The influence of cannabidiol (CBD) on brain development is inadequately understood. Since CBD is considered a non-intoxicating drug, it has attracted great interest concerning its potential medical ...applicability, including in pregnant women and children. Here, we elucidated the response of perinatal rat cortical neurons and astrocytes to CBD at submicromolar (0.1, 0.5, 1, 5 µM) concentrations attainable in humans. The effect of CBD was concentration- and time-dependent and cell-specific. In neurons, 0.1 µM CBD induced an early and transient change in mitochondrial membrane potential (ΔΨm), ATP depletion, and caspase-8 activation, followed by rapid ATP recovery and progressive activation of caspase-9 and caspase-3/7, resulting in early apoptotic cell death with reduction and shortening of dendrites, cell shrinkage, and chromatin condensation. The decrease in neuronal viability, ATP depletion, and caspase activation due to CBD exposure was prevented by transient receptor potential vanilloid 1 (TRPV1) antagonist. In astrocytes, 0.5 µM CBD caused an immediate short-term dysregulation of ΔΨm, followed by ATP depletion with transient activation of caspase-8 and progressive activation of caspase-9 and caspase-3/7, leading to early apoptosis and subsequent necroptosis. In astrocytes, both TRPV1 and cannabinoid receptor 1 (CB
) antagonists protected viability and prevented apoptosis. Given that CBD is a non-intoxicating drug, our results clearly show that this is not the case during critical periods of brain development when it can significantly interfere with the endogenous cannabinoid system.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The involvement of serotonin (5-HT) in chronic pain mechanisms is established. 5-HT inhibits central painful stimuli, but recent data suggests that 5-HT could also enhance pain stimulus from the ...periphery, where mast cells play an important role. We aimed in our study to clarify the influence of selected tricyclic antidepressants (TCAs) on mast cell function: secretion, uptake, and reuptake of 5-HT, that could interfere with 5-HT levels and in this way contribute to the generation of pain. As an experimental model, we used isolated rat peritoneal mast cells and incubated them with selected TCAs (clomipramine, amitriptyline, doxepin, and imipramine) under different experimental conditions. 5-HT release, uptake, and reuptake were determined spectrofluorometrically. We showed that TCAs were able to inhibit 5-HT secretion from mast cells, as well as uptake of exogenous 5-HT and reuptake of secreted 5-HT back into mast cells. The effects of TCAs were concentration dependent; higher concentrations of TCAs inhibited the secretion of 5-HT induced by compound 48/80, whereas lower concentrations of TCAs inhibited 5-HT uptake. The most effective TCA was halogenated clomipramine. As TCAs are well introduced in chronic pain treatment, the insight into mechanisms of action is important for an understanding of their effect in various pain conditions.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The discovery of the endocannabinoid system has raised public interest in the medicinal use of cannabis, phytocannabinoids, and synthetic cannabinoids, which has always been closely regulated due to ...their psychotropic effects and potential abuse. The review takes a quick look at the current legal framework in the European Union, which regulates cannabis use and cultivation for medicinal purposes in line with the United Nations Conventions on the production, trade, and use of cannabis, phytocannabinoids, and synthetic cannabinoids. And while the EU legislation precisely defines requirements and marketing authorisation procedures for medicinal products for all EU member states, there is no common regulatory framework for magistral and officinal preparations containing cannabinoids, as they are exempt from marketing authorisation. Instead, their regulation is left to each member state, and it is quite uneven at this point, mainly due to cultural and historical differences between the countries, leading to different access to non-authorised medicinal products. Therefore, to meet great public interest, harmonised approaches on cannabinoid-containing products without marketing authorisation would be welcome to level the playing field in the EU.
Background Astrocytes maintain central nerve system homeostasis and are relatively resistant to cell death. Dysfunction of cell death mechanisms may underlie glioblastoma genesis and resistance to ...cancer therapy; therefore more detailed understanding of astrocytic death modalities is needed in order to design effective therapy. The purpose of this study was to determine the effect of VAS2870, a pan-NADPH oxidase inhibitor, on staurosporine-induced cell death in astrocytes. Materials and methods Cultured rat astrocytes were treated with staurosporine as activator of cell death. Cell viability, production of reactive oxygen species (ROS), and mitochondrial potential were examined using flow cytometric analysis, while chemiluminescence analysis was performed to assess caspase 3/7 activity and cellular ATP. Results We show here for the first time, that VAS2870 is able to prevent staurosporine-induced cell death. Staurosporine exerts its toxic effect through increased generation of ROS, while VAS2870 reduces the level of ROS. Further, VAS2870 partially restores mitochondrial inner membrane potential and level of ATP in staurosporine treated cells. Conclusions Staurosporine induces cell death in cultured rat astrocytes through oxidative stress. Generation of ROS, mitochondrial membrane potential and energy level are sensitive to VAS2870, which suggests NADPH oxidases as an important effector of cell death. Consequently, NADPH oxidases activation pathway could be an important target to modulate astrocytic death.
