Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats
Abstract
Methylphenidate (MPH) is a central stimulant, prescribed for the treatment of attention deficit/hyperactivity disorder. The long-term behavioral consequences of MPH treatment are unknown. In this study, the oxidative stress and neuroinflammation induced by various doses of MPH were investigated. Forty adult male rats were divided into 5 groups; and treated with different doses of MPH for 21 days. Twenty four hours after drug treatment, Open Field Test (OFT) was performed in all animals. At the end of the study, blood cortisol level (BCL) was measured and hippocampus was isolated and oxidative stress and inflammation parameters and histological changes were analyzed. Chronic MPH at all doses decreased central square entries, number of rearing, ambulation distance and time spent in central square in OFT. BCL increased in doses 10 and 20mg/kg of MPH. Furthermore, MPH in all doses markedly increased lipid peroxidation, mitochondrial oxidized glutathione (GSSG) level, Interleukin 1β (IL-1β) and Tumor Necrosis Factor α (TNF-α) in isolated hippocampus. MPH (10 and 20mg/kg) treated groups had decreased mitochondrial reduced glutathione (GSH) content, and reduced superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRx) activities. 10 and 20mg/kg of MPH change cell density and morphology of cells in Dentate Gyrus (DG) and CA1 areas of hippocampus. Chronic treatment with high doses of MPH can cause oxidative stress, neuroinflammation and neurodegeneration in hippocampus of adult rats.
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In rats, methylphenidate administration has been reported to produce neuroinflammation and oxidative stress in the hippocampus and cerebral cortex, as measured by the inflammatory markers tumor necrosis factor α and interleukin 1β.
“In rats, MPH administration has been reported to produce neuroinflammation and oxidative stress in the hippocampus and cerebral cortex, as measured by the inflammatory markers tumor necrosis factor α and interleukin 1β (264, 265).”
Chronic abuse of MPH induces the expression of inflammatory cytokines, such as TNFα and IL-1β.
“The chronic abuse of MPH also induces the expression of inflammatory cytokines, such as TNFα and IL-1β [148, 196, 197].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [197]
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Faraone, S. V. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.02.001 · Cited by 631 · see citing works
Quintero, J., Gutiérrez-Casares, J. R., & Álamo, C. (2022) · Neurology and Therapy · doi:10.1007/s40120-022-00392-2 · Cited by 70 · see citing works
“Several studies have exposed that the long-term use of MPH induces the DA neuron loss and microglia activation causing an increase in proinflammatory markers TNFa and IL-1b, among others, resulting in the activation of neuroinflammation and triggering a neurodegenerative process [192, 193].”
BackgroundInfluentialSchmitz, F., Pierozan, P., Rodrigues, A. F., Biasibetti, H., Grings, M., Zanotto, B., Coelho, D. M., Vargas, C. R., Leipnitz, G., & Wyse, A. T. S. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-0289-1 · Cited by 35 · see citing works
- Authors
- Motaghinejad, M., Motevalian, M., & Shabab, B.
- Affiliations
- Iran University of Medical Sciences (IR)
- Corresponding author
- Motevalian, Manijeh
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 619
- Pages
- 106-113
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2191245370
- Cited by
- 72
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 11 · 2019: 8 · 2018: 6 · 2017: 11 · 2016: 7
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- methylphenidate, chronic drug administration, oxidative stress, neuroinflammation, hippocampus, neurodegeneration, lipid peroxidation, glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase, IL-1β, TNF-α, blood cortisol, open field behavior, dentate gyrus, CA1, attention deficit hyperactivity disorder
- MeSH terms
- Central Nervous System Stimulants, Animals, Cell Count, Dose-Response Relationship, Drug, Glutathione, Glutathione Peroxidase, Glutathione Reductase, Hippocampus, Hydrocortisone, Inflammation, Male, Malondialdehyde, Methylphenidate, Mitochondria, Motor Activity, Superoxide Dismutase, Tumor Necrosis Factor-alpha, Rats, Wistar, Pyramidal Cells, Oxidative Stress, Dentate Gyrus, Interleukin-1beta
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