulatory and cytotoxic effect. The results obtained indicate that the polysaccharides from are potent inducers of IL-6 cytokines and, most importantly, of TNF-α. PcSPs showed no evidence of antigenic activity or hypersensitivity when administered intraperitoneally in mice. Furthermore, the in vivo study revealed an improvement of local inflammatory response against stress in the peritoneum. These findings suggest that the PcSPs from might have potential as a valuable ingredient in nutraceutical products.
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http://dx.doi.org/10.3390/biom11040488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063939PMC
March 2021

Abrupt cessation of reboxetine along alcohol deprivation results in alcohol intake escalation after reinstatement of drinking.

Addict Biol 2021 05 20;26(3):e12957. Epub 2020 Aug 20.

Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, Madrid, Spain.

Major depression (MD) is a frequent comorbidity in alcohol use disorder (AUD) patients. Antidepressant prescription is often limited by poor clinical outcomes or unwanted side effects in comorbid AUD-MD patients. Recent studies suggest that abrupt cessation of selective serotonin reuptake inhibitors antidepressant treatment increases alcohol consumption after an alcohol deprivation period in rats. However, the appearance of this effect after the treatment with selective noradrenaline reuptake inhibitors (SNRIs) is not known. Here, we report that interruption of subchronic (14 days) treatment with the SNRIs reboxetine (15 mg/kg/day intraperitoneally) resulted in escalation of ethanol intake when the animals resume alcohol self-administration. This effect of reboxetine treatment cessation was associated with a profound deactivation of the endocannabinoid/acylethanolamide signaling system in the prefrontal cortex but not in the dorsal hippocampus, as reflected by the decrease in the protein expression of the cannabinoid CB receptor, the PPARα receptor, the 2-arachidonoylglycerol synthesizing enzymes DAGLα and DGALβ, and the endocanabinoid degrading enzyme MAGL. This was associated with dysregulation of the expression of glutamic acid receptors GluN1, GluA1, and mGlu5 in the medial prefrontal cortex and the dorsal hippocampus of the animals exposed to reboxetine. The present results further support the idea that abrupt cessation of antidepressant therapy along alcohol deprivation time can boost alcohol intake after relapse through mechanisms associated with endocannabinoid/glutamate signaling dysregulation. This finding might be relevant for patients suffering AUD/MD comorbidity where antidepressant therapy must be monitored with caution for avoiding unwanted side effects if adherence to the treatment is not fully achieved.
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http://dx.doi.org/10.1111/adb.12957DOI Listing
May 2021

D-Pinitol from Is an Orally Active Natural Inositol That Reduces Pancreas Insulin Secretion and Increases Circulating Ghrelin Levels in Wistar Rats.

Nutrients 2020 Jul 8;12(7). Epub 2020 Jul 8.

Laboratorio de Medicina Regenerativa, Instituto IBIMA de Málaga, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain.

To characterize the metabolic actions of D-Pinitol, a dietary inositol, in male Wistar rats, we analyzed its oral pharmacokinetics and its effects on (a) the secretion of hormones regulating metabolism (insulin, glucagon, IGF-1, ghrelin, leptin and adiponectin), (b) insulin signaling in the liver and (c) the expression of glycolytic and neoglucogenesis enzymes. Oral D-Pinitol administration (100 or 500 mg/Kg) resulted in its rapid absorption and distribution to plasma and liver compartments. Its administration reduced insulinemia and HOMA-IR, while maintaining glycaemia thanks to increased glucagon activity. In the liver, D-Pinitol reduced the key glycolytic enzyme pyruvate kinase and decreased the phosphorylation of the enzymes AKT and GSK-3. These observations were associated with an increase in ghrelin concentrations, a known inhibitor of insulin secretion. The profile of D-Pinitol suggests its potential use as a pancreatic protector decreasing insulin secretion through ghrelin upregulation, while sustaining glycaemia through the liver-based mechanisms of glycolysis control.
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http://dx.doi.org/10.3390/nu12072030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400942PMC
July 2020

Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases.

