Kannabisaren terapia erabilera

Kalamua aspaldidanik erabili da kultura eta garai ezberdinetan zenbait gaixotasuni aurre egiteko. Lan honetan, zientziaren ikuspuntu zientifiko batetik jorratuko dugu kannabisaren eta bere eratorkinen terapia erabilera, gaur egun dauden ebidentzia zientifikoak azalduz

Kannabisaren terapia erabilera

Kalamua aspaldidanik erabili da kultura eta garai ezberdinetan zenbait gaixotasuni aurre egiteko. Lan honetan, zientziaren ikuspuntu zientifiko batetik jorratuko dugu kannabisaren eta bere eratorkinen terapia erabilera, gaur egun dauden ebidentzia zientifikoak azalduz

Alkohola edatearen eragina garun nerabean

Alcohol consumption is very accepted and highly developed in our society; and its overconsume has economic, social and health consequences. In most cases the onset of consumption occurs during adolescence. Since, the brain is an organ that is still maturing, it is clear that alcohol consumption has consequences for its development. Due to its biological characteristics, the adolescent brain is not able to foresee the consequences of an action. This increases the risk for consumption of alcohol and other addictive substances. Therefore, it is necessary to make adolescents aware of the harmful consequences of excessive alcohol consumption, so that they can change their consumption pattern. For this purpose, in the present work we begin explaining the consequences of excessive alcohol consumption in the adult brain, and some characteristics of the adolescent brain, to end with the consequences of drinking in the adolescent brain.; Jakina da gure gizartean alkoholaren kontsumoa oso hedatuta eta onartuta dagoela; eta horren gehiegizko kontsumoak eragin ekonomikoak, sozialak eta osasunekoak ditu. Gehienetan alkoholaren lehendabiziko kontsumoa nerabezaroan gertatzen da. Jakinda garun nerabea heltzen ari den organoa dela, argi dago alkoholaren kontsumoak eraginak dituela haren garapenean. Haren ezaugarri biologikoak direla eta, garun nerabeak ez du gaitasun nahikoa ekintzen ondorioak aurreikusteko, eta horrek handitu egiten du alkoholaz gain beste droga batzuk gehiegi kontsumitzeko arriskua. Beraz, beharrezkoa egiten da nerabeei ezagutaraztea zeintzuk diren alkohola edatearen eragin kaltegarriak, beren kontsumo patroia alda dezaten. Horretarako, lan honetan alkoholaren gehiegizko kontsumoak garun helduan dituen eraginak azaltzen hasten gara, eta garun nerabean dituen eraginak azalduz amaituko dugu, tartean garun nerabeak dituen hainbat ezaugarri aipatuz

Characterization of dopamine D2 receptor coupling to G proteins in postmortem brain of subjects with schizophrenia

Background: Alterations of dopamine D-1 (D1R) and D-2 receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects. Methods: G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [S-35]GTP gamma S-binding stimulation induced by increasing concentrations (10(-10)-10(-3) M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration-response curves to NPA stimulation of [S-35]GTP gamma S binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17). Results: In caudate, [S-35]GTP gamma S-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [S-35]GTP gamma S-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC50H = 7.94 nM; EC50L = 7.08 mu M) and control (EC50H = 7.24 nM; EC50L = 15.14 mu M) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters. Conclusions: Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [S-35]GTP gamma S-binding assays appears to be restricted to signalling through inhibitory G(i/o) proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder.This work was supported by the Spanish State Research Agency and EDR Funds (SAF-2017-88126-R to JJM;PID2019-106404RB-100 to LFC), the Basque Government (IT1211/19 to JJM ; ELKARTEK Programme KK-2019/00049 to RD-A), and the National Institutes of Health (R01MH084894 & NIH-R01MH111940 to JG-M)

Oral and Palmitate Paliperidone Long-Acting Injectable Formulations’ Use in Schizophrenia Spectrum Disorders: A Retrospective Cohort Study from the First Episode Psychosis Intervention Program (CRUPEP)

