Neuroprotective effects of various doses of topiramate against methylphenidate-induced oxidative stress and inflammation in isolated rat amygdala: the possible role of CREB/BDNF signaling pathway
Abstract
Methylphenidate (MPH) abuse damages brain cells. The neuroprotective effects of topiramate (TPM) have been reported previously, but its exact mechanism of action still remains unclear. This study investigated the in vivo role of various doses of TPM in the protection of rat amygdala cells against methylphenidate-induced oxidative stress and inflammation. Seventy adult male rats were divided into seven groups. Groups 1 and 2 received normal saline (0.7 ml/rat) and MPH (10 mg/kg), respectively, for 21 days. Groups 3, 4, 5, 6, and 7 were concurrently treated with MPH (10 mg/kg) and TPM (10, 30, 50, 70, and 100 mg/kg), respectively, for 21 days. elevated plus maze (EPM) was used to assess motor activity disturbances. In addition, oxidative, antioxidantand inflammatory factors and CREB, Ak1, CAMK4, MAPK3, PKA, BDNF, and c FOS gene levels were measured by RT-PCR, and also, CREB and BDNF protein levels were measured by WB in isolated amygdalae. MPH significantly disturbed motor activity and TPM (70 and 100 mg/kg) neutralized its effects. MPH significantly increased lipid peroxidation, mitochondrial GSSG levels and IL-1β and TNF-α level and CAMK4 gene expression in isolated amygdala cells. In contrast, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and CREB, BDNF Ak1, MAPK3, PKA, BDNF, and c FOS expression significantly decreased. The various doses of TPM attenuated these effects of MPH. It seems that TPM can be used as a neuroprotective agent and…
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CREB1, involved in synchronization of circadian rhythmicity, has been shown to be modulated by MPH treatment.
“CREB1, involved in synchronization of circadian rhythmicity, has also been shown to be modulated by MPH treatment [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 [148]
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 [148]
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 [148]
With MPH at 10 mg/kg, an increase of the inflammatory markers in the amygdale has been observed.
“With MPH at 10 mg/kg, an increase of the inflammatory markers in the amygdale has been observed [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 [148]
More recent studies have shown that the expression of BDNF is downregulated by MPH.
“On the other hand, more recent studies have shown that the expression of BDNF is downregulated by MPH [145, 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 [148]
These proteins act upstream in the CREB pathway signalling favouring CREB/BDNF phosphorylation and the activation of this signalling pathway.
“These proteins act upstream in the CREB pathway signalling favouring CREB/BDNF phosphorylation and the activation of this signalling pathway [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 [148]
One study in ADHD that investigated markers of oxidative stress and inflammation showed that MPH downregulated c-FOS.
“One study in ADHD that investigated markers of oxidative stress and inflammation showed that MPH downregulated c-FOS (gene involved in circadian rhythm) [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 [148]
c-FOS is downregulated by MPH.
“It has been described that c-FOS is downregulated by MPH [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 [148]
Motaghinejad et al. showed that MPH downregulates CREB1 and its product BDNF.
“Motaghinejad et al. showed that MPH downregulates CREB1 [148], a major transcription factor in brain development and neurogenesis [215], and its product BDNF, which acts downstream in the CREB pathway signalling [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 [148]
The use of neuroprotective agents reverses the effects of MPH, increasing the expression of CREB and BDNF.
“The use of neuroprotective agents reverses the effects of MPH, increasing the expression of CREB and BDNF [148, 221].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [148]
c-FOS acts downstream in the CREB pathway signalling.
“c-FOS, as does BDNF, acts downstream in the CREB pathway signalling [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 [148]
CAMK4 expression is activated by MPH; it has been suggested that CAMK4 increase could amplify calcium influx and be involved in the increase of oxidative stress and inflammation.
“Another protein related to oxidative stress is CAMK4, whose expression is activated by MPH; it has been suggested that CAMK4 increase could amplify calcium influx and be involved in the increase of oxidative stress and inflammation [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 [148]
MAPK3 and AK1 are both downregulated by MPH.
“Other proteins related to neural viability are MAPK3 and AK1, both downregulated by MPH [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 [148]
MPH has been shown to promote ROS via RAC1 and CAMK4 activation, although the evidence regarding whether MPH use indeed induces or reduces oxidative stress is not clear.
“Moreover, MPH has been shown to promote ROS via RAC1and CAMK4 activation, although the evidence regarding whether MPH use indeed induces or reduces oxidative stress is not clear.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [148]
Cites
Activation of p75NTR by proBDNF facilitates hippocampal long-term depression
Woo, N. H., Teng, H. K., Siao, C.-J., Chiaruttini, C., Pang, P. T., Milner, T. A., Hempstead, B. L., & Lu, B. (2005) · Nature Neuroscience · doi:10.1038/nn1510 · Cited by 815 · see citing works
Yamamoto, B. K., & Raudensky, J. (2008) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-008-9121-7 · Cited by 167 · see citing works
Methylphenidate and cocaine: the same effects on gene regulation?
YANO, M., & STEINER, H. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.10.004 · Cited by 94 · see citing works
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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
“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].”
BackgroundInfluential
- Authors
- Motaghinejad, M., Motevalian, M., Falak, R., Heidari, M., Sharzad, M., & Kalantari, E.
- Affiliations
- Iran University of Medical Sciences (IR)
- Tehran University of Medical Sciences (IR)
- Corresponding author
- Motevalian, Manijeh
- Venue
- Journal of Neural Transmission
- Published
- 2016-09-24
- Volume
- 123
- Issue
- 12
- Pages
- 1463-1477
- ISSN
- 0300-9564 (ISSN-L)
- 1435-1463
- OpenAlex
- W2521839510
- Cited by
- 49
- References
- 3
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 8 · 2017: 2 · 2016: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neural Transmission (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Iran University of Medical Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Keywords
- topiramate, methylphenidate, neuroprotection, amygdala, oxidative stress, neuroinflammation, CREB/BDNF signaling, CaMKIV, ERK1, c-fos, lipid peroxidation, glutathione peroxidase, superoxide dismutase, glutathione reductase, IL-1β, TNF-α, motor activity, stimulant abuse, neurodegeneration
- MeSH terms
- Topiramate, Central Nervous System Stimulants, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Encephalitis, Fructose, Glutathione, Glutathione Peroxidase, Glutathione Reductase, Male, Methylphenidate, Mitochondria, Superoxide Dismutase, Lipid Peroxidation, Signal Transduction, Oxidative Stress, Neuroprotective Agents, Maze Learning, Brain-Derived Neurotrophic Factor, CREB-Binding Protein, Rats
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