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Brain-derived neurotrophic factor protects serotonergic neurons against 3,4-methylenedioxymethamphetamine ("Ecstasy") induced cytoskeletal damage


Bavato, Francesco; Stamatakos, S; Ohki, Cristine Marie Yde; Seifritz, Erich; Romualdi, Patrizia; Grünblatt, Edna; Quednow, Boris B (2022). Brain-derived neurotrophic factor protects serotonergic neurons against 3,4-methylenedioxymethamphetamine ("Ecstasy") induced cytoskeletal damage. Journal of Neural Transmission, 129(5-6):703-711.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") use has been linked to persistent alterations of the brain serotonergic (5-HT) system in animal and human studies, but the molecular underpinnings are still unclear. Cytoskeletal structures such as neurofilament light chain (NfL) are promising markers of drug-induced brain toxicity and may be involved in MDMA neurotoxicity. The brain-derived neurotrophic factor (BDNF) promotes the growth and sprouting of 5-HT neurons and its differential response to MDMA administration was suggested to mediate dose- and region-dependent 5-HT damage by MDMA. However, the role of BDNF pre-treatment in preventing MDMA neurotoxicity and the potential effects of MDMA on NfL are still elusive. Therefore, a differentiated 5-HT neuronal cell line obtained from rat raphe nucleus (RN46A) was treated in vitro with either MDMA, BDNF, MDMA + BDNF, or vehicle. Cell viability (measured by MTT) and intracellular NfL levels (immunocytochemistry assay) were reduced by MDMA, but partially rescued by BDNF co-treatment. Our findings confirmed that BDNF levels can influence MDMA-induced 5-HT damage, and support BDNF to be a crucial target for neuroprotective interventions of the 5-HT system. We also provide evidence on the sensitivity of NfL to MDMA neurotoxicity, with potential implications for in-vivo monitoring of drug-induced neurotoxicity.

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") use has been linked to persistent alterations of the brain serotonergic (5-HT) system in animal and human studies, but the molecular underpinnings are still unclear. Cytoskeletal structures such as neurofilament light chain (NfL) are promising markers of drug-induced brain toxicity and may be involved in MDMA neurotoxicity. The brain-derived neurotrophic factor (BDNF) promotes the growth and sprouting of 5-HT neurons and its differential response to MDMA administration was suggested to mediate dose- and region-dependent 5-HT damage by MDMA. However, the role of BDNF pre-treatment in preventing MDMA neurotoxicity and the potential effects of MDMA on NfL are still elusive. Therefore, a differentiated 5-HT neuronal cell line obtained from rat raphe nucleus (RN46A) was treated in vitro with either MDMA, BDNF, MDMA + BDNF, or vehicle. Cell viability (measured by MTT) and intracellular NfL levels (immunocytochemistry assay) were reduced by MDMA, but partially rescued by BDNF co-treatment. Our findings confirmed that BDNF levels can influence MDMA-induced 5-HT damage, and support BDNF to be a crucial target for neuroprotective interventions of the 5-HT system. We also provide evidence on the sensitivity of NfL to MDMA neurotoxicity, with potential implications for in-vivo monitoring of drug-induced neurotoxicity.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
04 Faculty of Medicine > Psychiatric University Hospital Zurich > Department of Child and Adolescent Psychiatry
04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Neurology
Health Sciences > Neurology (clinical)
Health Sciences > Psychiatry and Mental Health
Life Sciences > Biological Psychiatry
Uncontrolled Keywords:Brain-derived neurotrophic factor, Ecstasy, MDMA, Neurofilament light chain, Neurotoxicity, Serotonergic neurons
Language:English
Date:June 2022
Deposited On:16 Aug 2022 13:21
Last Modified:27 Jun 2024 01:38
Publisher:Springer
ISSN:0300-9564
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1007/s00702-022-02502-8
PubMed ID:35420371
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)