Brain apoptosis signaling pathways are regulated by methylphenidate treatment in young and adult rats
Abstract
Methylphenidate (MPH) is commonly prescribed for children who have been diagnosed with attention deficit hyperactivity disorder (ADHD); however, the action mechanisms of methylphenidate have not been fully elucidated. Studies have shown a relationship between apoptosis signaling pathways and psychiatric disorders, as well as in therapeutic targets for such disorders. So, we investigated if chronic treatment with MPH at doses of 1, 2 and 10mg/kg could alter the levels of pro-apoptotic protein, Bax, anti-apoptotic protein, Bcl-2, caspase-3 and cytochrome c in the brain of young and adult Wistar rats. Our results showed that MPH at all doses increased Bax in the cortex; the Bcl-2 and caspase-3 were increased with MPH (1mg/kg) and were reduced with MPH (2 and 10mg/kg); the cytochrome c was reduced in the cortex after treatment with MPH at all doses; in the cerebellum there was an increase of Bax with MPH at all doses, however, there was a reduction of Bcl-2, caspase-3, and cytochrome c with MPH (2 and 10mg/kg); in the striatum the treatment with MPH (10mg/kg) decreased caspase-3 and cytochrome c; treatment with MPH (2 and 10mg/kg) increased Bax and decreased Bcl-2 in the hippocampus; and the caspase-3 and cytochrome c were reduced in the hippocampus with MPH (10mg/kg). In conclusion, our results suggest that MPH influences plasticity in the brain of young and adult rats; however, the effects were dependent of age and brain area, on the one hand activating the initial cascade of a…
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MPH modulates apoptosis-related proteins including BCL2, BAX, CASP3 and CYC1.
“The apoptosis-related proteins reported to be modulated by MPH include apoptosis regulator Bcl-2 (BCL2), apoptosis regulator BAX (BAX), caspase-3 (CASP3) and cytochrome c1, haem protein, mitochondrial precursor (CYC1) [147].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [147]
MPH has a broader range of modulation encompassing dopaminergic and adrenergic neurotransmission, inducing activation of ADRB1 and DRD2, modulating proteins involved in neuronal survival such as BCL2, BAX, CASP3 and CYC1, acting as an immunoregulator owing to its effect on TNF, and affecting circadian rhythm through CREB1.
“MPH has a broader range of modulation encompassing dopaminergic and adrenergic neurotransmission, inducing the activation of ADRB1 and DRD2 [143, 144] and modulating proteins involved in neuronal survival such as BCL2, BAX, CASP3 and CYC1 [147], acting as an immunoregulator owing to its effect on TNF [148] and affecting circadian rhythm through CREB1, involved in its synchronization [148].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [147]
BAX (pro-apoptotic) and BCL2, CASP3 and CYC1 (anti-apoptotic) proteins have been regulated by MPH, although the MoA of MPH remains elusive as MPH effects were dependent on age and brain area.
“BAX (pro-apoptotic) and BCL2, CASP3 and CYC1 (anti-apoptotic) proteins have been regulated by MPH, although the MoA of MPH remains elusive as MPH effects were dependent on age and brain area [147].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [147]
Apoptotic enzymes have been related to MPH although its MoA in that regard remains unclear.
“Apoptotic enzymes have been related to MPH although its MoA in that regard remains unclear.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [147]
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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
“apoptosis-related proteins reported to be modulated by MPH include apoptosis regulator Bcl-2 (BCL2), apoptosis regulator BAX (BAX), caspase3 (CASP3) and cytochrome c1, haem protein, mitochondrial precursor (CYC1) [147].”
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
- Réus, G. Z., Scaini, G., Jeremias, G. C., Furlanetto, C. B., Morais, M. O. S., Mello-Santos, L. M., Quevedo, J., & Streck, E. L.
- Affiliations
- Universidade do Extremo Sul Catarinense (BR)
- Corresponding author
- Streck, Emilio L.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 1583
- Pages
- 269-276
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2079040308
- Cited by
- 37
- References
- 5
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 3
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Academia Brasileira de Ciências
- Instituto Mente e Cérebro - Neurociência
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- United Nations Educational, Scientific and Cultural Organization
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Universidade do Extremo Sul Catarinense
- Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- methylphenidate, apoptosis signaling, attention deficit hyperactivity disorder, Bax, Bcl-2, caspase-3, cytochrome c, brain regions, age-dependent effects, cortical neurons, cerebellum, striatum, hippocampus, neuroprotection
- MeSH terms
- Central Nervous System Stimulants, Animals, Brain, Dose-Response Relationship, Drug, Methylphenidate, Immunoblotting, Signal Transduction, Rats, Wistar, Apoptosis, Neuroprotective Agents, Proto-Oncogene Proteins c-bcl-2, Cytochromes c, bcl-2-Associated X Protein, Caspase 3
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