Cannabis; epidemiological, neurobiological and psychopathological issues: an update

This document is the Accepted Manuscript version of the following article: Maria Antonietta De Luca, Gaetano Di Chiara, Cristina Cadoni, Daniele Lecca, Laura Orsolini, Duccio Papanti, John Corkery, Fabrizio Schifano, 'Cannabis; Epidemiological, Neurobiological and Psychopathological Issues: An Update', CNS & Neurological Disorders - Drug Targets, Vol. 16, 2017. The published manuscript is available at EurekaSelect via https://doi.org/10.2174/1871527316666170413113246. Published by Bentham Science.Cannabis is the illicit drug with both the largest current levels of consumption and the highest reported lifetime prevalence levels in the world. Across different countries, the prevalence of cannabis use varies according to the individual income, with the highest use being reported in North America, Australia and Europe. Despite its ‘soft drug’ reputation, cannabis misuse may be associated with several acute and chronic adverse effects. The present article aims at reviewing several papers on epidemiological, neurobiological and psychopathological aspects of the use of cannabis. The PubMed database was here examined in order to collect and discuss a range of identified papers. Cannabis intake usually starts during late adolescence/early adulthood (15-24 years) and drastically decreases in adulthood with the acquisition of working, familiar and social responsibilities. Clinical evidence supports the current socio-epidemiological alarm concerning the increased consumption among youngsters and the risks related to the onset of psychotic disorders. The mechanism of action of cannabis presents some analogies with other abused drugs, e.g. opiates. Furthermore, it has been well demonstrated that cannabis intake in adolescence may facilitate the transition to the use and/or abuse of other psychotropic drugs, hence properly being considered a ‘gateway drug’. Some considerations on synthetic cannabimimetics are provided here as well. In conclusion, the highest prevalence of cannabis use and the social perception of a relatively low associated risk are in contrast with current knowledge based on biological and clinical evidence. Indeed, there are concerns relating to cannabis intake association with detrimental effects on both cognitive impairment and mental health.Peer reviewe

Lights and shadows of schizophrenia therapy research : Lessons from oral risperidone and olanzapine

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The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPC-neuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents

A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G

Introduction: A large number of risk and protective factors have been identified during the SARS-CoV-2 pandemic which may influence the outcome of COVID-19. Among these, recent studies have explored the role of HLA-G molecules and their immunomodulatory effects in COVID-19, but there are very few reports exploring the genetic basis of these manifestations. The present study aims to investigate how host genetic factors, including HLA-G gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection. Materials and Methods: We compared the immune-genetic and phenotypic characteristics between COVID-19 patients (n = 381) with varying degrees of severity of the disease and 420 healthy controls from Sardinia (Italy). Results: HLA-G locus analysis showed that the extended haplotype HLA-G*01:01:01:01/UTR-1 was more prevalent in both COVID-19 patients and controls. In particular, this extended haplotype was more common among patients with mild symptoms than those with severe symptoms [22.7% vs 15.7%, OR = 0.634 (95% CI 0.440 – 0.913); P = 0.016]. Furthermore, the most significant HLA-G 3’UTR polymorphism (rs371194629) shows that the HLA-G 3’UTR Del/Del genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X2 = 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X2 = 11.257, P = 0.004). However, no significant differences were observed for the soluble HLA-G levels in patients and controls. Finally, we showed that SARS-CoV-2 infection in the Sardinian population is also influenced by other genetic factors such as β-thalassemia trait (rs11549407C>T in the HBB gene), KIR2DS2/HLA-C C1+ group combination and the HLA-B*58:01, C*07:01, DRB1*03:01 haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal LZTFL1 gene variant (rs35044562A>G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, HLA-G 3’UTR Del/Del genotype was independent from the other significant variables [ORM = 0.4 (95% CI 0.2 – 0.7), PM = 6.5 x 10-4]. Conclusion: Our results reveal novel genetic variants which could potentially serve as biomarkers for disease prognosis and treatment, highlighting the importance of considering genetic factors in the management of COVID-19 patients

The G Protein-Coupled Receptor GPR17: Overview and Update

The GPR17 receptor is a G protein-coupled receptor (GPCR) that seems to respond to two unrelated families of endogenous ligands: nucleotide sugars (UDP, UDP-galactose, and UDP-glucose) and cysteinyl leukotrienes (LTD4 , LTC4 , and LTE4 ), with significant affinity at micromolar and nanomolar concentrations, respectively. This receptor has a broad distribution at the level of the central nervous system (CNS) and is found in neurons and in a subset of oligodendrocyte precursor cells (OPCs). Unfortunately, disparate results emerging from different laboratories have resulted in a lack of clarity with regard to the role of GPR17-targeting ligands in OPC differentiation and in myelination. GPR17 is also highly expressed in organs typically undergoing ischemic damage and has various roles in specific phases of adaptations that follow a stroke. Under such conditions, GPR17 plays a crucial role; in fact, its inhibition decreases the progression of ischemic damage. This review summarizes some important features of this receptor that could be a novel therapeutic target for the treatment of demyelinating diseases and for repairing traumatic injury

Composition of Metallic Elements and Size Distribution of Fine and Ultrafine Particles in a Steelmaking Factory

Background: The characteristics of aerosol, in particular particle size and chemical composition, can have an impact on human health. Particle size distribution and chemical composition is a necessary parameter in occupational exposure assessment conducted in order to understand possible health effects. The aim of this study was to characterize workplace airborne particulate matter in a metallurgical setting by synergistically using two different approaches; Methodology: Analysis of inhalable fraction concentrations through traditional sampling equipment and ultrafine particles (UFP) concentrations and size distribution was conducted by an Electric Low-Pressure Impactor (ELPI+™). The determination of metallic elements (ME) in particles was carried out by inductively coupled plasma mass spectrometry; Results: Inhalable fraction and ME concentrations were below the limits set by Italian legislation and the American Conference of Governmental Industrial Hygienists (ACGIH, 2017). The median of UFP was between 4.00 104 and 2.92 105 particles/cm3. ME concentrations determined in the particles collected by ELPI show differences in size range distribution; Conclusions: The adopted synergistic approach enabled a qualitative and quantitative assessment of the particles in steelmaking factories. The results could lead to a better knowledge of occupational exposure characterization, in turn affording a better understanding of occupational health issues due to metal fumes exposure