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Licensed Unlicensed Requires Authentication Published by De Gruyter November 7, 2013

Liposomal-formulated curcumin [Lipocurc™] targeting HDAC (Histone Deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson’s disease: implications for epigenetics-based nanotechnology-driven drug platform

  • Simon Chiu EMAIL logo , Kristen J. Terpstra , Yves Bureau , Jirui Hou , Hana Raheb , Zack Cernvosky , Vladimir Badmeav , John Copen , Mariwan Husni and Michael Woodbury-Farina

Abstract

Background: Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson’s disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain.

Methods: In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem.

Results: We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025).

Conclusions: We demonstrated for the first time Lipocurc™’s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

Acknowledgments

This study was financially supported by SignPath Pharma Inc., with financial contributions from Discretionary Research Account of Dr Simon Chiu, Lawson Health Research Institute, London, Ontario, Canada. We thank Ms. Susan Thompson (LHRI Research Accountant) and Ms. Nicole Thomas (LHRI Research Accounts manager) for managing the study. We express our sincerest thanks to Dr Majeed M. CEO of Sabinsa Inc. N.J. for creating and sustaining the vision of translating curcumin extract to CNS drug candidate for treatment of neurological disorders. Preliminary results were presented by Kristen Terpstra at research poster session of Movement Disorder Society 16th International Congress of Parkinson’s Disease and Movement Disorders in Dublin, Ireland, June 17–21, 2012. Abstract published in Movement Disorders, Volume 27, June 2012, Abstract Supplement.

References

1. RochetJC, HayBA, GuoM. Molecular insights into Parkinson’s disease. Prog Mol Biol Transl Sci2012;107:12588.Search in Google Scholar

2. GenevièveP, DelcuveDH, DavieJR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors: review. Clin Epigenetics2012;4:5.10.1186/1868-7083-4-5Search in Google Scholar PubMed PubMed Central

3. CoppedeF. Genetics and epigenetics of Parkinson’s disease. Sci World J2012;ID 489830:112.10.1100/2012/489830Search in Google Scholar PubMed PubMed Central

4. Meza-SosaR, valle-GarciaD, Pedraza-AlvaG, Perex-MartinezL. Role of microRNAs in central nervous system development and pathology. J Neurosci Res2012;90:112.10.1002/jnr.22701Search in Google Scholar PubMed

5. KimJ, InoueK, IshiiJ, VantiWB, VoronovSV, MurchisonE, et al. A microRNA feedback circuit in midbrain dopamine neurons. Science2007;317:12204.10.1126/science.1140481Search in Google Scholar PubMed PubMed Central

6. Miñones-MoyanoE, PortaS, EscaramísG, RabionetR, IraolaS, KagerbauerB, et al. MicroRNA profiling of Parkinsons disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet2011;20:306778. Epub ahead of print 10 May 2011.10.1093/hmg/ddr210Search in Google Scholar PubMed

7. LinazasoyoG. Potential applications of nanotechnologies to Parkinson’s disease therapy. Parkinsonism Relat Disord14:38392.10.1016/j.parkreldis.2007.11.012Search in Google Scholar PubMed

8. FuS, KurzrockR. Development of curcumin as an epigenetic agent. Cancer2010;116:46706.10.1002/cncr.25414Search in Google Scholar PubMed

9. ZhouH, ChristopherS. Beevers and Shile Huang targets of curcumin. Curr Drug Targets2011;12:33247.10.2174/138945011794815356Search in Google Scholar PubMed PubMed Central

10. SunM, SuX, DingB, HeZ, LiuX, YuA, et al. Advances in nanotechnology-based delivery systems for curcumin. Nanomedicine2012;7:1085100.10.2217/nnm.12.80Search in Google Scholar PubMed

11. ChiuS, LiuE, MajeedM, VishwanathaJK, RanjanA, MaitraA, et al. Intravenous curcumin distribution in the rat brain. J Anticancer Res2011;31:90712.Search in Google Scholar

12. MatabudulD, PucajK, BolgerG, VcelarB, MajeedM, HelsonL. Tissue distribution of (Lipocurc™) liposomal curcumin and tetrahydrocurcumin following two- and eight-hour infusions in beagle dogs. Anticancer Res2012;32:435964.Search in Google Scholar

13. NuytemansK, TheunsJ, CrutsM, Van BroeckhovenC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat2010;31:76380.10.1002/humu.21277Search in Google Scholar PubMed PubMed Central

14. KilarskiLL, PearsonJP, NewswayV, MajounieE, KnipeMD, MisbahuddinA, et al. Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson’s disease. Mov Disord2012;27:15229. DOI:10.1002/mds.25132. Epub ahead of print 6 Sep 2012.Search in Google Scholar

15. KahlePJ, WaakJ, GasserT. DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med2009;47:135461.10.1016/j.freeradbiomed.2009.08.003Search in Google Scholar PubMed

16. BatelliS, AlbaniD, RamettaR, PolitoL, PratoF, PesaresiM, et al. DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinsons disease and involvement of HSP70. PLoS One2008;3:e1884.Search in Google Scholar

