An update on the exploratory use of curcumin in neuropsychiatric disorders

This article belongs to the Special Issue Dietary Antioxidants against Neurodegenerative Diseases.Curcumin is a polyphenol extracted from the rhizome of the turmeric plant. Beyond its common use as a culinary spice in Eastern Asia, curcumin has been proposed as a therapeutic compound due to its antioxidant, anti-inflammatory and neuroprotective properties. Thus, its efficacy has been evaluated in various inflammatory-based psychiatric disorders, such as schizophrenia, depression, or autism. Our aim is to review those preclinical and clinical studies carried out in psychiatric disorders whose therapeutic approach has involved the use of curcumin and, therefore, to discern the possible positive effect of curcumin in these disorders. Preclinical studies and completed clinical trials of curcumin for psychiatric disorders published from January 2005 to October 2021 were identified through searching relevant databases until 31st October 2021. Sixty-five preclinical studies and 15 clinical trials and open-label studies were selected. Results showed a bias toward studies in depression and, to a lesser extent, schizophrenia. In all disorders, the results were positive in reducing psychiatric deficits. Despite the considerable number of beneficial outcomes reported, the small number of trials and the heterogeneity of protocols make it difficult to draw solid conclusions about the real potency of curcumin in psychiatric disorders.M.L.S.-M. was supported by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (project number PI17/01766, and grant number BA21/00030), co-financed by the European Regional Development Fund (ERDF), "A way to make Europe", CIBER de Salud Mental (project number CB07/09/0031), Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); and Fundación Alicia Koplowitz (FAK16/01). D.R.-M. was supported by Consejería de Educación e investigación, Comunidad de Madrid, co-funded by the European Social Fund "Investing in your future" (grant, PEJD-2018-PRE/BMD-7899). N.L.-R. was supported by the Instituto de investigación Sanitaria Gregorio Marañón, "Programa Intramural de Impulso a la I+D+I 2019". The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)

The Poly I:C maternal immune stimulation model shows unique patterns of brain metabolism, morphometry, and plasticity in female rats

Introduction: Prenatal infections are associated with an increased risk of the onset of schizophrenia. Rodent models of maternal immune stimulation (MIS) have been extensively used in preclinical studies. However, many of these studies only include males, omitting pathophysiological features unique to females. The aim of this study is to characterize the MIS model in female rats using positron emission tomography (PET), structural magnetic resonance imaging (MR), and neuroplasticiy studies. Methods: In gestational day 15, Poly I:C (or Saline) was injected into pregnant Wistar rats to induce the MIS model. Imaging studies: [18F]-fluoro-2-deoxy-D-glucose-PET scans of female-offspring were acquired at post-natal day (PND) 35 and PND100. Furthermore, T2-MR brain images were acquired in adulthood. Differences in FDG uptake and morphometry between groups were assessed with SPM12 and Regions of Interest (ROI) analyses. Ex vivo study: The density of parvalbumin expressing interneurons (PV), perineuronal nets (PNN), and parvalbumin expressing interneurons surrounded by perineuronal nets (PV-PNN) were evaluated in the prelimbic cortex and basolateral amygdala using confocal microscopy. ROIs and neuroplasticity data were analyzed by 2-sample T-test and 2-way-ANOVA analyses, respectively. Results: A significant increase in brain metabolism was found in all animals at adulthood compared to adolescence. MIS hardly modified brain glucose metabolism in females, highlighting a significant hypometabolism in the thalamus at adulthood. In addition, MIS induced gray matter (GM) enlargements in the pituitary, hippocampus, substantia nigra, and cingulate cortex, and GM shrinkages in some thalamic nuclei, cerebelar areas, and brainstem. Moreover, MIS induced white matter shrinkages in the cerebellum, brainstem and corpus callosum, along with cerebrospinal fluid enlargements in the lateral and 4th ventricles. Finally, MIS reduced the density of PV, PNN, and PV-PNN in the basolateral amygdala. Conclusion: Our work showed in vivo the differential pattern of functional and morphometric affectation in the MIS model in females, as well as the deficits caused at the synaptic level according to sex. The differences obtained highlight the relevance of including both sexes in psychiatric research in order to consider their pathophysiological particularities and successfully extend the benefits obtained to the entire patient population.MS-M was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI17/01766, BA21/0030); co-financed by European Regional Development Fund (ERDF), “A way to make Europe”; project PID2021_128862OB-I00 funded by MCIN/AEI/10.13039/501100011033/FEDER, UE; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM; project number CB07/09/0031); Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085); and Fundación Alicia Koplowitz. MC-V was supported by Fundación Tatiana Pérez de Guzmán el Bueno as scholarship holder of this institution, and EU Joint Programme—Neurodegenerative Disease Research (JPND). DR-M was supported by Consejería de Educación e Investigación, Comunidad de Madrid, co-funded by European Social Fund “Investing in your future” (grant number PEJD-2018-PRE/BMD-7899). NL-R was supported by Instituto de Investigación Sanitaria Gregorio Marañón, “Programa Intramural de Impulso a la I+D+I 2019”. MD’s work was supported by Ministerio de Ciencia e Innovación (MCIN) and Instituto de Salud Carlos III (PT20/00044). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). JN was supported by the project RTI2018-098269-B-I00 and PID2021-127595OB-I00 financed by the Spanish Ministry of Science and Innovation/AEI/10.13039/501100011033/(“FEDER Una manera de hacer Europa”) and the Generalitat Valenciana (PROMETEU/2020/024)

