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Purpose Sharing and developing digital educational resources and open educational resources has been proposed as a way to harmonize and improve clinical pharmacology and therapeutics (CPT) education in European medical schools. Previous research, however, has shown that there are barriers to the adoption and implementation of open educational resources. The aim of this study was to determine perceived opportunities and barriers to the use and creation of open educational resources among European CPT teachers and possible solutions for these barriers. Methods CPT teachers of British and EU medical schools completed an online survey. Opportunities and challenges were identified by thematic analyses and subsequently discussed in an international consensus meeting. Results Data from 99 CPT teachers from 95 medical schools were analysed. Thirty teachers (30.3%) shared or collaboratively produced digital educational resources. All teachers foresaw opportunities in the more active use of open educational resources, including improving the quality of their teaching. The challenges reported were language barriers, local differences, lack of time, technological issues, difficulties with quality management, and copyright restrictions. Practical solutions for these challenges were discussed and include a peer review system, clear indexing, and use of copyright licenses that permit adaptation of resources. Conclusion Key challenges to making greater use of CPT open educational resources are a limited applicability of such resources due to language and local differences and quality concerns. These challenges may be resolved by relatively simple measures, such as allowing adaptation and translation of resources and a peer review system.

Background: In neurodegenerative diseases, hydrogen peroxide (H2O2) and the production of reactive oxygen species (ROS) have been implicated in the activation of well-known inflammatory signalling pathways. Microglial cells can assume two opposite phenotypes: M2 anti-inflammatory phenotype, in the early stages of neurodegenerative diseases, and the M1 pro-inflammatory subtype that become prevalentwith the diseases progression. Recently, different studies have demonstrated that microglia communicate with neuronal and non neuronal cells by releasing microvescicles (MVs) that contribute to disease progression. Targeting microglia M2 polarization represent an interesting therapeutic approach to inhibit local neurodegeneration, for example inducing the release of insulin growth factor-1 (IGF-1), a beneficial factor against inflammation. Our previous studies have demonstrated that hexarelin, a well-known growth hormone secretagogues (GHS), is endowed with antioxidant, anti-inflammatory and neuroprotective activities, promotes neurogenesis and inhibits cytotoxic effects of β-amyloid in N9 cells, but can also stimulate the release of IGF-1. In this study, we explored the ability of hexarelin to modulated the phenotype of N9 cells and how the induction of M2 microglia phenotype can oppose H2O2-induced neurotoxicity in mouse neuroblastoma Neuro2A cells. Methods: N9 cells were incubated with hexarelin 10-6 M for 24 h. Cells were used to quantify mRNA levels of iNOS and Arg1 for the evaluation of M1/M2 polarization by Real Time PCR, while medium was collected for subsequent experiments. N9 collected media were processed by two centrifugations at 1000xg for 10 and 20 minutes, respectively. The supernatant was ultracentrifugated at 110’000xg for 70 minutes and the pellet resuspended. Before use, MVs were quantified by NanoSight instrument. Neuro2A cells were treated with H2O2 100 µM for 24 h. At the end of the treatment, H2O2 was removed and substituted with N9 conditioned media, purified MVs, or N9 conditioned media deprived of MVs for 24 h. mRNA levels of Bax, BCL-2, caspase-3 and caspase-7 were measured by Real Time PCR. Results: Hexarelin-treated N9 cells showed a prevalence of M2 anti-inflammatory phenotype, with the down-regulation of iNOS and the up-regulation of Arg1 mRNA levels. H2O2 100 µM induced the activation of apoptosis pathway: the mRNA level of pro-apoptotic Bax significantly increased, as well as the levels of caspase-3 and caspase-7, while BCL-2 mRNA levels were reduced. N9 collected media and MVs extracted inhibited the apoptosis activation: Bax, caspase-3 and caspase-7 mRNA levels were reduced while anti-apoptotic BCL-2 mRNA levels were increased. Conclusion: Our results suggest that hexarelin modulated the phenotype of N9 microglial cells, inducing a polarization toward the M2 anti-inflammatory phenotype. Medium derived by hexarelin-treated N9 cells and MVs reduced the toxic effect of H2O2. Further experiments are needed to clarify the composition of MVs underlying the neuroprotective effects.

