Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Medicinal Chemistry
  4. Volume 32, Issue 8
  5. Article
Volume 32, Issue 8
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

Background

Parkinson's disease (PD) is an irreversible, progressive disorder that profoundly impacts both motor and non-motor functions, thereby significantly diminishing the individual’s quality of life. Dihydrosinularin (DHS), a natural bioactive molecule derived from soft corals, exhibits low cytotoxicity and anti-inflammatory properties. However, the therapeutic effects of DHS on neurotoxins and PD are currently unknown.

Objective

This study investigated whether DHS could mitigate 6-hydroxydopamine (6-OHDA)-induced neurotoxicity and explored the role of neuroprotective PI3K downstream signaling pathways, including that of AKT, ERK, JNK, BCL2, and NFκB, in DHS-mediated neuroprotection.

Methods

We treated the human neuroblastoma cell line, SH-SY5Y, with the neurotoxin 6-OHDA to establish a cellular model of PD. Meanwhile, we assessed the anti-apoptotic and neuroprotective properties of DHS through cell viability, apoptosis, and immunostaining assays. Furthermore, we utilized the PI3K inhibitor LY294002 to validate the therapeutic target of DHS.

Results

Based on the physicochemical properties of DHS, it can be inferred that it has promising oral bioavailability and permeability across the blood-brain barrier (BBB). It was demonstrated that DHS upregulates phosphorylated AKT and ERK while downregulating phosphorylated JNK. Consequently, this enhances the expression of BCL2, which exerts a protective effect on neuronal cells by inhibiting caspase activity and preventing cell apoptosis. The inhibition of PI3K significantly reduced the relative protective activity of DHS in 6-OHDA-induced neurotoxicity, suggesting that the neuroprotective effects of DHS are mediated through the activation of PI3K signaling.

Conclusion

By investigating the mechanisms involved in 6-OHDA-induced neurotoxicity, we provided evidence concerning the therapeutic potential of DHS in neuroprotection. Further research into DHS and its mechanisms of action holds promise for developing novel therapeutic strategies for PD.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673323198240823070219
2024-09-03
2025-06-22

  • From This Site

    /content/journals/cmc/10.2174/0109298673323198240823070219
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
The full text of this item is not currently available.

