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Suppressing NLRP3 activation and PI3K/AKT/mTOR signaling ameliorates amiodarone-induced pulmonary fibrosis in rats: a possible protective role of nobiletin

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Abstract

Amiodarone (AMD), a medicine used to treat life-threatening arrhythmias, is frequently linked to pulmonary fibrosis (PF). Despite the involvement of NLRP3 inflammasome and PI3K/Akt/mTOR axis in fibrosis modulation and development, their significance in the etiology of AMD-induced PF remains uncertain. Nobiletin (NOB), a citrus flavonoid, has recently gained attention for its ability to reduce fibrotic processes in a variety of organs through inhibiting NLRP3-associated inflammation and suppressing PI3K/AKT/mTOR fibrotic pathway. Therefore, this research aimed to investigate the possible beneficial impact of NOB against AMD-induced PF, taking into account the roles of NLRP3 and PI3K/AKT/mTOR axis in its pathogenesis. Twenty-four rats were randomly specified into Vehicle; NOB 20 mg/kg; AMD 30 mg/kg, and NOB + AMD. All treatments were administered orally once a day for 4 weeks. The lung oxidant/antioxidant status, as well as the expression of inflammatory and fibrotic markers were all assessed. The results revealed that NOB, by improving Nrf2/HO-1 pathway, could reduce ROS production and NLRP3 activation, which in turn hindered IL-1β release, prohibited TGF-β1-related PI3K/AKT/mTOR cascade, suppressed α-SMA expression, and impeded collagen deposition. These findings point to a novel strategy by which NOB may alleviate the AMD-prompted NLRP3 inflammatory responses and associated PF through blocking PI3K/AKT/mTOR signaling.

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Abbreviations

AKT:

Ak strain transforming/protein kinase B

AMD:

Amiodarone

Casp-1:

Caspase-1

HO-1:

Heme Oxygenase-1

IL-1β:

Interlukin-1β

MC:

Methylcellulose

MDA:

Malondialdeyde

mTOR:

Mammalian target of rapamycin

NLRP3:

NOD-: LRR- and pyrin domain-containing protein 3

NOB:

Nobiletin

Nrf2:

Nuclear factor erythroid 2-related factor 2

PF:

Pulmonary fibrosis

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

TAC:

Total antioxidant capacity

TGF-β1:

Transforming growth factor beta-1

α-SMA:

Alpha-smooth muscle actin expression

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Acknowledgements

The authors would like to express their gratitude to the members of the Biochemistry Department, Faculty of Medicine-Cairo University, Egypt and to the members of the Histology Department, Faculty of Veterinary Medicine-Cairo University, Egypt for their efforts. Sincere gratitude and appreciation are extended to Dr. Ola A. El Naggar, the psychiatry registrar at Health Education England Northeast, for her significant contribution to the linguistic rewriting of the manuscript.

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Authors and Affiliations

  1. Pharmacology and Environmental Toxicology, Environmental Studies and Research Institute (ESRI), University of Sadat City, Sadat City, Minofia Governorate, Egypt

    Manar M. El Tabaa

  2. Medical Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt

    Maram M. El Tabaa

  3. Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt

    Rehab M. Elgharabawy

  4. Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah, Kingdom of Saudi Arabia

    Rehab M. Elgharabawy

  5. Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Walaa G. Abdelhamid

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  1. Manar M. El Tabaa
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ManMElT conception, study design, methodology, data analysis and/or interpretation, drafting and revising the manuscript, supervision. MarMElT methodology, data acquisition, investigation, study design, revising the manuscript. RME and WGA conception, study design, methodology, revising the manuscript.

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Correspondence to Manar M. El Tabaa.

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El Tabaa, M.M., El Tabaa, M.M., Elgharabawy, R.M. et al. Suppressing NLRP3 activation and PI3K/AKT/mTOR signaling ameliorates amiodarone-induced pulmonary fibrosis in rats: a possible protective role of nobiletin. Inflammopharmacol 31, 1373–1386 (2023). https://doi.org/10.1007/s10787-023-01168-2

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