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Targeting the TLR4/NF-κΒ Axis and NLRP1/3 Inflammasomes by Rosuvastatin: A Role in Impeding Ovariectomy-Induced Cognitive Decline Neuropathology in Rats

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Abstract

Postmenopausal hormone-related cognitive decline has gained an immense interest to explore the underlying mechanisms and potential therapies. The current work aimed to study the possible beneficial effect of rosuvastatin (ROS) on the cognitive decline induced by ovariectomy in rats. Four groups were used as follows: control group, control + rosuvastatin, ovariectomy, and ovariectomy + rosuvastatin. After sham operation or ovariectomy, rats were given saline or oral dosages of ROS (2 mg/kg) every day for 30 days. The cognitive functions were assessed using the Morris water maze paradigm, Y-maze test, and new object recognition test. After rat killing, TLR4, caspase-8, and NLRP mRNA expression and protein levels of ASC, AIM2, caspase-1, NLRP1, and PKR were measured in hippocampus. This was complemented by the estimation of tissue content of NF-κΒ, IL-1β, and IL-18 and serum lipid profile quantification. Rosuvastatin showed a promising potential for halting the cognitive impairments induced by estrogen decline through interfering with the TLR4/NF-κΒ/NLRP1/3 axis and inflammasomes activation and the subsequent pyroptosis. This was complemented by the amendment in the deranged lipid profile. Rosuvastatin may exert a beneficial role in attenuating the inflammatory and apoptotic signaling mechanisms associated with postmenopausal cognitive decline. Further investigations are needed to unveil the relationship between deranged plasma lipids and cognitive function.

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Data Availability

The datasets generated and/or analyzed during the current study are not publicly available by the Cairo University policies but are available from the corresponding author on reasonable request.

Abbreviations

NLRs:

Nucleotide-binding oligomerization domain (NOD)-like receptors

ASC:

Apoptosis-associated speck-like protein containing a CARD

ALRs:

Absent-in-melanoma-2 (AIM2)-like receptors

OVX:

Ovariectomized

ROS:

Rosuvastatin

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

TLR4:

Toll-like receptor-4

NF- κB:

Nuclear factor kappa B

PKR:

Double-stranded RNA-dependent protein kinase

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Acknowledgements

The authors appreciate Taif University Researchers Supporting Project number (TURSP-2020/29), Taif University, Taif, Saudi Arabia.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Muhammed A. Saad & Muhammad Y. Al-Shorbagy

  2. School of Pharmacy, Newgiza University, Giza, Egypt

    Muhammed A. Saad

  3. Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, 4184, Ajman, United Arab Emirates

    Muhammad Y. Al-Shorbagy

  4. Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia

    Hany H. Arab

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Contributions

M.A.S, H.H.A, and M.Y.S conceived the study and jointly designed and performed the experiments; M.A.S performed the statistical analysis; M.A.S, H.H.A, and M.Y.S interpreted the data and wrote the article; and H.H.A. and M.Y.A. provided technical support and reviewed the manuscript.

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Correspondence to Muhammad Y. Al-Shorbagy.

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The Ethics Research Committee of Faculty of Pharmacy authorized the study protocol [Approval number: PT-3078]. The study protocol also follows the US National Institute of Health's Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85–23, revised 1996).

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Saad, M.A., Al-Shorbagy, M.Y. & Arab, H.H. Targeting the TLR4/NF-κΒ Axis and NLRP1/3 Inflammasomes by Rosuvastatin: A Role in Impeding Ovariectomy-Induced Cognitive Decline Neuropathology in Rats. Mol Neurobiol 59, 4562–4577 (2022). https://doi.org/10.1007/s12035-022-02852-0

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  • DOI: https://doi.org/10.1007/s12035-022-02852-0

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