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Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling

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Abstract

This study investigated the protective effect of Kaempferol against CdCl2-induced hippocampal damage and memory deficit in rats and investigated if such effects involve modulating the activity of AMPK/PTEN/Akt/mTOR axis. Adult male rats (n = 12/group) were divided into control or CdCl2-treated rats received the vehicle of Kaempferol for consecutive 6 weeks. Also, hippocampal cells were treated with CdCl2 in the presence or absence of Kaempferol for 24 h with or without 1 h pre-incubation with compound C, an AMPK inhibitor or with bpV a PTEN inhibitor. Kaempferol improved the behavioral of CdCl2-treated rats, preserved hippocampus structure and reduced hippocampal levels of ROS and protein levels of Bax and cleaved caspase-3. In both control and CdCl2-treated rats, Kaempferol significantly increased hippocampal levels of GSH levels and protein levels of Nfr2, Bcl2 and synaptic proteins (SNAP-25, PSD-25, and synapsin). Concomitantly, it increased the activity of PTEN and AMPK and subsequently, decreased the activity of Akt and mTOR. In cultured cells, individual pharmacological inhibition of PTEN by bpv or AMPK of compound C (CC) partially prevented the stimulatory effect of Kaempferol on Akt/mTOR and its inhibitory effect on cell death whereas a combination of both inhibitors completely prevented this. Also, inhibition of PTEN alone completely abolished the inhibitory effect of Kaempferol by synaptic proteins, whereas inhibition of AMPK completely abolished its stimulatory effect of Nfr2. In conclusion, Kaempferol protects against CdCl2-induced memory deficits and hippocampal apoptosis by its antioxidant potential and inhibition of Akt/mTOR axis and requires the activation of PTEN and AMPK.

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Acknowledgements

All authors extend their appreciation to the deanship of Scientific Research at King Khalid University, Abha, KSA for funding this work through the research groups program under Grant Number (R.G.P.1/46/40). They also would like to thank their technical staff at the animal house for taking care of the animals and helping in tissue dissection.

Funding

This study was funded by the Deanship of Scientific Research at King Khalid University, Abha, Saudi Arabia (R.G.P.1/46/40). Also, this research was funded by Deanship of Scientific Research at Princess Nourah Bint Abdulrahman University through the Fast-track Research Funding Program.

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Authors and Affiliations

  1. Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia

    Attalla Farag El-kott

  2. Department of Zoology, College of Science, Damanhour University, Damanhur, Egypt

    Attalla Farag El-kott

  3. Department of Biology, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia

    Mashael Mohammed Bin-Meferij

  4. Department of Applied Medical Sciences, College of Health Sciences, PAAET, Shuwaikh, Kuwait

    Samy M. Eleawa

  5. King Faisal Medical City (Southren Region), Central Laboratories, Abha, Saudi Arabia

    Majed M. Alshehri

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  1. Attalla Farag El-kott
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  2. Mashael Mohammed Bin-Meferij
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Contributions

AE and MBM proposed the study and obtained the fund. AE, SME, HD designed the experimental procedure. AE, HD, MA performed the experimental procedure and analyzed the data. AE and HD wrote the initial draft and SME finalized the final version.

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Correspondence to Attalla Farag El-kott.

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El-kott, A.F., Bin-Meferij, M.M., Eleawa, S.M. et al. Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling. Neurochem Res 45, 295–309 (2020). https://doi.org/10.1007/s11064-019-02911-4

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