Melatonin Derivative 6a As a PARP-1 Inhibitor for the Treatment of Parkinson's Disease

Overview

Journal Front Pharmacol

Date 2024 Mar 13

PMID 38476326

Authors

Qing-Wei Ma

Rui-Ting Han

Zi-Jie Wu

Jun-Jie Zhou

Meng-Ting Chen

Xiang-Zhi Zhang

Wen-Zhe Ma

Na Feng

Affiliations

Soon will be listed here.

Abstract

Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in ; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.

Citing Articles

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Li J, Cheng X, Ma R, Zou B, Zhang Y, Wu M J Transl Med. 2025; 23(1):279.

PMID: 40050860 PMC: 11884077. DOI: 10.1186/s12967-025-06280-1.

References

Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A . PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry. 2021; 26(10):6083-6099. PMC: 8758491. DOI: 10.1038/s41380-021-01207-w. View

Martire S, Mosca L, DErme M . PARP-1 involvement in neurodegeneration: A focus on Alzheimer's and Parkinson's diseases. Mech Ageing Dev. 2015; 146-148:53-64. DOI: 10.1016/j.mad.2015.04.001. View

Wang Y, Kim N, Haince J, Kang H, David K, Andrabi S . Poly(ADP-ribose) (PAR) binding to apoptosis-inducing factor is critical for PAR polymerase-1-dependent cell death (parthanatos). Sci Signal. 2011; 4(167):ra20. PMC: 3086524. DOI: 10.1126/scisignal.2000902. View

Berry B, Vodickova A, Muller-Eigner A, Meng C, Ludwig C, Kaeberlein M . Optogenetic rejuvenation of mitochondrial membrane potential extends lifespan. Nat Aging. 2023; 3(2):157-161. PMC: 9980297. DOI: 10.1038/s43587-022-00340-7. View

Caldwell K, Willicott C, Caldwell G . Modeling neurodegeneration in . Dis Model Mech. 2020; 13(10). PMC: 7648605. DOI: 10.1242/dmm.046110. View

Hanzlikova H, Kalasova I, Demin A, Pennicott L, Cihlarova Z, Caldecott K . The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication. Mol Cell. 2018; 71(2):319-331.e3. PMC: 6060609. DOI: 10.1016/j.molcel.2018.06.004. View

Wang Y, An R, Umanah G, Park H, Nambiar K, Eacker S . A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 2016; 354(6308). PMC: 5134926. DOI: 10.1126/science.aad6872. View

Schulz T, Zarse K, Voigt A, Urban N, Birringer M, Ristow M . Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007; 6(4):280-93. DOI: 10.1016/j.cmet.2007.08.011. View

Kim E, Wang B, Sastry N, Masliah E, Nelson P, Cai H . NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Hum Mol Genet. 2015; 25(2):211-22. PMC: 4706110. DOI: 10.1093/hmg/ddv445. View

10.

Martinez B, Petersen D, Gaeta A, Stanley S, Caldwell G, Caldwell K . Dysregulation of the Mitochondrial Unfolded Protein Response Induces Non-Apoptotic Dopaminergic Neurodegeneration in Models of Parkinson's Disease. J Neurosci. 2017; 37(46):11085-11100. PMC: 5688521. DOI: 10.1523/JNEUROSCI.1294-17.2017. View

11.

Malpartida A, Williamson M, Narendra D, Wade-Martins R, Ryan B . Mitochondrial Dysfunction and Mitophagy in Parkinson's Disease: From Mechanism to Therapy. Trends Biochem Sci. 2020; 46(4):329-343. DOI: 10.1016/j.tibs.2020.11.007. View

12.

He L, Du J, Zhou J, Chen M, Luo L, Li B . Synthesis of Melatonin Derivatives and the Neuroprotective Effects on Parkinson's Disease Models of . Front Chem. 2022; 10:918116. PMC: 9213837. DOI: 10.3389/fchem.2022.918116. View

13.

Lapierre L, De Magalhaes Filho C, McQuary P, Chu C, Visvikis O, Chang J . The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun. 2013; 4:2267. PMC: 3866206. DOI: 10.1038/ncomms3267. View

14.

Wullschleger S, Loewith R, Hall M . TOR signaling in growth and metabolism. Cell. 2006; 124(3):471-84. DOI: 10.1016/j.cell.2006.01.016. View

15.

Cipriani G, Rapizzi E, Vannacci A, Rizzuto R, Moroni F, Chiarugi A . Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction. J Biol Chem. 2005; 280(17):17227-34. DOI: 10.1074/jbc.M414526200. View

16.

Brunetti G, Di Rosa G, Scuto M, Leri M, Stefani M, Schmitz-Linneweber C . Healthspan Maintenance and Prevention of Parkinson's-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in . Int J Mol Sci. 2020; 21(7). PMC: 7178172. DOI: 10.3390/ijms21072588. View

17.

Sun J, Liu J, Gao C, Zheng J, Zhang J, Ding Y . Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury. Acta Biomater. 2021; 140:573-585. DOI: 10.1016/j.actbio.2021.12.023. View

18.

Kam T, Mao X, Park H, Chou S, Karuppagounder S, Umanah G . Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease. Science. 2018; 362(6414). PMC: 6431793. DOI: 10.1126/science.aat8407. View

19.

Zheng J, Luo Z, Chiu K, Li Y, Yang J, Zhou Q . glycopetide prolong lifespan and alleviate Parkinson's disease in . Front Aging Neurosci. 2023; 15:1156265. PMC: 10353607. DOI: 10.3389/fnagi.2023.1156265. View

20.

Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E . Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One. 2010; 5(2):e9313. PMC: 2824828. DOI: 10.1371/journal.pone.0009313. View