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Novel NMDA-receptor antagonists ameliorate vanadium neurotoxicity

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Abstract

Various NMDA-receptor antagonists have been investigated for their therapeutic potential in Alzheimer’s disease with memantine shown to be safe and with relative efficacy. There is, however, need to develop novel drugs to counter tolerance and with better efficacy in ameliorating neurodegeneration. We have shown neurodegeneration in different models of vanadium-exposed mice. This study was designed to evaluate and ascertain the potency of three novel NMDA-receptor antagonists (Compounds A, B and C) to ameliorate neurodegeneration in vanadium-exposed mice. One-month-old mice (n = 6) received sterile water (control) and another group (n = 6) was treated with vanadium (3 mg/kg sodium metavanadate) intraperitoneally for 1 month. Three other groups (n = 6) received vanadium and compounds A, B and C (4.35 mg/kg, 30 mg/kg and 100 mg/kg, respectively) simultaneously for the same period. Assessment of pathologies and neurodegeneration in different brain regions was done to test the ameliorative effects of the 3 antagonists using different immunohistochemical markers. Vanadium exposure resulted in reduced calbindin expression and pyknosis of Purkinje cells, cell loss and destruction of apical dendrites with greater percentage of cytoplasmic vacuolations, morphological alterations characterized by cell clustering and multiple layering patterns in the Purkinje cell layer. In addition, the observed degeneration included demyelination, increased GFAP-immunoreactive cells and microgliosis. Simultaneous administration of the compounds to vanadium-exposed mice resulted in the preservation of cellular integrity in the same anatomical regions and restoration of the cells’ vitality with reduced astroglial and microglial activation.

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Funding

This work was supported in part by the University of the Sciences in Philadelphia (USCIENCES) Grant for research collaboration of AA and OJO and Tertiary Education Trust Fund (TETFUND) TO OJO and ETO.

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Authors and Affiliations

  1. Department of Veterinary Anatomy, University of Ibadan, Oyo, Nigeria

    A. D. Ladagu, O. R. Folarin & J. O. Olopade

  2. Department of Anatomy, University of Ibadan, Oyo, Nigeria

    F. E. Olopade

  3. Department of Pharmacognosy, University of Ibadan, Oyo, Nigeria

    T. O. Elufioye

  4. Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA

    J. V. Wallach, M. B. Dybek & A. Adejare

Authors
  1. A. D. Ladagu
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  2. F. E. Olopade
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  3. O. R. Folarin
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  4. T. O. Elufioye
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  5. J. V. Wallach
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  6. M. B. Dybek
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  7. J. O. Olopade
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  8. A. Adejare
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Contributions

LAD performedthe animal experiments, histology, statistics and write-up. OFE performed the statistical analysis and data interpretations; FOR performed the histology of animal tissues; ETO was involved in project design; WJV and DMB were involved in the synthesis of the NMDA-R antagonists. OJO and AA were involved in experiment design, supervision and approval of final draft. In addition, AA was involved in design of the antagonists. All authors read and approved the manuscript.

Corresponding author

Correspondence to J. O. Olopade.

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Ladagu, A.D., Olopade, F.E., Folarin, O.R. et al. Novel NMDA-receptor antagonists ameliorate vanadium neurotoxicity. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1729–1738 (2020). https://doi.org/10.1007/s00210-020-01882-6

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  • DOI: https://doi.org/10.1007/s00210-020-01882-6

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