In several neurodegenerative diseases, including amyotrophic lateral sclerosis, alterations of redox homeostasis within the cell lead to oxidative stress, abnormalities in mitochondrial morphology and biochemistry, damage to DNA, RNA, proteins and lipids, and ultimately to apoptosis. Intracellular hydrogen peroxide (H2O2), generated through oxidative stress, activates the apoptotic pathway by the phosphorylation of the pro-apoptotic regulator Bax and the downregulation of the anti-apoptotic protein Bcl-2, with the subsequent activation of caspases – 3 and – 7. Consequently, phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) are modulated, supporting cell survival or inducing cell death. Hexarelin is a well-known growth hormone secretagogue endowed with growth hormone-releasing effects and neuroprotective activities, such as prevention of status epilepticus and promotion of neurogenesis. Moreover, hexarelin reduced the activation of caspase – 3 and caspase – 7 caused by brain hypoxia-ischemia procedures in neonatal rats, and exerted protective effects against β-amyloid cytotoxicity in vitro. In this study, we explored the protective effects of hexarelin against oxidative stress and its anti-apoptotic mechanism to attenuate H2O2-induced neurotoxicity in Neuro-2A cells, a mouse neuroblastoma cell line. Neuro-2A cells were incubated with increasing concentration of H2O2 for 24 h. MTT assay was used to measure changes in the viability of cells, and 100 µM H2O2 was selected as the lower concentration that significantly induced a reduction of cells survival. Further measurements by real-time PCR analysis showed that 24 hours treatment with 100 µM H2O2 induced significant changes in caspases – 3 and – 7, Bax and Bcl-2 mRNA levels, inducing cell apoptosis. Hexarelin blunted H2O2 effects both increasing cell viability and by opposing changes in caspases – 3 and – 7, Bax and Bcl-2 mRNA levels. Western blot analysis confirmed that hexarelin activate the Akt, p38 and ERK1/2 pathways. In conclusion, our results suggest that hexarelin exerts neuroprotective activities against H2O2-induced toxicity in Neuro-2A cells. Further experiments are needed to identify the precise molecular mechanisms underlying this neuroprotective effects and to clarify whether other GHS moieties exert the same neuroprotective effects.

CONTRIBUTORS IN THE NETWORK OF TEACHERS IN PHARMACOTHERAPY (NOTIP) (ALPHABETIZED BY COUNTRY): Atanasova, Ivanka (Sofia University St. Kliment Ohridski, Sofia, Bulgaria); Ganeva, Maria (Trakia University, Stara Zagora, Bulgaria); Gatchev, Emil (Medical University of Sofia, Sofia, Bulgaria); Kostadinova, II (Medical University Plovdiv, Plovdiv, Bulgaria); Mimica Matanovic, S (University of Osijek, Osijek, Croatia); Vitezic, D (University of Rijeka Medical School, Rijeka, Croatia); Wozniak, Greta (University of Cyprus, Nicosia, Cyprus); Kmonickova, E (Charles University, Pilsen, Czech Republic); Urbanek, Karel (Palacky University, Olomouc, Czech Republic); Damkier, P (University of Southern Denmark, Odense, Denmark); Huupponen, RK (University of Turku, Turku, Finland); Auffret, Marine (Hospices civils de Lyon, Lyon, France); Bejan-Angoulvant, T (Université de Tours, Tours, France); Chouchana, Laurent (Hospital Cochin, Paris, France); Cracowski, Jean-Luc (University Grenoble Alpes, La Tronche, France); Drici, MD (University of Nice Côte d'Azur, Nice, France); Faillie, JL (CHU Montpellier, Montpellier, France); Geniaux, Hélène (CHU de Limoges, Limoges, France); Molimard, M (Université de Bordeaux, Bordeaux, France); Orlikowski, D (Versailles Saint-Quentin-en-Yvelines University, Versailles, France); Palin, Karine (University of Bordeaux, Bordeaux, France); Pers, Y-M (CHU Montpellier, Montpellier, France); Picard, Nicolas (CHU de Limoges, Limoges, France); Simon, N (Aix-Marseille University, Marseille, France); Toussirot, E (CHU de Besancon, Besancon, France); Boger, RH (University Medical Center Hamburg-Eppendorf, Hamburg, Germany); Cascorbi, I (University of Kiel, Kiel, Germany); Mueller, SC (University