Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats
Abstract
Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA A receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α 2 adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D 2 receptor antagonist. Open field test (OFT) was used to investigate the disturbances in motor activity. Hippocampal neurodegenerative parameters were evaluated. Protein expressions of CREB/BDNF and Akt/GSK3 signaling pathways were also evaluated. Cresyl violet staining was performed to show and confirm the changes in the shape of the cells. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased Bcl-2 expression, the level of reduced form of glutathione (GSH) and the levels and activities of superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes. TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induce…
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MPH modulates several other proteins including adrenergic, DA and glutamate receptors (ADRA2A, ADRA2B, ADRB1, DRD1, DRD5, DRD2, GRIA1).
“First, other NT pathways have been reported to be stimulated by MPH, including adrenergic, DA and glutamate receptors (e.g. alpha-2A adrenergic receptor [ADRA2A] and alpha-2B adrenergic receptor [ADRA2B], beta-1 adrenergic receptor [ADRB1], DA receptor 1A [DRD1], DA receptor 1B [DRD5], DA receptor 2 [DRD2]) and glutamate receptor 1 (GRIA1) [142–144].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [144]
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 [144]
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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
“On the other hand, MPH activates HTR1A and DRD2 (and potentially other G-coupled receptors) that might have a reinforcing feedback role on MPH modulation of the NT imbalance through further regulation of DAT1 [174].”
BackgroundInfluential
- Authors
- Motaghinejad, M., Motevalian, M., Fatima, S., Beiranvand, T., & Mozaffari, S.
- Affiliations
- Iran University of Medical Sciences (IR)
- Corresponding author
- Motevalian, Manijeh
- Venue
- Journal of Neural Transmission
- Published
- 2017-08-09
- Volume
- 124
- Issue
- 11
- Pages
- 1369-1387
- ISSN
- 0300-9564 (ISSN-L)
- 1435-1463
- OpenAlex
- W2742623299
- Cited by
- 57
- References
- 3
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 12 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 2
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neural Transmission (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- topiramate, methylphenidate, neuroprotection, hippocampal neurodegeneration, NMDA receptor, non-NMDA receptors, GABAA receptor, alpha2-adrenoceptors, dopamine D2 receptor, CREB/BDNF signaling, oxidative stress, neuroinflammation, neuronal apoptosis, glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase, lipid peroxidation, Bcl-2, Bax
- MeSH terms
- Topiramate, Central Nervous System Stimulants, Animals, Disease Models, Animal, Exploratory Behavior, Fructose, Glutathione, Glutathione Peroxidase, Glutathione Reductase, Male, Methylphenidate, Superoxide Dismutase, Lipid Peroxidation, Signal Transduction, Rats, Wistar, Receptors, Neurotransmitter, Neurotransmitter Agents, Neuroprotective Agents, Brain-Derived Neurotrophic Factor, Neurotoxicity Syndromes, Proto-Oncogene Proteins c-akt, Rats
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