References

  1. MhyreT.R. BoydJ.T. HamillR.W. Maguire-ZeissK.A. Parkinson’s Disease.Subcell. Biochem.20126538945510.1007/978‑94‑007‑5416‑4_1623225012
     [Google Scholar]
  2. CummingsJ. MontesA. KambojS. CachoJ.F. The role of basket trials in drug development for neurodegenerative disorders.Alzheimers Res. Ther.20221417310.1186/s13195‑022‑01015‑635614479
     [Google Scholar]
  3. MüllerT. Drug therapy in patients with Parkinson’s disease.Transl. Neurodegener.2012111010.1186/2047‑9158‑1‑1023211041
     [Google Scholar]
  4. GibbW.R.G. LeesA.J. The significance of the Lewy body in the diagnosis of idiopathic Parkinson’s disease.Neuropathol. Appl. Neurobiol.1989151274410.1111/j.1365‑2990.1989.tb01147.x2542825
     [Google Scholar]
  5. TrinhJ. FarrerM. Advances in the genetics of Parkinson disease.Nat. Rev. Neurol.20139844545410.1038/nrneurol.2013.13223857047
     [Google Scholar]
  6. BetarbetR. ShererT.B. DiD.A. GreenamyreJ.T. Mechanistic approaches to Parkinson’s disease pathogenesis.Brain Pathol.200212449951010.1111/j.1750‑3639.2002.tb00468.x12408237
     [Google Scholar]
  7. GeeP. SanR.H.C. DavisonA.J. StichH.F. Clastogenic and mutagenic actions of active species generated in the 6-hydroxydopamine/oxygen reaction: Effects of scavengers of active oxygen, iron, and metal chelating agents.Free Radic. Res. Commun.199216111010.3109/107157692090491531516844
     [Google Scholar]
  8. ZhangD. ZhangJ.J. LiuG.T. The novel squamosamide derivative FLZ protects against 6-hydroxydopamine-induced apoptosis through inhibition of related signal transduction in SH-SY5Y cells.Eur. J. Pharmacol.20075611-31610.1016/j.ejphar.2006.11.01517359966
     [Google Scholar]
  9. StottS.R.W. BarkerR.A. Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of P arkinson’s disease.Eur. J. Neurosci.20143961042105610.1111/ejn.1245924372914
     [Google Scholar]
  10. FengC.W. ChenN.F. WenZ.H. YangW.Y. KuoH.M. SungP.J. SuJ.H. ChengS.Y. ChenW.F. In vitro and in vivo neuroprotective effects of stellettin b through anti-apoptosis and the Nrf2/HO-1 pathway.Mar. Drugs201917631510.3390/md1706031531146323
     [Google Scholar]
  11. FengC.W. HungH.C. HuangS.Y. ChenC.H. ChenY.R. ChenC.Y. YangS.N. WangH.M.D. SungP.J. SheuJ.H. TsuiK.H. ChenW.F. WenZ.H. Neuroprotective effect of the marine-derived compound 11-dehydrosinulariolide through DJ-1-related pathway in in vitro and in vivo models of parkinson’s disease.Mar. Drugs2016141018710.3390/md1410018727763504
     [Google Scholar]
  12. ChangF. LeeJ.T. NavolanicP.M. SteelmanL.S. SheltonJ.G. BlalockW.L. FranklinR.A. McCubreyJ.A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy.Leukemia200317359060310.1038/sj.leu.240282412646949
     [Google Scholar]
  13. Fernandez-GomezF.J. PastorM.D. Garcia-MartinezE.M. Melero-Fernandez de MeraR. Gou-FabregasM. Gomez-LazaroM. CalvoS. SolerR.M. GalindoM.F. JordánJ. Pyruvate protects cerebellar granular cells from 6-hydroxydopamine-induced cytotoxicity by activating the Akt signaling pathway and increasing glutathione peroxidase expression.Neurobiol. Dis.200624229630710.1016/j.nbd.2006.07.00516978869
     [Google Scholar]
  14. FengH. XiF. Miltirone attenuates reactive oxygen species-dependent neuronal apoptosis in MPP+-induced cell model of parkinson’s disease through regulating the PI3K/Akt pathway.Neurochem. Res.202247103137314910.1007/s11064‑022‑03669‑y35810264
     [Google Scholar]
  15. ZhuJ. ShenW. GaoL. GuH. ShenS. WangY. WuH. GuoJ. PI3K/Akt-independent negative regulation of JNK signaling by MKP-7 after cerebral ischemia in rat hippocampus.BMC Neurosci.2013141110.1186/1471‑2202‑14‑123280045
     [Google Scholar]
  16. WestonC.R. DavisR.J. The JNK signal transduction pathway.Curr. Opin. Cell Biol.200719214214910.1016/j.ceb.2007.02.00117303404