Front Pharmacol 2020 27;11:730. Epub 2020 May 27.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.
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http://dx.doi.org/10.3389/fphar.2020.00730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266982PMC
May 2020

Differential hepatoprotective role of the cannabinoid CB and CB receptors in paracetamol-induced liver injury.

Br J Pharmacol 2020 07 15;177(14):3309-3326. Epub 2020 Apr 15.

UGC Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.

Background And Purpose: Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB and CB receptors in liver fibrogenesis and inflammation.

Experimental Approach: The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg ·day ) of paracetamol (acetaminophen), previously treated with selective CB (ACEA) and CB (JWH015) agonists (10 mg·kg ), or lacking CB and CB receptors.

Key Results: Acute paracetamol increased the expression of CB , ABHD6 and COX-2, while repeated paracetamol increased that of CB and COX-2 and decreased that of DAGLβ. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB and CB increments. Acute paracetamol-exposed CB KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol.

Conclusion And Implications: The differential role of CB versus CB receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
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http://dx.doi.org/10.1111/bph.15051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312315PMC
July 2020

Perinatal free-choice of a high-calorie low-protein diet affects leptin signaling through IRS1 and AMPK dephosphorylation in the hypothalami of female rat offspring in adulthood.

Acta Physiol (Oxf) 2019 06 21;226(2):e13244. Epub 2019 Jan 21.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.

Aim: We aimed to investigate whether a dysregulated maternal diet during gestation and lactation induces long-lasting changes in the hypothalamic control of feeding behavior in the offspring and whether this effect is sex specific.

Methods: The study included an analysis of appetite-regulating metabolic hormones and hypothalamic signaling in male and female offspring in adulthood after exposure to a free-choice high-calorie palatable low-protein (P) diet or standard chow (C) during (pre)gestation/lactation (maternal) and/or postweaning (offspring).

Results: Maternal exposure to the P diet resulted in decreased protein intake and body weight gain in dams and decreased body weight gain in offspring during lactation. The maternal P diet (PC) specifically increased feed efficacy and decreased body weight and cholesterol levels in the female offspring in adulthood, but no changes in adiposity or leptin levels were found. In contrast, P diet exposure after weaning (CP and PP) increased caloric intake, adiposity and circulating levels of leptin in the male and female offspring in adulthood. The hypothalami of the female offspring exposed to the maternal P diet (PC and PP) expressed high levels of the phospho-leptin receptor and low levels of SOCS3, phospho-IRS1 and phospho-AMPK, regardless of the postweaning diet. The hypothalami of the female rats in the PC group also showed increased levels of STAT3 and the orexigenic neuropeptide Agrp.

Conclusions: Maternal exposure to a free-choice high-calorie low-protein diet induces a long-term feed efficacy associated with changes in leptin signaling through IRS-1 and AMPK dephosphorylation in the hypothalami of female offspring in adulthood.
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http://dx.doi.org/10.1111/apha.13244DOI Listing
June 2019

Cannabinoid dependence induces sustained changes in GABA release in the globus pallidus without affecting dopamine release in the dorsal striatum: A dual microdialysis probe study.

Addict Biol 2018 11 13;23(6):1251-1261. Epub 2018 Nov 13.

Laboratorio de Neuropsicofarmacología, Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Málaga, Spain.

A dual probe microdialysis study was designed to characterize GABA and dopamine (DA) release in the basal ganglia of cannabinoid-dependent Wistar rats. Whereas chronic administration of the cannabinoid receptor agonist WIN55,212 (WIN) resulted in increased basal GABA release, the D2 agonist receptor-mediated control of GABA and DA release elicited by quinpirole was similar in both cannabinoid-dependent and non dependent animals. However, quinpirole did induce a greater number of more stereotypies in cannabinoid-dependent animals, indicating a dysregulated behavioral response.
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http://dx.doi.org/10.1111/adb.12694DOI Listing
November 2018

PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: Evaluation of a novel oleic acid conjugate in preclinical rat models.

Biochem Pharmacol 2018 11 6;157:235-243. Epub 2018 Sep 6.

