Modeling chronic brain exposure to amphetamines using primary rat neuronal cortical cultures

Nogueira, T.; Araújo, S. da Costa; Carvalho, Félix; Pereira, Frederico C.; Fernandes, Eduarda; Bastos, Maria de Lourdes; Costa, Vera Marisa; Capela, João Paulo

doi:10.1016/j.neuroscience.2014.07.009

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…MDMA neurotoxic effects have been reported in several neuronal culture models, including cultured serotonergic neurons, primary cortical neurons, primary hippocampal neurons, SH-SY5Y cells, PC-12 cells, and neurons derived from embryonic carcinoma cells. ,− Importantly, although MDMA is a recognized serotonergic toxicant, neurotoxicity has also been observed in SH-SY5Y neuroblastoma cells and cultured cortical neurons. ,, SH-SY5Y cells have pathological characteristics similar to those of cultured cortical and serotonergic neurons . Consistent with a previous study, our study showed that MDMA induced dose-dependent death in SH-SY5Y cells and cultured cortical neurons.…”

Section: Discussionsupporting

confidence: 90%

Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Shih

Yeh

et al. 2020

Chem. Res. Toxicol.

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Methylenedioxymethamphetamine (MDMA) is a psychostimulant with high abuse potential and severe neurotoxicity. According to our previous study, MDMA promotes autophagosome accumulation and contributes to cell death in cultured cortical and serotonergic neurons. However, the detailed mechanism underlying autophagy dysfunction remains unclear. Lysosomes play an important role in autophagic degradation. The present study aimed to examine the role of lysosomal function in autophagic flux in neuronal cultures exposed to MDMA. We showed that MDMA induced enlarged vesicles that accumulate in SH-SY5Y neuroblastoma cells. In addition, we demonstrated that MDMA stimulated dynamin-dependent but clathrin-independent endocytosis, which might contribute to vacuole expansion. Morphological and Western blot analyses revealed that MDMA induced lysosomal swelling, whereas the activity of the lysosomal hydrolytic enzymes cathepsin B and cathepsin D was decreased in SH-SY5Y and cultured cortical neurons, which might lead to autophagosome accumulation and autophagic degradation blockage. Intriguingly, inactivation of cathepsins B and D led to cell death and autophagy–lysosomal dysregulation, which mimicked MDMA-induced neurotoxicity. Consequently, impairment of lysosomal proteolysis and blockage of autophagy degradation contributed to MDMA-induced neurotoxicity in neuronal cultures.

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Section: Discussionsupporting

confidence: 90%

Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Shih

Yeh

et al. 2020

Chem. Res. Toxicol.

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“…The cause of injury is likely ascribed to a high concentration of MDMA itself, but unlikely MDMA-elicited increase in 5-HT. MDMA-elicited cell death is well documented in literature, including those with Petri dish studies at the MDMA concentrations exceeding 200 μM [44]. In the present study, we found that systemic administration of MDMA caused a reduction in FG + but not TpH2 + .…”

Section: Discussionsupporting

confidence: 74%

“…However, although environments have an impact on the activity balance between 5-HT 1A and 5-HT 2A receptors as discussed above, those mechanisms are unlikely to contribute to serotonergic injury. It has been suggested that MDMA at the concentration of 10 μM and higher was sufficient to cause mitochondrial dysfunction, producing reactive oxygen species (ROS; [44, 49]). It is likely that the MDMA concentration following the LD was far below the threshold level for changing mitochondrial function, which is worthy of further investigation.…”

Section: Discussionmentioning

confidence: 99%

Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats

Shokry

Shields

Callanan

et al. 2019

BMC Pharmacol Toxicol

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Background MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. Methods Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. Results Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. Conclusion Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification. Electronic supplementary material The online version of this article (10.1186/s40360-019-0326-6) contains supplementary material, which is available to authorized users.

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“…This cannot be considered as a 'real' false negative because here bcl-X L/S are the driving factors for apoptosis that the cell system is able to detect. The low-concentration study by Nogueira et al, (2014) show that D-amphetamine promoted significant mitochondrial dysfunction and elicited neuronal death in primary mixed neuronal/glial cultures. Moreover, in some cultures caspase 3 activity was activated.…”

Section: Ratmentioning

confidence: 99%

Literature review and appraisal on alternative neurotoxicity testing methods

Masjosthusmann

Barenys

El‐Gamal

et al. 2018

EFSA Supporting Publications

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The goal of this review was the evaluation of information on assessment methods in the field of alternative neurotoxicity (NT) testing. We therefore performed a systematic and comprehensive collection of scientific literature (in English) from the past 27 years until mid of 2017 on state of the art alternative testing methods including in vitro test methods, in silico methods and alternative non-mammalian models. This review identified a variety of test methods that have the ability to predict NT of chemicals based on predefined key NT endpoint categories (27). Those endpoint categories were derived from the Mode of Action (MoA) of known human neurotoxicants. Pre-evaluated MoAs of human neurotoxicants allowed the identification of performance characteristics with regard to the ability of a test system to correctly predict a chemical effect on an endpoint category. The most predictive in vitro model that covers a large variety of endpoint categories are primary rodent cells or tissues. Human based systems derived from induced pluripotent stem cells (iPSC) are promising and warrant human relevance. There is however not yet sufficient data on these models to demonstrate their suitability to reliably substitute primary rodent cells for NT testing purposes. Test methods for glia toxicity are rare and glia endpoint categories are clearly underrepresented. Therefore, a focus for future method development should be placed on glia, astrocytes, oligodendrocytes and microglia based models, preferably in a co-culture se up. The review on in silico methods, resulted into 54 QSARs publications, relevant for NT, of which 39 on blood brain barrier (BBB) permeation. The QSARs available in the publications were developed from data on drugs and chemicals, but there appears a limited set of experimental data for chemicals and pesticides on blood-brain barrier passage. The evaluation of NT methods using alternative whole organism approaches demonstrated a majority of data for C. elegans (nematode species), represented with high true prediction (96%). The main endpoint category was inhibition of cholinergic transmission, with specific endpoints for AChE activity and motor activity, the latter confirming the added value of a whole organism approach among alternative models. Though D. rerio, the zebrafish model appeared a www.efsa.europa.eu/publications 2 EFSA Supporting publication 2018:EN-1410The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights ...

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Modeling chronic brain exposure to amphetamines using primary rat neuronal cortical cultures

Cited by 7 publications

References 43 publications

Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells

Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats

Literature review and appraisal on alternative neurotoxicity testing methods

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