     [Google Scholar]
  17. WennströmS. DownwardJ. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor.Mol. Cell. Biol.19991964279428810.1128/MCB.19.6.427910330169
     [Google Scholar]
  18. NewmanD.J. CraggG.M. Marine natural products and related compounds in clinical and advanced preclinical trials.J. Nat. Prod.20046781216123810.1021/np040031y15332835
     [Google Scholar]
  19. CatanesiM. CaioniG. CastelliV. BenedettiE. d’AngeloM. CiminiA. Benefits under the Sea: The role of marine compounds in neurodegenerative disorders.Mar. Drugs20211912410.3390/md1901002433430021
     [Google Scholar]
  20. WeinheimerA.J. MatsonJ.A. HossainM.B. van der HelmD. Marine anticancer agents: Sinularin and dihydrosinularin, new cembranolides from the soft coral, Sinularia flexibilis.Tetrahedron Lett.197718342923292610.1016/S0040‑4039(01)83115‑4
     [Google Scholar]
  21. SuJ.H. WenZ.H. Bioactive cembrane-based diterpenoids from the soft coral Sinularia triangular.Mar. Drugs20119694495110.3390/md906094421747740
     [Google Scholar]
  22. ChenL.W. ChungH.L. WangC.C. SuJ.H. ChenY.J. LeeC.J. Anti-acne effects of cembrene diterpenoids from the cultured soft coral Sinularia flexibilis. Mar. Drugs2020181048710.3390/md1810048732992719
     [Google Scholar]
  23. WangS.C. LiR.N. LinL.C. TangJ.Y. SuJ.H. SheuJ.H. ChangH.W. Comparison of antioxidant and anticancer properties of soft coral-derived sinularin and dihydrosinularin.Molecules20212613385310.3390/molecules2613385334202721
     [Google Scholar]
  24. YangK.H. LinY.S. WangS.C. LeeM.Y. TangJ.Y. ChangF.R. ChuangY.T. SheuJ.H. ChangH.W. Soft coral-derived dihydrosinularin exhibits antiproliferative effects associated with apoptosis and DNA damage in oral cancer cells.Pharmaceuticals (Basel)2021141099410.3390/ph1410099434681218
     [Google Scholar]
  25. BassaniT.B. VitalM.A.B.F. RauhL.K. Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs.Arq. Neuropsiquiatr.201573761662310.1590/0004‑282X2015005726200058
     [Google Scholar]
  26. LeeK.Y. SungS.H. KimY.C. Neuroprotective bibenzyl glycosides of Stemona tuberosa roots.J. Nat. Prod.200669467968110.1021/np050415416643052
     [Google Scholar]
  27. ZhaoD.L. ZouL.B. LinS. ShiJ.G. ZhuH.B. Anti-apoptotic effect of esculin on dopamine-induced cytotoxicity in the human neuroblastoma SH-SY5Y cell line.Neuropharmacology200753672473210.1016/j.neuropharm.2007.07.01717904593
     [Google Scholar]
  28. LevitesY. YoudimM.B. MaorG. MandelS. Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures.Biochem. Pharmacol.2002631212910.1016/S0006‑2952(01)00813‑911754870
     [Google Scholar]
  29. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.2001461-332610.1016/S0169‑409X(00)00129‑011259830
     [Google Scholar]
  30. SuenderhaufC. HammannF. HuwylerJ. Computational prediction of blood-brain barrier permeability using decision tree induction.Molecules2012179104291044510.3390/molecules17091042922941223
     [Google Scholar]
  31. HayakawaR. HayakawaT. TakedaK. IchijoH. Therapeutic targets in the ASK1-dependent stress signaling pathways.Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci.201288843445310.2183/pjab.88.43423060232
     [Google Scholar]
  32. JeongY.E. LeeM.Y. Anti-inflammatory activity of Populus Deltoides leaf extract via modulating NF-κB and p38/JNK pathways.Int. J. Mol. Sci.20181912374610.3390/ijms1912374630477268
     [Google Scholar]
  33. BlandiniF. ArmenteroM.T. MartignoniE. The 6-hydroxydopamine model: News from the past.Parkinsonism Relat. Disord.200814Suppl. 2S124S12910.1016/j.parkreldis.2008.04.01518595767
     [Google Scholar]
