Artemisinin Conferred Cytoprotection to Human Retinal Pigment Epithelial Cells Exposed to Amiodarone-induced Oxidative Insult by Activating the CaMKK2/AMPK/Nrf2 Pathway

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2024 Sep 16

PMID 39285426

Authors

Chao Yang

Xia Zhao

Wenshu Zhou

Qin Li

Philip Lazarovici

Wenhua Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Ocular toxicity is a severe adverse effect that limits the chronic clinical use of the antiarrhythmic drug amiodarone. Here, we aimed to evaluate the cytoprotective effect of artemisinin and explore the potential signalling pathways in human retinal pigment epithelial (RPE) cell cultures.

Methods: D407 cell cultures were exposed to amiodarone and the impact of artemisinin was evaluated. The key parameters included lactate dehydrogenase (LDH) release, intracellular reactive oxygen species (ROS) generation, and the mitochondrial membrane potential (MMP). We also assessed the protein levels of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), phosphorylated adenosine monophosphate-activated protein kinase (AMPK)ɑ (p-AMPK), calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and nuclear factor erythroid 2-related factor 2 (Nrf2).

Results: Artemisinin reduced the cytotoxicity induced by amiodarone, as reflected by decreased LDH release, ROS generation, and MMP disruption. Additionally, artemisinin increased p-AMPK, CaMKK2, and Nrf2 protein levels. Inhibition of AMPK, CaMKK2, or Nrf2 abolished the cytoprotective effect of artemisinin. AMPK activation and Nrf2 knockdown further supported its protective role.

Conclusions: Artemisinin protected RPE cells from amiodarone-induced damage via the CaMKK2/AMPK/Nrf2 pathway. The in vivo experiments in mice confirmed its efficacy in preventing retinal injury caused by amiodarone. These results suggest that an artemisinin-based eye formulation could be repurposed for treating amiodarone-induced ocular toxicity.

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References

Koenekoop R, Lopez I, den Hollander A, Allikmets R, Cremers F . Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions. Clin Exp Ophthalmol. 2007; 35(5):473-85. DOI: 10.1111/j.1442-9071.2007.01534.x. View

Kim S, Park J . Morin hydrate attenuates CSE-induced lipid accumulation, ER stress, and oxidative stress in RPE cells: implications for age-related macular degeneration. Free Radic Res. 2019; 53(8):865-874. DOI: 10.1080/10715762.2019.1637862. View

Wang J, Li M, Geng Z, Khattak S, Ji X, Wu D . Role of Oxidative Stress in Retinal Disease and the Early Intervention Strategies: A Review. Oxid Med Cell Longev. 2022; 2022:7836828. PMC: 9586758. DOI: 10.1155/2022/7836828. View

Fisher S, Lewis G, Linberg K, Verardo M . Cellular remodeling in mammalian retina: results from studies of experimental retinal detachment. Prog Retin Eye Res. 2005; 24(3):395-431. DOI: 10.1016/j.preteyeres.2004.10.004. View

Sachdeva M, Cano M, Handa J . Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res. 2013; 119:111-4. PMC: 3946784. DOI: 10.1016/j.exer.2013.10.024. View

Tu Y . The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med. 2011; 17(10):1217-20. DOI: 10.1038/nm.2471. View

Jadeja R, Jones M, Abdelrahman A, Powell F, Thounaojam M, Gutsaeva D . Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration. Redox Biol. 2019; 28:101336. PMC: 6812120. DOI: 10.1016/j.redox.2019.101336. View

Boulton M, Dayhaw-Barker P . The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond). 2001; 15(Pt 3):384-9. DOI: 10.1038/eye.2001.141. View

Zhu X, Wang K, Zhou F, Zhu L . Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca/CaMKII-dependent activation of AMPK. Arch Pharm Res. 2018; 41(10):1009-1018. DOI: 10.1007/s12272-018-1059-6. View

10.

Zhao X, Fang J, Li S, Gaur U, Xing X, Wang H . Artemisinin Attenuated Hydrogen Peroxide (HO)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway. Int J Mol Sci. 2019; 20(11). PMC: 6600327. DOI: 10.3390/ijms20112680. View

11.

Passman R, Bennett C, Purpura J, Kapur R, Johnson L, Raisch D . Amiodarone-associated optic neuropathy: a critical review. Am J Med. 2012; 125(5):447-53. PMC: 3322295. DOI: 10.1016/j.amjmed.2011.09.020. View

12.

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

13.

Zhao Z, Chen Y, Wang J, Sternberg P, Freeman M, Grossniklaus H . Age-related retinopathy in NRF2-deficient mice. PLoS One. 2011; 6(4):e19456. PMC: 3084871. DOI: 10.1371/journal.pone.0019456. View

14.

Marmor M . Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol. 2000; 97(3-4):239-49. DOI: 10.1023/a:1002192829817. View

15.

Liao R, Yan F, Zeng Z, Farhan M, Little P, Quirion R . Amiodarone-Induced Retinal Neuronal Cell Apoptosis Attenuated by IGF-1 via Counter Regulation of the PI3k/Akt/FoxO3a Pathway. Mol Neurobiol. 2016; 54(9):6931-6943. DOI: 10.1007/s12035-016-0211-x. View

16.

Yan Y, Zhou X, Xu H, Melcher K . Structure and Physiological Regulation of AMPK. Int J Mol Sci. 2018; 19(11). PMC: 6274893. DOI: 10.3390/ijms19113534. View

17.

Wang K, Jiang Y, Wang W, Ma J, Chen M . Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress. Biochem Biophys Res Commun. 2015; 468(4):541-7. DOI: 10.1016/j.bbrc.2015.10.117. View

18.

Felszeghy S, Viiri J, Paterno J, Hyttinen J, Koskela A, Chen M . Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration. Redox Biol. 2018; 20:1-12. PMC: 6156745. DOI: 10.1016/j.redox.2018.09.011. View

19.

Kervinen M, Falck A, Hurskainen M, Hautala N . Bilateral optic neuropathy and permanent loss of vision after treatment with amiodarone. J Cardiovasc Pharmacol. 2013; 62(4):394-6. DOI: 10.1097/FJC.0b013e31829f9e40. View

20.

Xu L, Kong L, Wang J, Ash J . Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. Proc Natl Acad Sci U S A. 2018; 115(41):10475-10480. PMC: 6187182. DOI: 10.1073/pnas.1802724115. View