The effects of mango leaf extract during adolescence and adulthood in a rat model of schizophrenia

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60–70) or adolescent (postnatal day 35–49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk

The effects of mango leaf extract during adolescence and adulthood in a rat model of schizophrenia.

There is evidence that in schizophrenia, imbalances in inflammatory and oxidative processes occur during pregnancy and in the early postnatal period, generating interest in the potential therapeutic efficacy of anti-inflammatory and antioxidant compounds. Mangiferin is a polyphenolic compound abundant in the leaves of Mangifera indica L. that has robust antioxidant and anti-inflammatory properties, making it a potential candidate for preventive or co-adjuvant therapy in schizophrenia. Hence, this study set-out to evaluate the effect of mango leaf extract (MLE) in a model of schizophrenia based on maternal immune activation, in which Poly I:C (4 mg/kg) is administered intravenously to pregnant rats. Young adult (postnatal day 60-70) or adolescent (postnatal day 35-49) male offspring received MLE (50 mg/kg of mangiferin) daily, and the effects of MLE in adolescence were compared to those of risperidone, assessing behavior, brain magnetic resonance imaging (MRI), and oxidative/inflammatory and antioxidant mediators in the adult offspring. MLE treatment in adulthood reversed the deficit in prepulse inhibition (PPI) but it failed to attenuate the sensitivity to amphetamine and the deficit in novel object recognition (NOR) induced. By contrast, adolescent MLE treatment prevented the sensorimotor gating deficit in the PPI test, producing an effect similar to that of risperidone. This MLE treatment also produced a reduction in grooming behavior, but it had no effect on anxiety or novel object recognition memory. MRI studies revealed that adolescent MLE administration partially counteracted the cortical shrinkage, and cerebellum and ventricle enlargement. In addition, MLE administration in adolescence reduced iNOS mediated inflammatory activation and it promoted the expression of biomarkers of compensatory antioxidant activity in the prefrontal cortex and hippocampus, as witnessed through the reduction of Keap1 and the accumulation of NRF2 and HO1. Together, these findings suggest that MLE might be an alternative therapeutic or preventive add-on strategy to improve the clinical expression of schizophrenia in adulthood, while also modifying the time course of this disease at earlier stages in populations at high-risk.EB, JAG-P and ST-S work was supported by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Economía y Competitividad” (RTI2018-099778-B-I00); from the “Plan Nacional sobre Drogas, Ministerio de Sanidad, Consumo y Bienestar Social” (2019I041); from the “Ministerio de Salud-Instituto de Salud Carlos III” (PI18/01691); from the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud y Familias, Junta de Andalucía” (PI-0080- 2017, PI-0009-2017), “Consejería de Salud y Familias, Junta de Andalucía” (PI-0134-2018 and PEMP-0008-2020); from the “Consejería de Transformación Económica, Industria, Conocimiento y Universidad, Junta de Andalucía” (P20_00958 and CTS-510); from the CEIMAR (CEIJ-003); from the “Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz-INiBICA” (LI19/06IN-CO22; IN-C09); from the “CIBERSAM”: CIBER-Consorcio Centro de Investigación Biomédica en Red- (CB07/09/0033), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 955684. CM, LC and MTF-P were supported by the Spanish Ministry of Science and Technology (PID2020- 116229RB-I00) and European Regional Development Fund (ERDF). KM and JCL were supported by the “MICINN” (PID2019-109033RB-I00) and the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/ 09/0026), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. MLS-M was supported by the “Ministerio de Ciencia, Innovación, Instituto de Salud Carlos III” (PI17/ 01766, BA21/00030), co-financed by European Regional Development Fund (ERDF), “A way to make Europe”; from the “CIBERSAM”: CIBERConsorcio Centro de Investigación Biomédica en Red- (CB07/09/0031), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación; from the “Delegación del Gobierno para el Plan Nacional sobre Drogas” (2017/085); from the “Fundación Mapfre” and “Fundación Alicia Koplowitz.” MD work was supported by the “Ministerio de Ciencia e In review 18/ 28 Innovación” (MCIN) and “Instituto de Salud Carlos III” (ISCIII) (PT20/00044); from the “CIBERSAM” CIBERConsorcio Centro de Investigación Biomédica en Red-(CB07/ 09/0031). The CNIC is supported by the ISCIII, the MCIN and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome.