  34. JohriA. BealM.F. Mitochondrial dysfunction in neurodegenerative diseases.J. Pharmacol. Exp. Ther.2012342361963010.1124/jpet.112.19213822700435
     [Google Scholar]
  35. GalindoM.F. JordánJ. González-GarcíaC. CeñaV. Chromaffin cell death induced by 6-hydroxydopamine is independent of mitochondrial swelling and caspase activation.J. Neurochem.20038451066107310.1046/j.1471‑4159.2003.01592.x12603830
     [Google Scholar]
  36. von CoellnR. KüglerS. BährM. WellerM. DichgansJ. SchulzJ.B. Rescue from death but not from functional impairment: Caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals.J. Neurochem.200177126327311279282
     [Google Scholar]
  37. DaviesS.P. ReddyH. CaivanoM. CohenP. Specificity and mechanism of action of some commonly used protein kinase inhibitors.Biochem. J.200035119510510.1042/bj351009510998351
     [Google Scholar]
  38. TianL.L. ZhouZ. ZhangQ. SunY.N. LiC.R. ChengC.H. ZhongZ.Y. WangS.Q. Protective effect of (+/-) isoborneol against 6-OHDA-induced apoptosis in SH-SY5Y cells.Cell. Physiol. Biochem.20072061019103210.1159/00011068217975304
     [Google Scholar]
  39. ZhuangZ.Y. XuH. ClaphamD.E. JiR.R. Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization.J. Neurosci.200424388300830910.1523/JNEUROSCI.2893‑04.200415385613
     [Google Scholar]
  40. StarihaR.L. KimS.U. Mitogen-activated protein kinase signalling in oligodendrocytes: A comparison of primary cultures and CG-4.Int. J. Dev. Neurosci.200119442743710.1016/S0736‑5748(01)00025‑911378302
     [Google Scholar]
  41. HanB.H. XuD. ChoiJ. HanY. XanthoudakisS. RoyS. TamJ. VaillancourtJ. ColucciJ. SimanR. GirouxA. RobertsonG.S. ZamboniR. NicholsonD.W. HoltzmanD.M. Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury.J. Biol. Chem.200227733301283013610.1074/jbc.M20293120012058036
     [Google Scholar]
  42. GrilliM. PizziM. MemoM. SpanoP. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation.Science199627452911383138510.1126/science.274.5291.13838910280
     [Google Scholar]
  43. BhakarA.L. TannisL.L. ZeindlerC. RussoM.P. JobinC. ParkD.S. MacPhersonS. BarkerP.A. Constitutive nuclear factor-kappa B activity is required for central neuron survival.J. Neurosci.200222198466847510.1523/JNEUROSCI.22‑19‑08466.200212351721
     [Google Scholar]
  44. PiccioliP. PorcileC. StanzioneS. BisagliaM. BajettoA. BonaviaR. FlorioT. SchettiniG. Inhibition of nuclear factor-κB activation induces apoptosis in cerebellar granule cells.J. Neurosci. Res.20016661064107310.1002/jnr.125111746438
     [Google Scholar]
  45. GoffiF. BoroniF. BenareseM. SarnicoI. BenettiA. SpanoP.F. PizziM. The inhibitor of IkappaBalpha phosphorylation BAY 11-7082 prevents NMDA neurotoxicity in mouse hippocampal slices.Neurosci. Lett.2005377314715110.1016/j.neulet.2004.11.08815755516
     [Google Scholar]
  46. KaltschmidtB. UherekM. VolkB. BaeuerleP.A. KaltschmidtC. Transcription factor NF-κB is activated in primary neurons by amyloid β peptides and in neurons surrounding early plaques from patients with Alzheimer disease.Proc. Natl. Acad. Sci. USA19979462642264710.1073/pnas.94.6.26429122249
     [Google Scholar]
  47. LindbergM.F. DeauE. MiegeF. GreverieM. RocheD. GeorgeN. GeorgeP. MerletL. GavardJ. BrugmanS.J.T. AretE. TinnemansP. de GelderR. SadownikJ. VerhofstadE. SleegersD. SantangeloS. DairouJ. Fernandez-BlancoÁ. DierssenM. KrämerA. KnappS. MeijerL. Chemical, biochemical, cellular, and physiological characterization of leucettinib-21, a down syndrome and alzheimer’s disease drug candidate.J. Med. Chem.20236623156481567010.1021/acs.jmedchem.3c0188838051674
     [Google Scholar]
  48. RaghuvanshiR. BharateS.B. Preclinical and clinical studies on bryostatins, A class of marine-derived Protein Kinase C Modulators: A mini-review.Curr. Top. Med. Chem.202020121124113510.2174/156802662066620032511044432209043
