| 1. |
- Capela, Joao Paulo, et al.
(författare)
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The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons
- 2013
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Ingår i: NeuroToxicology. - : Elsevier BV. - 1872-9711 .- 0161-813X. ; 34, s. 254-263
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Tidskriftsartikel (refereegranskat)abstract
- 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 mu M) or DOI (10-100 mu M). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24 h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24 h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT2A-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT2A-receptors. (C) 2012 Elsevier Inc. All rights reserved.
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| 2. |
- Drude, Natascha Ingrid, et al.
(författare)
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Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research : a multi-stakeholder workshop report
- 2022
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Ingår i: Translational Medicine Communications. - : Springer Nature. - 2396-832X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory.
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| 3. |
- Endres, Matthias, et al.
(författare)
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Improving outcome after stroke: Overcoming the translational roadblock
- 2008
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Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 25:3, s. 268-278
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Forskningsöversikt (refereegranskat)abstract
- Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.
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| 4. |
- Macleod, Malcolm R., et al.
(författare)
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Hypothermia for Stroke: call to action 2010
- 2010
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4949 .- 1747-4930. ; 5:6, s. 489-492
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Tidskriftsartikel (refereegranskat)abstract
- The European Hypothermia Stroke Research Workshop was held in January 2010, in response to the alarming prospects of a significant increase of stroke expected in the coming years globally. Considering that a minority of patients (around 10%) are currently eligible for thrombolytic treatment, there is a need for an efficacious, cost-effective novel therapy that can be implemented broadly within European health care systems. Accordingly, the primary objective of the workshop was the definition of a research agenda aiming to assess the therapeutic benefits of hypothermia in patients with acute ischaemic stroke. The meeting was organised by the European Stroke Research Network for Hypothermia(EuroHyp) and attended by the representatives of World Stroke Organisation, European Stroke Organisation, Stroke Alliance for Europe, Society for Cryobiology and other organisations - specifically the European Space Agency, and small-and medium-sized enterprises based in EU member states. The participants adopted the 'Hypothermia for Stroke - Call to Action 2010', a declaration specifying the priorities for hypothermia research in acute ischaemic stroke. The research programme outlined - a clinical study programme designed to identify and validate therapeutic cooling as a novel treatment providing benefit to a large number of stroke patients-contains a well-integrated series of Phase II studies aiming to refine the intervention (depth, duration, and mode of cooling; antishivering strategy; patient selection) and a pivotal Phase III clinical trial. The proposed integrated Phase II and III clinical study programme would test the effectiveness of this optimised intervention, and would allow the development of evidence-based Clinical Practice Guidelines describing the optimal use of therapeutic hypothermia as a treatment strategy for stroke.
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| 5. |
- Mergenthaler, Philipp, et al.
(författare)
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A functional role of the cyclin-dependent kinase inhibitor 1 (p21(WAF1/CIP1)) for neuronal preconditioning
- 2013
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 33:3, s. 351-355
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxic preconditioning is thought to rely on gene products regulated by hypoxia-inducible factor (HIF)-1. Here, we show that the HIF-1 target gene cyclin-dependent kinase inhibitor 1, p21(WAF1/CIP1), is essential for neuroprotection by hypoxic/aglycemic or erythropoietin preconditioning using wild-type and p21(WAF1/CIP1)-deficient neurons. Furthermore, overexpression of wild-type p21(WAF1/CIP1) or phospho-mutants significantly increased cell death after hypoxia/aglycemia. Moreover, deferoxamine-induced endogenous tolerance did not involve p21(WAF1/CIP1) expression in cortical neurons. Our data suggest that balanced expression and potentially posttranslational regulation of p21(WAF1/CIP1) is required for hypoxic preconditioning. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 351-355; doi:10.1038/jcbfm.2012.213; published online 9 January 2013
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| 6. |
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| 7. |
- Ruscher, Karsten, et al.
(författare)
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Effect of 3,4-Methylenedioxyamphetamine on Dendritic Spines Dynamics in Rat Neocortical Neurons - Involvement of Heat Shock Protein 27.