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.This work has been funded by the Spanish Ministry of Economy and Competitiveness (Project no.: PSI2016-80541-P to EA and AH-M); Ministry of Science (PID2019- 104523RB-I00 to A-HM and PID2019-111594RB-100 to EA), Spanish Ministry of Health, Social Services and Equality (Network of Addictive Disorders - Project no.: RTA-RD16/ 020/0022 of the Institute of Health Carlos III and National Plan on Drugs, Project no.: 2016I073 to EA and 2017I042 to A H-M); The BBVA Foundation (Leonardo Grants) to AH-M; The European Union (Project no.: JUST- 2017- AG- DRUG-806996-JUSTSO) to EA; and the UNED (Plan for the Promotion of Research) to EA and AH-M. MLS-M was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (project PI17/01766), co-financed by the European Regional Development Fund (ERDF), ‘A way to make Europe’; project PID2021-128862OB-I00 funded by MCIN/AEI/ 10.13039/501100011033/FEDER, UE, CIBER de Salud Mental - Instituto de Salud Carlos III (project number CB07/09/0031); Delegación del Gobierno para el Plan Nacional sobre Drogas (project number 2017/085, 2022/008917); and Fundación Alicia Koplowitz. Fundación Tatiana Pérez de Guzmán el Bueno supported MC-V. MD’s work was supported by Ministerio de Ciencia e Innovación (MCIN) and Instituto de Salud Carlos III (PT20/00044). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence

Marijuana consumption during adolescence has been proposed to be a stepping stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self administration (1 mg/kg), food reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F] fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP treated rats showed a higher rate of cocaine self administration as compared to vehicle treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food reinforced operant task, pointing to the cocaine specific nature of the effect seen in self administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP treated females when compared to their vehicle treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self administration, in a sex specific fashion. This increased susceptibility could be related to thechanges in brain metabolic activity induced by cannabinoids during adolescenceThis work was supported by Grants FIS G03/05 (Red de Trastornos Adictivos), BSO2001-1099, FIS 01-05-01, Plan Nacional sobre Drogas (PNSD) 2001–2003, PNSD 2004–2007, GR-SAL/0260/2004 to EA and Grants INT/2012/ 2002, CB06/01/0079, and CENIT (2006–2009) to MDPublicad