Instituto IBIMA, Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Spain; Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28224, Spain. Electronic address:

Recent studies have demonstrated the utility of drugs modulating the endogenous cannabinoid system to control excessive alcohol intake. Among them, drugs interacting with acylethanolamide receptors including cannabinoid CB1 receptor antagonists/inverse agonists, peroxisome proliferator-activated receptor alpha (PPARα) agonists or peroxisome proliferator-activated receptor gamma (PPARγ) agonists have demonstrated utility in the reduction of alcohol intake in animal models. However, few studies have addressed the potential utility of combining these classes of drugs, especially because of expected safety problems. In the present work we took the advantage of the availability of two novel dual ligands for these receptors, to test the hypothesis that these types of drugs might reproduce and even improve the pharmacological profile of those drugs interacting with single targets. To this end we tested (R)-3-[(4-Benzyl-2-oxooxazolidin-3-yl)methyl]-N-[4-(dodecylcarbamoyl)phenyl]benzamide (NF 10-360), a dual PPARα/γ agonist, and N-[1-(3,4-dihydroxyphenyl)propan-2-yl]oleamide (OLHHA), a dual CB1 receptor antagonist/PPARα agonist, in animal models of alcohol consumption. Both drugs were effective in reducing alcohol intake and alcohol self-administration, being OLHHA a very potent alcohol intake inhibitor (EC 0.2 mg/kg). OLHHA also reduced self-administration of the opioid oxycodone. OLHHA actions on alcohol self-administration were replicated in alcohol-preferring Marchigian-Sardinian msP rats. Repeated administration of OLHHA did result neither in tolerance nor in toxicological or deleterious metabolic changes in the liver of msP rats. These data support the feasibility of developing novel dual ligands interacting with cannabinoid targets to treat alcohol use disorder in humans.
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http://dx.doi.org/10.1016/j.bcp.2018.09.008DOI Listing
November 2018

The adiponectin promoter activator NP-1 induces high levels of circulating TNFα and weight loss in obese (fa/fa) Zucker rats.

Sci Rep 2018 06 29;8(1):9858. Epub 2018 Jun 29.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga-Hospital Universitario Regional de Málaga, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010, Málaga, Spain.

Chronic NP-1 administration reduces body weight and hepatic steatosis despite induction of tolerance in adiponectin gene transcription with respect to the acute actions of this drug. This study explored the hypothesis that NP-1 could exert these effects through mechanisms independent of adiponectin. To this aim, we took advantage of the Zucker (fa/fa) rat model, which exhibits obesity, fatty liver and elevated leptin and adiponectin levels. Body weight and food intake were reduced after chronic NP-1 treatment. Plasma TNFα concentrations were elevated but no increase in adiponectin was found. Even so, NP-1 ameliorated fatty liver and corrected dyslipidemia by mechanisms probably associated with reduced feeding, transcription of Cpt1 and down-regulation of Hmgcr-CoA expression. In brown fat tissue NP-1 increased Dnmt1 (inhibitor of Adipoq) while it reduced Ucp1 expression and heat production, which excludes thermogenesis as a mechanism of the NP-1 slimming effect. The anti-obesity action of chronic NP-1 administration might be mediated by TNFα, which is known to have anorectic actions in the hypothalamus and to regulate both Dmnt1 and Ucp1 expression in adipose tissues. This finding opens up the possibility of using NP-1-mediated TNFα-induced weight loss as an innovative treatment of complicated obesity under strict pharmacologic control.
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http://dx.doi.org/10.1038/s41598-018-27871-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026175PMC
June 2018

A Positive Allosteric Modulator of the Serotonin 5-HT Receptor for Obesity.

J Med Chem 2017 12 17;60(23):9575-9584. Epub 2017 Nov 17.

Departamento de Química Orgánica I, Universidad Complutense de Madrid , E-28040 Madrid, Spain.

The 5-HTR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HTR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HTR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound 11 identified in this work supports the interest of a serotonin 5-HTR PAM as a promising therapeutic approach for obesity.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00994DOI Listing
December 2017

Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.