In the past decade, novel cell‐based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and ...preventing the development of end‐stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell‐based medicinal products developed for cardiac repair, with a focus on non‐manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non‐clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell‐based therapies for cardiac repair in the context of scientific observations.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Apoptosis and necroptosis are highly regulated, interconnected forms of a cell death. The distinction between them is critical, because necroptosis may cause significant cell loss and local ...inflammation, whereas apoptosis is essential for tissue homeostasis. The same stimulus can induce both apoptosis and necroptosis. Both forms of a cell death were detected in various pathologies, including pathologies in the central nervous system. Astrocytes are a large, heterogeneous cell population in the central nervous system, with many supportive, developmental functions. Although their demise may seriously impair normal functions of the central nervous system, it is still poorly understood. In this study, apoptosis and necroptosis were induced in cultured rat astrocytes by staurosporine. When a low concentration (10−7 M) of staurosporine was applied, a significantly increased proportion of early apoptotic cells was detected after regeneration in a staurosporine free medium. The proportion of necroptotic cells was already increased without regeneration after 3 hours of exposure to staurosporine. When a higher (10−6 M) concentration of staurosporine was applied, further significantly increased necroptosis was detected after regeneration in a staurosporine free medium. Necroptosis was significantly reduced when RIP1 kinase was inhibited by necrostatin-1, whereas inhibition of caspases with z-vad-fmk, an irreversible pan-caspase inhibitor, did not prevent necroptosis. This report of necroptosis induced by staurosporine represents a simple approach for the in vitro induction and detection of apoptosis and necroptosis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
INTRODUCTION: Poisonings continue to be an important public health problem. Here we review the incidence and trend of poisoning by medicaments, drugs and biological substances in Slovenia ...during a five-year period, 2001–2005. We also investigate the etiological and demographic characteristics of poisoning cases in the Slovenian population, based on acute-poisoning admissions to hospitals in Slovenia. PATIENTS, MATERIALS AND METHODS: This retrospective study comprised all cases of poisoning admitted to Slovenian hospitals during a five-year period. Data were obtained from the Annual Health Statistics and from the Institute of Public Health of the Republic of Slovenia. RESULTS: Poisonings by medicaments, drugs and biological substances were found to represent more than half (61%) of the poisonings treated in hospitals. Female poisonings were recorded at a higher rate than male poisonings. The majority of cases occurred in the age group 15–49 years but age groups 1–3 years and >65 years were also shown to be at risk. Children under 3 years of age were poisoned by accident, whereas most cases in teenagers and adults were intentional poisonings (attempted suicide); in the oldest age group, rates of intentional and unintentional poisonings were similar. Although there was a significant downward trend in the overall number of cases from 2001 to 2005, the incidence in children aged 1–3 years and in persons >65 years remained the same. CONCLUSIONS: Poisoning is an important health problem. A multidisciplinary approach is required so that preventive measures may be increased for all groups at risk.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
During the past decade, a large number of cell-based medicinal products have been tested in clinical trials for the treatment of various diseases and tissue defects. However, licensed products and ...those approaching marketing authorization are still few. One major area of challenge is the manufacturing and quality development of these complex products, for which significant manipulation of cells might be required. While the paradigms of quality, safety and efficacy must apply also to these innovative products, their demonstration may be demanding. Demonstration of comparability between production processes and batches may be difficult for cell-based medicinal products. Thus, the development should be built around a well-controlled manufacturing process and a qualified product to guarantee reproducible data from nonclinical and clinical studies.
Background Ethanol, a legal drug, is a big social problem in our country. First of all because of addiction development and also due to consequences of the chronic alcoholism. Ethanol effects to ...almost all organ systems. Consequences of its both, acute and chronic effects, are visible especially in the central nervous system (CNS). Mechanisms of ethanol toxic effects have been already well researched. Lately, many studies attributed at least a part of ethanol effects to its first metabolite acetaldehyde which is produced, mainly with catalase, in the CNS. Acetaldehyde should have key role in the chronic ethilism development. Conclusions Effects of ethanol on the CNS are well known, and its main toxic mechanisms on the CNS have been getting more and more known/researched. Last studies showed that acetaldehyde alone shows effects similar to ethanol. Similar are also some known mechanism of acetaldehyde action. “The most ethanol effects are consequence of its first metabolite action” is still speculative statement, until it will be confirmed that such acetaldehyde effects could be developed by acetaldehyde concentrations accessible in the brain after individual drinking of ethanol.
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