     [Google Scholar]
  49. LiuX. ShibataT. HisakaS. OsawaT. Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism.Brain Res.20091254182710.1016/j.brainres.2008.11.07619101523
     [Google Scholar]
  50. YeP. LiP. YangW. ZhaoY. ZhaoY. SunK. WangB. ChenY. Structure and neuroprotective effect of polysaccharide from viscera autolysates of squid Ommastrephes bartrami. Mar. Drugs201917318810.3390/md1703018830909471
     [Google Scholar]
  51. HuangS.Y. ChenN.F. ChenW.F. HungH.C. LeeH.P. LinY.Y. WangH.M. SungP.J. SheuJ.H. WenZ.H. Sinularin from indigenous soft coral attenuates nociceptive responses and spinal neuroinflammation in carrageenan-induced inflammatory rat model.Mar. Drugs20121091899191910.3390/md1009189923118711
     [Google Scholar]
  52. ChenN.F. HuangS.Y. LuC.H. ChenC.L. FengC.W. ChenC.H. HungH.C. LinY.Y. SungP.J. SungC.S. YangS.N. WangH.M. ChangY.C. SheuJ.H. ChenW.F. WenZ.H. Flexibilide obtained from cultured soft coral has anti-neuroinflammatory and analgesic effects through the upregulation of spinal transforming growth factor-β1 in neuropathic rats.Mar. Drugs20141273792381710.3390/md1207379224979268
     [Google Scholar]
  53. LinY.C. SuJ.H. LinS.C. ChangC.C. HsiaT.C. TungY.T. LinC.C. A soft coral-derived compound, 11-dehydrosinulariolide, induces G2/M cell cycle arrest and apoptosis in small cell lung cancer.Mar. Drugs2018161247910.3390/md1612047930513611
     [Google Scholar]
  54. ChenW.F. ChakrabortyC. SungC.S. FengC.W. JeanY.H. LinY.Y. HungH.C. HuangT.Y. HuangS.Y. SuT.M. SungP.J. SheuJ.H. WenZ.H. Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: A promising candidate for the treatment of Parkinson’s disease.Naunyn Schmiedebergs Arch. Pharmacol.2012385326527510.1007/s00210‑011‑0710‑222119889
     [Google Scholar]
  55. ChenC.H. ChenN.F. FengC.W. ChengS.Y. HungH.C. TsuiK.H. HsuC.H. SungP.J. ChenW.F. WenZ.H. A coral-derived compound improves functional recovery after spinal cord injury through its antiapoptotic and anti-inflammatory effects.Mar. Drugs201614916010.3390/md1409016027598175
     [Google Scholar]
  56. SuT.R. TsaiF.J. LinJ.J. HuangH.H. ChiuC.C. SuJ.H. YangY.T. ChenJ.Y.F. WongB.S. WuY.J. Induction of apoptosis by 11-dehydrosinulariolide via mitochondrial dysregulation and ER stress pathways in human melanoma cells.Mar. Drugs20121081883189810.3390/md1008188323015779
     [Google Scholar]
  57. WuC.H. ChaoC.H. HuangT.Z. HuangC.Y. HwangT.L. DaiC.F. SheuJ.H. Cembranoid-related metabolites and biological activities from the soft coral Sinularia flexibilis. Mar. Drugs201816827810.3390/md1608027830096866
     [Google Scholar]
  58. LiuC.I. WangR.Y.L. LinJ.J. SuJ.H. ChiuC.C. ChenJ.C. ChenJ.Y.F. WuY.J. Proteomic profiling of the 11-dehydrosinulariolide-treated oral carcinoma cells Ca9–22: Effects on the cell apoptosis through mitochondrial-related and ER stress pathway.J. Proteomics201275185578558910.1016/j.jprot.2012.07.03722885288
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673323198240823070219
Loading
Soft Corals-derived Dihydrosinularin Attenuates Neuronal Apoptosis in 6-hydroxydopamine-induced Cell Model of Parkinson's Disease by Regulating the PI3K Pathway
Curr. Med. Chem. 32, 1606 (2025); https://doi.org/10.2174/0109298673323198240823070219
/content/journals/cmc/10.2174/0109298673323198240823070219
/content/journals/cmc/10.2174/0109298673323198240823070219
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s web site along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 6-hydroxydopamine; Dihydrosinularin; natural bioactive molecule; neuroprotection; parkinson's disease; PI3K signaling pathway

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test