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Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ25−35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ25−35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ25−35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aβ25−35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ25−35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

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Data Availability

Data are available from the corresponding author on reasonable request.

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Acknowledgements

Authors are grateful to the Neuroscience Research Center at the Shahid Beheshti University of Medical Science for funding this work as part of the Ph.D. dissertation of Soudabeh Naderi (Grant number:15761). We would also like to thank Dr. Zehra Batool (University of Karachi, Department of Biochemistry, Karachi, Pakistan) for valuable suggestions.

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The authors have not disclosed any funding.

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Authors and Affiliations

  1. School of Medicine, Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Soudabeh Naderi

  2. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fereshteh Motamedi & Fariba Khodagholi

  3. Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran

    Hamid Gholami Pourbadie

  4. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Shahrbanoo Rafiei

  5. Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nima Naderi

  6. Neuroscience Research Center, Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahyar Janahmadi

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  1. Soudabeh Naderi
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Contributions

SN: Investigation, Methodology, Acquisition, Formal Analysis, Writing the original draft. MJ, FM: Conceptualization, Supervision, Methodology, Interpretation of data, Funding acquisition. HGP: Conceptualization, Methodology, Interpretation of data. FK: Conceptualization. SR, NN: Methodology. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Mahyar Janahmadi.

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Competing Interests

All authors have been substantially involved in the preparation of the present manuscript and no undisclosed groups or persons have had a primary role in the study. All authors have seen and approved the submitted version of the paper and accept responsibility for its content. The authors declare no conflict of interest and declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Naderi, S., Motamedi, F., Pourbadie, H.G. et al. Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells. Neurochem Res 49, 99–116 (2024). https://doi.org/10.1007/s11064-023-04006-7

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