Background: Long-acting injectable antipsychotics (LAIs) may be a suitable therapeutic option for those patients in earlier stages of psychosis to avoid relapses and disease progression. Despite that, there is a lack of evidence in the literature regarding the use of LAIs in this profile of patients. Methods: This is a retrospective cohort analysis to assess the efficacy, tolerability, and pattern of use of palmitate paliperidone long-acting injectable (PPLAI) formulations (1- and 3-month doses) compared to oral paliperidone/risperidone in patients with a nonaffective first episode of psychosis (FEP) over 12 months of follow-up. Relevant sociodemographic and clinical information were assessed, as well as main clinical scales: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, and Clinical Global Impression Scale Improvement and Severity measures. Results: The study included 48 patients, 16 per arm, who were aged 20-50 years and had an FEP. Significant improvements were registered for all treatment groups. Despite that, patients receiving PPLAI 1- and 3-month formulations obtained greater improvements than those in the oral group in the main domains assessed (P < .001). We found no statistically significant differences in hospitalizations between groups. Side effects were presented in 24% of patients. A trend towards reducing antipsychotic doses was observed in 43.8% of patients to achieve the minimum effective dose and avoid the occurrence of side effects. Conclusions: To our knowledge, this is the first study assessing the use of palmitate paliperidone long-acting formulations versus oral risperidone or paliperidone in FEP. Treatment with PPLAI formulations seems to be an effective therapeutic choice at earlier stages of the disease

Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Background: Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive. Methods: This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design. Results: No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (- 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression. Conclusion: Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.This work was supported by the Instituto de Salud Carlos III and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Plan Estatal de I+D+i 2013-2016 (FIS-PI13/01102 and SAF2016-75500-R to JCL), the Agencia Estatal de Investigacion (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-83053-R to JRC), the Basque Government (IT-616-13), CIBERSAM and the EDR Funds. JRC and BGB are Ramon y Cajal fellows (MINECO)

The endocannabinoid system in mental disorders: Evidence from human brain studies

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CBI receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487)

Glucocorticoid receptor dysregulation underlies 5-HT2AR-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model.

Prenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with polyinosinic-polycytidylic acid potassium salt as a mouse MIA model, we show here that upregulation of the serotonin 5-HT2A receptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the 5-HT2AR promoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulation of GR translocation in frontal cortex of schizophrenia subjects. We also found that repeated corticosterone administration augmented frontal cortex 5-HT2AR expression and reduced GR binding to the 5-HT2AR promoter. However, virally (adeno-associated virus) mediated augmentation of GR function reduced frontal cortex 5-HT2AR expression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and 5-HT2AR expression in the mouse frontal cortex that may carry implications for the pathophysiology underlying 5-HT2AR dysregulation in neurodevelopmental psychiatric disorders.National Institutes of Health R01MH084894 (to J. G.-M.), R01MH111940 (to J. G.-M.), NIH-N01DA-17-8932 (to P. M. B.), NIH-N01DA-19-8949 (to P. M. B.), and F30MH116550 (to J. M. S.), and Basque Government IT1211-19 (to J. J. M.) participated in the funding of this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment

[EN] Postsynaptic alpha(2A)-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for alpha(2)-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.This work was supported by Spanish MINECO (grant SAF2013-48586-R) and Basque Government (grant IT1211/19). The authors would like to thank the staff members of the Basque Institute of Legal Medicine for their cooperation in the study

Di-aryl guanidinium derivatives: Towards improved α2-Adrenergic affinity and antagonist activity

Compounds with excellent receptor engagement displaying alpha(2)-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR. Therefore, based on our broad experience in the topic, we have prepared eighteen di-aryl (phenyl and/or pyridin-2-yl) mono- or di-substituted guanidines and 2-aminoimidazolines. The in vitro alpha(2)-AR binding affinity experiments in human brain tissue showed the advantage of a 2-aminoimidazolinium cation, a di-arylmethylene core, a conformationally locked pyridin-2-yl-guanidine and a di-substituted guanidinium to achieve good alpha(2)-AR engagement. After different in vitro [S-35]GTP gamma S binding experiments in human prefrontal cortex tissue, it was possible to identify that compounds 7a, 7b and 7c were alpha(2)-AR partial agonist, whereas 8h was a potent alpha(2)-AR antagonist. Docking and MD studies with a model of alpha(2A)-AR and two crystal structures suggest that antagonism is achieved by compounds carrying a di-substituted guanidine which substituent occupy a pocket adjacent to TM5 without engaging S200(5.42) or S204(5.46), and a mono-substituted cationic group, which favorably interacts with E94(2.65). (c) 2020 Elsevier Masson SAS. All rights reserved.Thanks are given to the School of Chemistry at Trinity College Dublin (M.McM.) and to the Irish Research Council (A.K. -GOIPG/2014/457-and H.B.M. -GOIPG/2017/834-) for postgraduate support. This study was also supported by the Ministerio de Economia y Competitividad of Spain (SAF2013-48586-R) and the Basque Government (IT1211-19). The authors would like to thank the staff members of the Basque Institute of Legal Medicine for their cooperation in the study