- 2011
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Ingår i: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1370, s. 43-52
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Tidskriftsartikel (refereegranskat)abstract
- Along with chronic neurotoxic effects, the long-term consumption of amphetamines has been associated to psychiatric symptoms and memory disturbances. Dendritic spine dynamics have been discussed as a possible morphological correlate. However, the underlying mechanisms are still elusive. 3,4-Methylenedioxyamphetamine (MDA), a major drug of abuse and a main metabolite after 3,4-methylenedioxymethamphetamine (MDMA) intake, provokes a loss of dendritic spine like protrusions in primary cultures of rat cortical neurons. 3,4-Methylenedioxyamphetamine also induced a rapid activation of the p38 mitogen activated protein kinase (p38 MAPK) pathway and phosphorylation of heat shock protein 27 (hsp27) indicative for its decreased chaperone activity. Concurrent pharmacological inhibition of the p38 MAPK by SB203580 abolished hsp27 phosphorylation and diminished the loss of dendritic spine-like protrusions. Moreover, upon MDA treatment dendritic spine-like protrusions were stabilized in neurons constitutively expressing hsp27. In parallel experiments we observed a robust activation of the heat shock transcription factor 1 (HSF-1) and a subsequent increase of hsp27 and hsp70. The regulation of small heat shock proteins corroborates the existence of a neuronal stress response after MDA treatment. Pharmacological targeting of small heat shock protein phosphorylation may provide a new strategy to preserve spine integrity after amphetamine exposure.
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| 8. |
- Ruscher, Karsten, et al.
(författare)
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Housing in an enriched environment : A tool to study functional recovery after experimental stroke
- 2016. - 2nd
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Ingår i: Rodent Models of Stroke. - New York, NY : Springer New York. - 1940-6045 .- 0893-2336. - 9781493956180 - 9781493956203 ; 120, s. 85-92
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Bokkapitel (refereegranskat)abstract
- Physical therapy and social interactions between the stroke patient and health-care professionals or relatives facilitate the process of recovery and promote improvement of lost neurological function after stroke. These observations can be mimicked in an experimental setting by multimodal stimulation provided in the concept of enriched environment. The enriched environment is a housing condition for rodents combining social interactions and sensorimotor stimulation that improves lost neurological function without affecting the extent of brain damage after experimental stroke. This chapter deals with the concept of enriched housing and about performing studies using enriched environment as tool to investigate mechanisms of recovery after brain injury.
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| 9. |
- Ruscher, Karsten, et al.
(författare)
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Housing in an enriched environment : A tool to study functional recovery after experimental stroke
- 2010
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Ingår i: Rodent Models of Stroke. - Totowa, NJ : Humana Press. - 1940-6045 .- 0893-2336. - 9781607617495 - 9781607617501 ; 47, s. 85-91
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Bokkapitel (refereegranskat)abstract
- Physical therapy and social interactions between the stroke patient and health care professionals or relatives facilitate the process of recovery and promote the improvement of neurological function after stroke. These observations can be mimicked in the experimental setting with the concept of enriched environment. The enriched environment is a housing condition for rodents combining social interactions and sensorimotor stimulation that improves neurological function without affecting the extent of brain damage after experimental stroke. This chapter deals with the concept of enriched housing and performing studies using enriched environment as a tool to investigate mechanisms of recovery after brain injury.
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| 10. |
- Ruscher, Karsten, et al.
(författare)
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Neuroprotective effects of the beta-carboline abecarnil studied in cultured cortical neurons and organotypic retinal cultures.
- 2007
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Ingår i: Neuropharmacology. - : Elsevier BV. - 1873-7064 .- 0028-3908. ; 52:7, s. 1488-1495
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Tidskriftsartikel (refereegranskat)abstract
- Presently there is no neuroprotective pharmacological treatment of proven clinical safety and efficacy available. The purpose of this study was to investigate whether the ss-carboline, abecarnil (Abe), which has already passed clinical phase III trials in patients with anxiety disorders, is neuroprotective in in vitro models of cerebral ischemia or excitotoxicity. Abe (100 nM) protected cultured cortical neurons when applied 20 min before or 20 min after combined oxygen glucose deprivation (OGD). Furthermore, cultured cortical neurons were protected from NMDA excitotoxicity when Abe (100 nM) was administered 20 min before or concurrent with 100 mu M NMDA. In contrast, in adult rat organotypic retinal cultures, Abe failed to protect retinal ganglion cells (RGCs) against glutamate (Glu) excitotoxicity. Thus, although our data demonstrate that Abe is a potential neuroprotectant in cultured neurons, the lack of effect in an organotypical model of Glu toxicity indicates that further study is required before Abe might be considered for human neuroprotection trials. 2007 Elsevier Ltd. All rights reserved.
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