Front Pharmacol 2017 6;8:705. Epub 2017 Oct 6.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.

Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory -acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5-5-10-20 mM) and time-course (2-6-24 h) study in human HepG2 cells showed a biphasic response, with a decreased α expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (α, , and ), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of α and were decreased after 6 h of treatment and, after 24 h, the gene expression levels of and , as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (, αα, and )-related alterations observed after repeated APAP administration were aggravated in the liver of α-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.
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http://dx.doi.org/10.3389/fphar.2017.00705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635604PMC
October 2017

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner.

PLoS One 2017 27;12(3):e0174307. Epub 2017 Mar 27.

Departamento de Psicobiología. Facultad de Psicología, Universidad Complutense de Madrid. Campus de Somosaguas s/n, Pozuelo de Alarcón, Madrid, Spain.

Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174307PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367805PMC
September 2017

Effects of Intermittent Alcohol Exposure on Emotion and Cognition: A Potential Role for the Endogenous Cannabinoid System and Neuroinflammation.

Front Behav Neurosci 2017 7;11:15. Epub 2017 Feb 7.

Unidad de Gestion Clinica de Salud Mental, Instituto de Investigacion Biomedica de Malaga, Hospital Regional Universitario de Malaga, Universidad de Malaga Malaga, Spain.

Intermittent alcohol exposure is a common pattern of adolescent alcohol use that can lead to binge drinking episodes. Alcohol use is known to modulate the endocannabinoid system (ECS), which is involved in neuronal communication, neuroplasticity, neuroinflammation and behavior. Adolescent male Wistar rats were exposed to 4-week intermittent alcohol intoxication (3 g/kg injections for 4 days/week) or saline ( = 12 per group). After alcohol deprivation, adult rats were assessed for emotionality and cognition and the gene expression of the ECS and other factors related to behavior and neuroinflammation was examined in the brain. Alcohol-exposed rats exhibited anxiogenic-like responses and impaired recognition memory but no motor alterations. There were brain region-dependent changes in the mRNA levels of the ECS and molecular signals compared with control rats. Thus, overall, alcohol-exposed rats expressed higher mRNA levels of endocannabinoid synthetic enzymes (N-acyl-phosphatidylethanolamine phospholipase D and diacylglycerol lipases) in the medial-prefrontal cortex (mPFC) but lower mRNA levels in the amygdala. Furthermore, we observed lower mRNA levels of receptors CB CB and peroxisome proliferator-activated receptor-α in the striatum. Regarding neuropeptide signaling, alcohol-exposed rats displayed lower mRNA levels of the neuropeptide Y signaling, particularly NPY receptor-2, in the amygdala and hippocampus and higher mRNA levels of corticotropin-releasing factor in the hippocampus. Additionally, we observed changes of several neuroinflammation-related factors. Whereas, the mRNA levels of toll-like receptor-4, tumor necrosis factor-α, cyclooxygenase-2 and glial fibrillary acidic protein were significantly increased in the mPFC, the mRNA levels of cyclooxygenase-2 and glial fibrillary acidic protein were decreased in the striatum and hippocampus. However, nuclear factor-κβ mRNA levels were lower in the mPFC and striatum and allograft inflammatory factor-1 levels were differentially expressed in the amygdala and hippocampus. In conclusion, rats exposed to adolescent intermittent alcohol displayed anxiety-like behavior and cognitive deficits in adulthood and these alterations were accompanied by brain region-dependent changes in the gene expression of the ECS and other signals associated with neuroinflammation and behavior. An intermittent adolescent alcohol exposure has behavioral and molecular consequences in the adult brain, which might be linked to higher vulnerability to addictive behaviors and psychopathologies.
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http://dx.doi.org/10.3389/fnbeh.2017.00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293779PMC
February 2017

Plasma Chemokines in Patients with Alcohol Use Disorders: Association of CCL11 (Eotaxin-1) with Psychiatric Comorbidity.

Front Psychiatry 2016 18;7:214. Epub 2017 Jan 18.

Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga , Málaga , Spain.

Recent studies have linked changes in peripheral chemokine concentrations to the presence of both addictive behaviors and psychiatric disorders. The present study further explore this link by analyzing the potential association of psychiatry comorbidity with alterations in the concentrations of circulating plasma chemokine in patients of both sexes diagnosed with alcohol use disorders (AUD). To this end, 85 abstinent subjects with AUD from an outpatient setting and 55 healthy subjects were evaluated for substance and mental disorders. Plasma samples were obtained to quantify chemokine concentrations [C-C motif (CC), C-X-C motif (CXC), and C-X-C motif (CXC) chemokines]. Abstinent AUD patients displayed a high prevalence of comorbid mental disorders (72%) and other substance use disorders (45%). Plasma concentrations of chemokines CXCL12/stromal cell-derived factor-1 ( < 0.001) and CXCL1/fractalkine ( < 0.05) were lower in AUD patients compared to controls, whereas CCL11/eotaxin-1 concentrations were strongly decreased in female AUD patients ( < 0.001). In the alcohol group, CXCL8 concentrations were increased in patients with liver and pancreas diseases and there was a significant correlation to aspartate transaminase ( = +0.456,  < 0.001) and gamma-glutamyltransferase ( = +0.647,  < 0.001). Focusing on comorbid psychiatric disorders, we distinguish between patients with additional mental disorders ( = 61) and other substance use disorders ( = 38). Only CCL11 concentrations were found to be altered in AUD patients diagnosed with mental disorders ( < 0.01) with a strong main effect of sex. Thus, patients with mood disorders ( = 42) and/or anxiety ( = 16) had lower CCL11 concentrations than non-comorbid patients being more evident in women. The alcohol-induced alterations in circulating chemokines were also explored in preclinical models of alcohol use with male Wistar rats. Rats exposed to repeated ethanol (3 g/kg, gavage) had lower CXCL12 ( < 0.01) concentrations and higher CCL11 concentrations ( < 0.001) relative to vehicle-treated rats. Additionally, the increased CCL11 concentrations in rats exposed to ethanol were enhanced by the prior exposure to restraint stress ( < 0.01). Concordantly, acute ethanol exposure induced changes in CXCL12, CXCL1, and CCL11 in the same direction to repeated exposure. These results clearly indicate a contribution of specific chemokines to the phenotype of AUD and a strong effect of sex, revealing a link of CCL11 to alcohol and anxiety/stress.
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http://dx.doi.org/10.3389/fpsyt.2016.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242327PMC
January 2017

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators.

Front Behav Neurosci 2016 27;10:241. Epub 2016 Dec 27.

Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain.

Maternal malnutrition causes long-lasting alterations in feeding behavior and energy homeostasis in offspring. It is still unknown whether both, the endocannabinoid (eCB) machinery and the lipid metabolism are implicated in long-term adaptive responses to fetal reprogramming caused by maternal undernutrition. We investigated the long-term effects of maternal exposure to a 20% standard diet restriction during preconceptional and gestational periods on the metabolically-relevant tissues hypothalamus, liver, and perirenal fat (PAT) of male and female offspring at adulthood. The adult male offspring from calorie-restricted dams (RC males) exhibited a differential response to the CB1 antagonist AM251 in a chocolate preference test as well as increased body weight, perirenal adiposity, and plasma levels of triglycerides, LDL, VLDL, bilirubin, and leptin. The gene expression of the cannabinoid receptors and was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (αβ) and several key regulators of fatty-acid β-oxidation (), mitochondrial respiration (), and lipid flux (γ) was found in their PAT. The female offspring from calorie-restricted dams exhibited higher plasma levels of LDL and glucose as well as a reduction in chocolate and caloric intake at post-weaning periods in the feeding tests. Their liver showed a decreased gene expression of α, γ, the eCBs-degrading enzymes and , the lipogenic enzymes and , and the liver-specific cholesterol biosynthesis regulators and . Our results suggest that the long-lasting adaptive responses to maternal caloric restriction affected cannabinoid-regulated mechanisms involved in feeding behavior, adipose β-oxidation, and hepatic lipid and cholesterol biosynthesis in a sex-dependent manner.
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http://dx.doi.org/10.3389/fnbeh.2016.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187359PMC
December 2016

Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring.

