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The Novel Potential Therapeutic Utility of Montelukast in Alleviating Autistic Behavior Induced by Early Postnatal Administration of Thimerosal in Mice

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Abstract

Background and Aim

Thimerosal (THIM) is a mercury-containing preservative widely used in many biological and medical products including many vaccines. It has been accused of being a possible etiological factor for some neurodevelopmental disorders such as autistic spectrum disorders (ASDs). In our study, the potential therapeutic effect of montelukast, a leukotriene receptor antagonist used to treat seasonal allergies and asthma, on THIM mice model (ASDs model) was examined.

Methodology

Newborn mice were randomly distributed into three groups: (Group 1) Control (Cont.) group received saline injections. (Group 2) THIM-treated (THIM) group received THIM intramuscular (IM) at a dose of 3000 μg Hg/kg on postnatal days 7, 9, 11, and 15. (Group 3) Montelukast-treated (Monte) group received THIM followed by montelukast sodium (10 mg/kg/day) intraperitoneal (IP) for 3 weeks. Mice were evaluated for growth development, social interactions, anxiety, locomotor activity, and cognitive function. Brain histopathology, alpha 7 nicotinic acetylcholine receptors (α7nAChRs), nuclear factor kappa B p65 (NF-κB p65), apoptotic factor (Bax), and brain injury markers were evaluated as well.

Results

THIIM significantly impaired social activity and growth development. Montelukast mitigated THIM-induced social deficit probably through α7nAChRs upregulation, NF-κB p65, Bax, and brain injury markers downregulation, thus suppressing THIM-induced neuronal toxicity and inflammation.

Conclusion

Neonatal exposure to THIM can induce growth retardation and abnormal social interactions similar to those observed in ASDs. Some of these abnormalities could be ameliorated by montelukast via upregulation of α7nAChRs that inhibited NF-κB activation and significant suppression of neuronal injury and the associated apoptosis.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt

    Lobna A. Abdelzaher & I. E. M. Ashry

  2. Department of Histology, Faculty of Medicine, Assiut University, Assiut, Egypt

    Ola A. Hussein

Authors
  1. Lobna A. Abdelzaher
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  2. Ola A. Hussein
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  3. I. E. M. Ashry
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Contributions

Lobna A. Abdelzaher and I. E. M. Ashry designed the study, collected all specimens, performed all the behavioral and ELISA experiments, and analyzed and interpreted the data. Lobna A. Abdelzaher was a major contributor in writing the manuscript. Ola A. Hussein performed all the histopathological, immunohistochemical, and electron microscopy studies and analyzed and interpreted their results. All authors read and approved the final manuscript.

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Correspondence to Lobna A. Abdelzaher.

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All the animal procedures were performed with approval from the Institutional Animal Care and Use Committee of Faculty of Medicine, Assuit University, and according to the National Institutes of Health Guidelines for the Human and treatment of Animals.

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Abdelzaher, L.A., Hussein, O.A. & Ashry, I.E.M. The Novel Potential Therapeutic Utility of Montelukast in Alleviating Autistic Behavior Induced by Early Postnatal Administration of Thimerosal in Mice. Cell Mol Neurobiol 41, 129–150 (2021). https://doi.org/10.1007/s10571-020-00841-2

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  • DOI: https://doi.org/10.1007/s10571-020-00841-2

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