Medicine Rostock, Rostock, Germany); Regenthal, R (University of Leipzig, Leipzig, Germany); Schwab, M (Eberhard Karl University of Tübingen, Tübingen, Germany); Schwaninger, MS (University of Luebeck, Luebeck, Germany); Thuermann, PA (University Witten/Herdecke, Witten, Germany); Wojnowski, L (University Medical Center Mainz, Mainz, Germany); Kouvelas, D (Aristotle University of Thessaloniki, Thessaloniki, Greece); Riba, P (Semmelweis University, Budapest, Hungary); Kerins, David M (University College, Cork, Ireland); Williams, David J (Royal College of Surgeons in Ireland, Dublin, Ireland); Cosentino, M (University of Insubria, Varese, Italy); De Ponti, Fabrizio (University of Bologna, Bologna, Italy); Filippelli, Amelia (University of Salerno, Baronissi, Italy); Leone, R (University of Verona, Verona, Italy); Locatelli, Vittorio (University of Milano - Bicocca, Monza, Italy); Jansone, Baiba (University of Latvia, Riga, Latvia); Gulbinovic, Romaldas (Vilnius University, Vilnius, Lithuania); Mifsud, Janet (University of Malta, Msida, Malta); Braszko, Jan J (Medical University of Bialystok, Bialystok, Poland); kocic, I (Medical University of Gdansk, Gdansk, Poland); Breitenfeld, Luiza (Beira Interior University, Covilh~a, Portugal); Castelo-Branco, M (University of Beira Interior, Covilh~a, Portugal); Conea, Simona (“Vasile Goldis” Western University of Arad, Arad, Romania); Magyar, Ioan (University of Oradea, Oradea, Romania); Bevc, S (University of Maribor, Maribor, Slovenia); Krzan, Mojca (University of Ljubljana, Ljubljana, Slovenia); Bernal, ML (University of Zaragoza, Zaragoza, Spain); Capellà, D (University of Girona, Girona, Spain); Carcas, A (Universidad Autónoma de Madrid, University of Maribor, Spain); De Abajo, FJ (University of Alcalá, Alcalá de Henares, Spain); Lopez-Rico, M (University of Salamanca, Salamanca, Spain); Lucena, MI (University of Malaga, Malaga, Spain); Pontes, C (Universitat Autonoma de Barcelona, Sabadell, Spain); Sanz, EJ (Universidad de La Laguna, La Laguna, Spain); Böttiger, Y (Linköping University, Linköping, Sweden); Le Grevès, Madeleine (Uppsala University, Uppsala, Sweden); de Waard-Siebinga, I (University Medical Center Groningen, Groningen, The Netherlands); Janssen, Ben JA (Maastricht University, Maastricht, The Netherlands); Knol, Wilma (University Medical Center Utrecht, Utrecht, The Netherlands); Pandit, Rahul (University Medical Center Utrecht, Utrecht, The Netherlands); van Rosse, F (Erasmus Medical Center, Rotterdam, The Netherlands); Dent, G (Keele University, Keele, United Kingdom); Ferro, Albert (King's College London, London, United Kingdom); Hitchings, AW (St George's, University of London, London, United Kingdom); Kapil, V (Queen Mary University London, London, United Kingdom); Linton, KD (University of Sheffield, Sheffield, United Kingdom); Loke, YK (University of East Anglia, Norwich, United Kingdom); Okorie, Michael (Brighton and Sussex Medical School, Brighton, United Kingdom); Plumb, Richard David (Queen's University Belfast, Belfast, United Kingdom); Pontefract, Sarah (University of Birmingham, Birmingham, United Kingdom); Ranmuthu, S (Queen Mary University London, London, United Kingdom); Sampson, AP (University of Southampton, Southampton, United Kingdom); Thanacoody, HKR (Newcastle University, Newcastle upon Tyne, United Kingdom); Whitfield, Jonathan P (University of Aberdeen, Aberdeen, United Kingdom); Wilson, Kurt (University of Manchester, Manchester, United Kingdom) Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re‐used widely across a variety of educational systems, they may be ideally suited for this purpose Methods With a cross‐sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e‐learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge‐based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in‐part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion Digital educational resources, ranging from e‐learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real‐life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials.