Front Behav Neurosci 2016 1;10:208. Epub 2016 Nov 1.

Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de MadridMadrid, Spain; Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de MálagaMálaga, Spain.

Exposure to inadequate nutritional conditions in critical windows of development has been associated to disturbances on metabolism and behavior in the offspring later in life. The role of the endocannabinoid system, a known regulator of energy expenditure and adaptive behaviors, in the modulation of these processes is unknown. In the present study, we investigated the impact of exposing rat dams to diet restriction (20% less calories than standard diet) during pre-gestational and gestational periods on: (a) neonatal outcomes; (b) endocannabinoid content in hypothalamus, hippocampus and olfactory bulb at birth; (c) metabolism-related parameters; and (d) behavior in adult male offspring. We found that calorie-restricted dams tended to have a reduced litter size, although the offspring showed normal weight at birth. Pups from calorie-restricted dams also exhibited a strong decrease in the levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG), arachidonic acid (AA) and palmitoylethanolamide (PEA) in the hypothalamus at birth. Additionally, pups from diet-restricted dams displayed reduced levels of AEA in the hippocampus without significant differences in the olfactory bulb. Moreover, offspring exhibited increased weight gain, body weight and adiposity in adulthood as well as increased anxiety-related responses. We propose that endocannabinoid signaling is altered by a maternal caloric restriction implemented during the preconceptional and pregnancy periods, which might lead to modifications of the hypothalamic and hippocampal circuits, potentially contributing to the long-term effects found in the adult offspring.
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http://dx.doi.org/10.3389/fnbeh.2016.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088205PMC
November 2016

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring.

PLoS One 2016 2;11(11):e0165432. Epub 2016 Nov 2.

Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010, Málaga, Spain.

Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165432PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091916PMC
June 2017

Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats.

PLoS One 2016;11(9):e0163752. Epub 2016 Sep 23.

Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense, Madrid, Spain.

Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats with a strong sexual dimorphism. The potential impact of these alterations in early adulthood remains to be elucidated.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035052PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163752PLOS
September 2016

Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice.

PLoS One 2016 22;11(6):e0157956. Epub 2016 Jun 22.

Laboratorio de Investigación, IBIMA, Hospital Regional Universitario de Málaga, 29010, Málaga, Spain.

High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157956PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917096PMC
July 2017

Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators.

Biofactors 2016 Nov 23;42(6):600-611. Epub 2016 May 23.

UGC Salud Mental, Instituto De Investigación Biomédica De Málaga (IBIMA), Universidad De Málaga-Hospital Universitario Regional De Málaga, Avda. Carlos Haya 82, Pabellón De Gobierno, Málaga, Spain.

To investigate the role of glucagon-like-peptide-1 receptor (GLP-1R) in peripheral lipid metabolism. Both lean and high-fat diet (HFD)-induced obesity (DIO) rats were used to compare the peripheral effects of the subcutaneous and repeated administration of the GLP-1R agonist liraglutide on the expression of key regulators involved in lipid metabolism, β-oxidation and thermogenesis in liver, abdominal muscle, and epididymal white adipose tissue (eWAT). We observed that liraglutide reduced caloric intake, body weight, and plasma levels of triglycerides and VLDL in a diet-independent manner. However, changes in liver fat content and the expression of lipid metabolism regulators were produced in a diet and tissue-dependent manner. In lean rats, liraglutide increased the gene/protein expression of elements involved in lipogenesis (ChREBP, Acaca/ACC, Fasn/FAS, Scd1/SCD1, PPARα/γ), β-oxidation (CPT1b), and thermogenesis (Cox4i1, Ucp1/UCP1) in eWAT and muscle, which suggest an increase in fatty-acid flux and utilization to activate energy expenditure. Regarding DIO rats, the specific reduction of liver lipid content by liraglutide was associated with a decreased expression of main elements involved in lipogenesis (phospho-ACC), peroxisomal β-oxidation (ACOX1), and lipid flux/storage (Pparγ/PPARγ) in liver, which suggest a recovery of lipid homeostasis. Interestingly, the muscle of DIO rats treated with liraglutide showed a decreased expression of PPARγ and the thermogenic factor UCP1. These results help us to better understand the peripheral mechanisms regulating lipid metabolism that underlay the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity. © 2016 BioFactors, 42(6):600-611, 2016.
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http://dx.doi.org/10.1002/biof.1295DOI Listing
November 2016

