Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6
Abstract
Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.
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Effects of Meth were ameliorated in IL-6 KO animals.
“Here, the effects of Meth were found to be ameliorated in IL-6 KO animals.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Ladenheim et al., 2000
IL-6 is implicated in Meth-induced astrogliosis, oxidative stress, and neurotoxicity in several brain regions including the striatum, frontal cortex, and hippocampus.
“Several groups have extended this finding to show that Meth induces PICs across several brain regions including brain reward pathways, and Ladenheim et al. implicated IL-6 in Meth-induced astrogliosis, oxidative stress, and neurotoxicity in several brain regions including the striatum, frontal cortex, and hippocampus (Ladenheim et al., 2000).”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Ladenheim et al., 2000
Methamphetamine-induced neurotoxicity is attenuated in IL-6 knockout mice.
“Here, the effects of Meth were found to be ameliorated in IL-6 KO animals.”
From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Ladenheim et al., 2000
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“dative stress, and neurotoxicity in several brain regions including the striatum, frontal cortex, and hippocampus (Ladenheim et al., 2000).”
BackgroundInfluentialRelevance of chronic stress and the two faces of microglia in Parkinson's disease
Herrera, A. J., Espinosa-Oliva, A. M., Carrillo-Jiménez, A., Oliva-Martín, M. J., García-Revilla, J., García-Quintanilla, A., de Pablos, R. M., & Venero, J. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00312 · Cited by 42 · see citing works
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- Authors
- Ladenheim, B., Krasnova, I. N., Deng, X., Oyler, J. M., Polettini, A., Moran, T. H., Huestis, M. A., & Cadet, J. L.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Cadet, Jean Lud
- ORCID
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2000-12-01
- Volume
- 58
- Issue
- 6
- Pages
- 1247-1256
- ISSN
- 0026-895X (ISSN-L)
- 1521-0111
- OpenAlex
- W2281194714
- Cited by
- 131
- References
- 53
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 9 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 7 · 2014: 11 · 2013: 6 · 2012: 10
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-24605, P01HD024605)
- NHLBI Division of Intramural Research
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- methamphetamine neurotoxicity, interleukin-6, IL-6 knockout mice, apoptosis, dopamine transporter, serotonin transporter, dopamine depletion, serotonin depletion, gliosis, DNA fragmentation, neuroimmune response, caudate-putamen, frontal cortex, hippocampus
- MeSH terms
- Amphetamine, Animals, Benzodiazepines, Carrier Proteins, Chromatography, High Pressure Liquid, Drug Interactions, Membrane Glycoproteins, Methamphetamine, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Mutation, Nerve Tissue Proteins, Temperature, Dopamine Agents, Interleukin-6, Mice, Knockout, Neurotoxicity Syndromes, In Situ Nick-End Labeling, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins, Mice
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