Hexarelin is a well-known Growth Hormone Secretagogues (GHS) that possesses growth hormone-releasing effects and neuroprotective activities, such as prevention of status epilepticus and promotion of neurogenesis. Moreover, hexarelin reduces the activation of caspase 3 and 7 caused by brain hypoxia-ischemia in neonatal and adult rats and exerts protective effects against β-amyloid cytotoxicity. Several neurodegenerative diseases (NDDs), such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Huntington’s disease (HD), are characterized by an increased production of reactive oxygen species (ROS), which lead to a dysregulation of mitochondrial dynamics, neuronal plasticity and apoptosis. In particular, ROS cause the downregulation of the anti-apoptotic protein Bcl-2 and the phosphorylation of the pro-apoptotic molecule Bax, with the subsequent activation of caspases 3 and 7. In this study, we explored the protective effects of hexarelin against oxidative stress and its anti-apoptotic mechanisms to attenuate H2O2-induced neurotoxicity using mouse neuroblastoma Neuro2A cells. MTT assay was used to measure changes in the viability of Neuro2A cells at different concentrations of H2O2 for 24 hours, and 100 μM H2O2 was selected as the lower concentration that significantly induced oxidative stress and a reduction of cells survival. Further assays showed that 24 hours treatment with 100 μM H2O2 induced significant changes in caspase 3 and caspase 7 mRNA levels and induced apoptosis. Treatment of Neuro2A cells with hexarelin blunted 100 μM H2O2 effects in MTT assay and cytotoxicity assay (CCK8). The apoptosis mechanism induced by H2O2 was reduced by hexarelin, which was confirmed by real-time PCR analysis of caspase 3, caspase 7, Bcl-2 and Bax mRNA expression. In conclusion, our results suggest that hexarelin exerts neuroprotective activities against H2O2-induced toxicity in Neuro2A cells. Further experiments are needed to identify the molecular mechanisms underlying the neuroprotective effects.

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and several evidences have shown that it is implicated in the pathogenesis of different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington’s disease and Alzheimer’s disease. Glycosaminoglycans (GAGs) are a group of sulphated and linear polysaccharides that exert a variety of biological functions, such as allowing the diffusion of soluble signalling molecules, like insulin-like growth factor-1 (IGF-1), within the extracellular matrix. Previous studies demonstrated that GAGs enhanced the neuroprotective effects of IGF-1 in wobbler mice, leading to a significant increase of motor neuron survival. However, given the high tumorigenic potential of exogenous IGF-1 administration, alternative methods to increase endogenous IGF-1 expression should be develop. Growth hormone secretagogues (GHS) are a family of peptides that stimulates the secretion of growth hormone and IGF-1, and exerts protective effects against β-amyloid cytotoxicity. Based on these data, the purpose of the study was to evaluate the neuroprotective role of the combination GHS and GAGs against glutamate toxicity in the GT1-7 mouse hypothalamic neuronal cell line. Our preliminary results suggest that GHS and GAGs, given alone or in combination, counteracted the reduction of cell viability induced by the incubation with glutamate. Moreover, glutamate treatment induced the activation of the proinflammatory transcription factor NF-κB, which was suppressed by the incubation with both GAGs and GHS. In conclusion, our results suggest that GHS and GAGs co-administration exerted neuroprotective and anti-inflammatory activities against glutamate-induced toxicity in GT1-7 neuronal cells. Further experiments are needed to identify the molecular mechanisms underlying the neuroprotective effects of GHS/GAGs association, so that they could be considered as a novel therapeutical approach in the treatment of neurodegenerative disease.