Aprendizajes y trayectorias del sector agroalimentario mexicano durante el TLCAN

Ante la firma del Tratado México, Estados Unidos y Canadá (T-MEC), es importante hacer un balance de los efectos que dejó tras de sí el Tratado de Libre Comercio de América del Norte (TLCAN) en el sector agropecuario. Por ello, connotados especialistas analizan factores socioeconómicos del sistema agroalimentario mexicano en el contexto de las relaciones comerciales con Estados Unidos y Canadá. Los 10 estudios que contiene el libro Aprendizajes y trayectorias del sector agroalimentario mexicano durante el TLCAN son de gran valía para la obtención de conocimiento especializado para comprender críticamente las lógicas, trayectorias, evolución y comportamientos de las cadenas productivas a la luz de la firma de los tratados comerciales de América del Norte, así como sus efectos en el campo mexicano, territorios rurales y consumidoresFinanciación del Instituto Interamericano de Cooperación para la Agricultura en colaboración con autore

Understanding Deep Brain Stimulation: In Vivo Metabolic Consequences of the Electrode Insertional Effect

Deep brain stimulation (DBS) is a neurosurgery technique widely used in movement disorders, although its mechanism of action remains unclear. In fact, apart from the stimulation itself, the mechanical insertion of the electrode may play a crucial role. Here we aimed to distinguish between the insertional and the DBS effects on brain glucose metabolism. To this end, electrodes were implanted targeting the medial prefrontal cortex in five adult male Wistar rats. Positron Emission Tomography (PET) studies were performed before surgery (D0) and seven (D7) and nine days (D9) after that. DBS was applied during the 18FDG uptake of the D9 study. PET data were analysed with statistical parametric mapping. We found an electrode insertional effect in cortical areas, while DBS resulted in a more widespread metabolic pattern. The consequences of simultaneous electrode and DBS factors revealed a combination of both effects. Therefore, the insertion metabolic effects differed from the stimulation ones, which should be considered when assessing DBS protocols

MosaicExplorerJ: Interactive stitching of terabyte-size tiled datasets from lightsheet microscopy [version 2; peer review: 2 approved]

© 2020 Tosi S et al.We introduce MosaicExplorerJ, an ImageJ macro to stitch 3D tiles from terabyte-size microscopy datasets. As opposed to existing software, stitching does not require any prior information on the actual positions of the tiles, sample fiducials, or conversion of raw TIFF images, and the stitched images can be explored instantly. MosaicExplorerJ was specifically designed to process lightsheet microscopy datasets from optically cleared samples. It can handle multiple fluorescence channels, dual-side lightsheet illumination and dual-side camera detection.The preparation of some of the datasets that were used to test MosaicExplorerJ was partially funded by project TEC2016-78052-R from the Spanish Ministry of Economy and Competitiveness and RTC2017-6600-1 from Ministry of Science, Innovation and Universities, as well as project PI17/01766 from Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (co-financed by European Regional Development Fund (ERDF), “A way of making Europe")

MosaicExplorerJ: Interactive stitching of terabyte-size tiled datasets from lightsheet microscopy

© 2021 Tosi S et al.We introduce MosaicExplorerJ, an ImageJ macro to stitch 3D tiles from terabyte-size microscopy datasets organized on a regular 2D grid. As opposed to existing software, stitching does not require any prior information on the actual positions of the tiles, or conversion of raw TIFF images to a multi-resolution format for interactive exploration and fast processing. MosaicExplorerJ was specifically designed to process lightsheet microscopy datasets from optically cleared samples. It can handle multiple fluorescence channels, dual-sided lightsheet illumination and dual-sided camera detection.This publication was supported by COST Action NEUBIAS (CA15124), funded by COST (European Cooperation in Science and Technology). MJB acknowledges the support of Jérôme Lejeune Foundation. : The preparation of some of the datasets that were used to test MosaicExplorerJ was partially funded by project TEC2016-78052-R from the Spanish Ministry of Economy and Competitiveness and RTC2017-6600-1 from Ministry of Science, Innovation and Universities, as well as project PI17/01766 from Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III (cofinanced by European Regional Development Fund (ERDF), “A way of making Europe")