Benzyl-1,2,4-triazoles as CB 1 Cannabinoid Receptor Ligands: Preparation and In Vitro Pharmacological Evaluation.

Int J Med Chem 2016 31;2016:1257098. Epub 2016 Mar 31.

Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.
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http://dx.doi.org/10.1155/2016/1257098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834188PMC
April 2016

Environmental Enrichment, Age, and PPARα Interact to Regulate Proliferation in Neurogenic Niches.

Front Neurosci 2016 9;10:89. Epub 2016 Mar 9.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga-Hospital Universitario Regional de Málaga Málaga, Spain.

Peroxisome proliferator-activated receptor alpha (PPARα) ligands have been shown to modulate recovery after brain insults such as ischemia and irradiation by enhancing neurogenesis. In the present study, we investigated the effect of the genetic deletion of PPARα receptors on the proliferative rate of neural precursor cells (NPC) in the adult brain. The study was performed in aged Pparα(-/-) mice exposed to nutritional (treats) and environmental (games) enrichments for 20 days. We performed immunohistochemical analyses of cells containing the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) and the immature neuronal marker doublecortin (Dcx+) in the main neurogenic zones of the adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ), and/or hypothalamus. Results indicated a reduction in the number of BrdU+ cells in the neurogenic zones analyzed as well as Dcx+ cells in the SGZ during aging (2, 6, and 18 months). Pparα deficiency alleviated the age-related reduction of NPC proliferation (BrdU+ cells) in the SVZ of the 18-months-old mice. While no genotype effect on NPC proliferation was detected in the SGZ during aging, an accentuated reduction in the number of Dcx+ cells was observed in the SGZ of the 6-months-old Pparα(-/-) mice. Exposing the 18-months-old mice to nutritional and environmental enrichments reversed the Pparα(-/-)-induced impairment of NPC proliferation in the neurogenic zones analyzed. The enriched environment did not modify the number of SGZ Dcx+ cells in the 18 months old Pparα(-/-) mice. These results identify PPARα receptors as a potential target to counteract the naturally observed decline in adult NPC proliferation associated with aging and impoverished environments.
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http://dx.doi.org/10.3389/fnins.2016.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783391PMC
March 2016

Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

Eur Neuropsychopharmacol 2016 Mar 7;26(3):477-92. Epub 2016 Jan 7.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Avda. Carlos Haya 82, 29010, Málaga, Spain. Electronic address:

In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could contribute to the specifically increased GluN1 expression observed in the hippocampus of cocaine-sensitized mice.
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http://dx.doi.org/10.1016/j.euroneuro.2015.12.040DOI Listing
March 2016

Exposure to a Highly Caloric Palatable Diet During Pregestational and Gestational Periods Affects Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Adiposity and Anxiety-Like Behaviors in Male Rat Offspring.

Front Behav Neurosci 2015 6;9:339. Epub 2016 Jan 6.

Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid Madrid, Spain.

