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Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study

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Abstract

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.

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Data availability

The datasets used during the current study are available on reasonable request.

Abbreviations

MOD :

Modafinil

Se :

Selenium

PCEs :

Pharmaceutical cognitive enhancers

WADA :

World Anti-Doping Agency

DA :

Dopamine

ROS :

Reactive oxygen species

NF-κB :

Nuclear factor-kappa B

Bax :

Bcl-2-associated X protein

LPO :

Lipid peroxidation

MDA :

Malondialdehyde

CAT :

Catalase

TAC :

Total antioxidant capacity

PI3K :

Phosphoinositide 3-kinase

Akt :

Protein kinase B

mTOR :

Mammalian target of rapamycin

GS3K :

Glycogen synthase kinase 3

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Authors and Affiliations

  1. Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Shaimaa A. Shehata & Mahrous A. Ibrahim

  2. Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Eman Kolieb

  3. Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Dina A. Ali

  4. Center of Excellence in Molecular & Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Dina A. Ali & Shymaa Ahmed Maher

  5. Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Shymaa Ahmed Maher

  6. Histology and Cell Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt

    Horeya Erfan Korayem

  7. Forensic Medicine and Clinical Toxicology, College of Medicine, Jouf University, 72341, Aljouf, Saudi Arabia

    Mahrous A. Ibrahim

  8. Department of Chemistry, College of Sciences, University of Sharjah, P. O. Box 27272, Sharjah, United Arab Emirates

    Mohamed S. Nafie

  9. Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt

    Mohamed S. Nafie

  10. Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Alsharqia, Egypt

    Shimaa H. Ameen

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  1. Shaimaa A. Shehata
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  2. Eman Kolieb
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Contributions

SAS: conceptualization, methodology, investigation, resources, project administration, and writing–original draft preparation. EK: conceptualization, methodology, investigation, and writing–original draft preparation. DAA: conceptualization, methodology, investigation, and writing–original draft preparation. SAM: conceptualization, methodology, investigation, and writing–original draft preparation. HEK: methodology, investigation, and writing–original draft preparation. MAI: conceptualization, project administration, supervision, writing, review, and editing. MSN: investigation, formal analysis, and data curation. SHA: data curation, visualization, writing, review, and editing. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Mahrous A. Ibrahim.

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All the experiment procedures performed on animals were in accordance with protocols and International Guidelines for Care and Use of Laboratory Animals in research and approved by the Research Ethical Committee of the Faculty of Medicine, Suez Canal University, according to referenced authority acceptance number (Research 4614#).

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Shehata, S.A., Kolieb, E., Ali, D.A. et al. Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study. Environ Sci Pollut Res 31, 458–480 (2024). https://doi.org/10.1007/s11356-023-31093-4

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