Exposure to unbalanced diets during pre-gestational and gestational periods may result in long-term alterations in metabolism and behavior. The contribution of the endocannabinoid system to these long-term adaptive responses is unknown. In the present study, we investigated the impact of female rat exposure to a hypercaloric-hypoproteic palatable diet during pre-gestational, gestational and lactational periods on the development of male offspring. In addition, the hypothalamic and hippocampal endocannabinoid contents at birth and the behavioral performance in adulthood were investigated. Exposure to a palatable diet resulted in low weight offspring who exhibited low hypothalamic contents of arachidonic acid and the two major endocannabinoids (anandamide and 2-arachidonoylglycerol) at birth. Palmitoylethanolamide, but not oleoylethanolamide, also decreased. Additionally, pups from palatable diet-fed dams displayed lower levels of anandamide and palmitoylethanolamide in the hippocampus. The low-weight male offspring, born from palatable diet exposed mothers, gained less weight during lactation and although they recovered weight during the post-weaning period, they developed abdominal adiposity in adulthood. These animals exhibited anxiety-like behavior in the elevated plus-maze and open field test and a low preference for a chocolate diet in a food preference test, indicating that maternal exposure to a hypercaloric diet induces long-term behavioral alterations in male offspring. These results suggest that maternal diet alterations in the function of the endogenous cannabinoid system can mediate the observed phenotype of the offspring, since both hypothalamic and hippocampal endocannabinoids regulate feeding, metabolic adaptions to caloric diets, learning, memory, and emotions.
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http://dx.doi.org/10.3389/fnbeh.2015.00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701936PMC
January 2016

Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle.

PLoS One 2015 15;10(12):e0145244. Epub 2015 Dec 15.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga-Hospital Universitario Regional de Málaga, Málaga, Spain.

Cannabinoid CB1 receptors peripherally modulate energy metabolism. Here, we investigated the role of CB1 receptors in the expression of glucose/pyruvate/tricarboxylic acid (TCA) metabolism in rat abdominal muscle. Dihydrolipoamide dehydrogenase (DLD), a flavoprotein component (E3) of α-ketoacid dehydrogenase complexes with diaphorase activity in mitochondria, was specifically analyzed. After assessing the effectiveness of the CB1 receptor antagonist AM251 (3 mg kg(-1), 14 days) on food intake and body weight, we could identified seven key enzymes from either glycolytic pathway or TCA cycle--regulated by both diet and CB1 receptor activity--through comprehensive proteomic approaches involving two-dimensional electrophoresis and MALDI-TOF/LC-ESI trap mass spectrometry. These enzymes were glucose 6-phosphate isomerase (GPI), triosephosphate isomerase (TPI), enolase (Eno3), lactate dehydrogenase (LDHa), glyoxalase-1 (Glo1) and the mitochondrial DLD, whose expressions were modified by AM251 in hypercaloric diet-induced obesity. Specifically, AM251 blocked high-carbohydrate diet (HCD)-induced expression of GPI, TPI, Eno3 and LDHa, suggesting a down-regulation of glucose/pyruvate/lactate pathways under glucose availability. AM251 reversed the HCD-inhibited expression of Glo1 and DLD in the muscle, and the DLD and CB1 receptor expression in the mitochondrial fraction. Interestingly, we identified the presence of CB1 receptors at the membrane of striate muscle mitochondria. DLD over-expression was confirmed in muscle of CB1-/- mice. AM251 increased the pyruvate dehydrogenase and glutathione reductase activity in C2C12 myotubes, and the diaphorase/oxidative activity in the mitochondria fraction. These results indicated an up-regulation of methylglyoxal and TCA cycle activity. Findings suggest that CB1 receptors in muscle modulate glucose/pyruvate/lactate pathways and mitochondrial oxidative activity by targeting DLD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145244PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682857PMC
June 2016

Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.

Dis Model Mech 2015 Oct;8(10):1213-25

Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1242/dmm.019919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610231PMC
October 2015

Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice.

Dis Model Mech 2015 Jul 14;8(7):721-31. Epub 2015 May 14.

Laboratorio de Investigación, IBIMA/Universidad de Málaga, 29010 Málaga, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII) and Ministerio de Ciencia e Innovación (MICINN), Spain Unidad de Gestión Clínica de Salud Mental, Hospital Universitario Regional de Málaga, 29010 Málaga, Spain

Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL-6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6(-/-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCα/β), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCα/β, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis.
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http://dx.doi.org/10.1242/dmm.019166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486858PMC
July 2015
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