17. MartinatC, ShendelmanS, JonasonA, LeeteT, BealMF, YangL, et al. Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-derived cell model of primary parkinsonism. PLOS2004;2:e327.10.1371/journal.pbio.0020327Search in Google Scholar PubMed PubMed Central

18. KimR, SmithPD, ALyeasinH, HayleyS, MountMP, PownallS, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress. PNAS2005;102:521520.10.1073/pnas.0501282102Search in Google Scholar PubMed PubMed Central

19. AntonyPM, DiederichNJ, BallingR. Parkinson’s disease mouse models in translational research. Mamm Genome2011;22:40119.10.1007/s00335-011-9330-xSearch in Google Scholar PubMed PubMed Central

20. LiL, BraitehFS, KurzrockR. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer2005;104:132231.10.1002/cncr.21300Search in Google Scholar PubMed

21. LiL, AhmedB, MehtaK, KurzrockR. Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Mol Cancer Ther2007; 6L12761282.10.1158/1535-7163.MCT-06-0556Search in Google Scholar PubMed

22. LundbladM, AnderssonM, WinklerC, KirikD, WierupN, CenciMA. Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson’s disease. Eur J Neurosci2002;15:12032.10.1046/j.0953-816x.2001.01843.xSearch in Google Scholar PubMed

23. WalshRN, CumminsRQ. The open-field test: a critical review. Psychol Bull1976;83:482504.10.1037/0033-2909.83.3.482Search in Google Scholar

24 LaneRD, GlazerWM, HansenTE, BermanWH, KramerSI. Assessment of tardive dyskinesia using the abnormal involuntary movement scale. J Nerv Ment Dis1985;173:3537.10.1097/00005053-198506000-00005Search in Google Scholar PubMed

25 HeneryS, GeorgeT, HallB, BasijiiD, OrtynW, MorrisseyP. Quantitative image based apoptotic index measurement using multispectral imaging flow cytometry: a comparison with standard photometric methods. Apoptosis2008;13:105463.10.1007/s10495-008-0227-4Search in Google Scholar

26. ChiuS, MishraRK. Antagonism of morphine-induced catalepsy by L-prolyl-L-leucyl-glycinamide. Eur J Pharmacol1979;53:11419.10.1016/0014-2999(79)90156-0Search in Google Scholar

27. CohenJ. A power primer. Psychol Bull1992;112:1559.10.1037/0033-2909.112.1.155Search in Google Scholar

28. ZbarskyV, DatlaKP, ParkarS, RaiDK, AruomaOI, DexterDT. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res2005;39:111925.10.1080/10715760500233113Search in Google Scholar PubMed

29 TripanichkulW, JaroensuppaperchE-O. Ameliorating effects of curcumin on 6-OHDA-induced dopaminergic denervation, glial response, and SOD1 reduction in the striatum of hemiparkinsonian mice. Eur Rev Med Pharmacol Sci2013;17:13608.Search in Google Scholar

30. MansouriZ, SabetkasaeiM, MoradiF, MasoudniaF, AtaieA. Curcumin has neuroprotection effect on homocysteine rat model of Parkinson. J Mol Neurosci2012;47:23442. Epub ahead of print 15 Mar 2012.10.1007/s12031-012-9727-3Search in Google Scholar PubMed

31. RayB, BishtS, MaitraA, MaitraA, LahiriDK. Neuroprotective and neurorescue effects of a novel polymeric nanoparticle formulation of curcumin (NAnoCURC™) in the neuronal cell culture and animal model: implications for Alzheimer’s disease. J Alzheimers Dis2011;23:6177.10.3233/JAD-2010-101374Search in Google Scholar PubMed PubMed Central

32. MythriRB, JagathaB, PradhanN, AndersenJ, BharathMM. Mitochondrial complex I inhibition in Parkinson’s disease: how can curcumin protect mitochondria?Antioxid Redox Signal2007;9:399408.10.1089/ars.2006.1479Search in Google Scholar PubMed

33. IshikawaS, TairaT, NikiT, Takahashi-NikiK, MaitaC, MaitaH, et al. Oxidative status of DJ-1 dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-hydroxl-L-phenyalanine (L-DOPA) decarboxylase with DJ-1. J Biol Chem2010;284:2883244.10.1074/jbc.M109.019950Search in Google Scholar PubMed PubMed Central

34. Bora-TatarG, Dayangac ErdenD, AsD, DalkaraS, YelekciK, Erdem-YurterH. Molecular modifications of dicarboxylic acid derivatives as potent histone deacetylase inhibitors: activity and docking studies. Bioorg Med Chem2007;17:521928.10.1016/j.bmc.2009.05.042Search in Google Scholar PubMed

35. WenboZ, BercuryK, CummiskeyJ, LuongN, LebinJ, FreedCR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem2011;286:1494151.10.1074/jbc.M110.211029Search in Google Scholar PubMed PubMed Central

36. SahaRN, PahanK. HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ2006;13:53950.10.1038/sj.cdd.4401769Search in Google Scholar PubMed PubMed Central

37. RyuH, LeeJ, OlofssonBA, MwidauA, DedeogluA, EscuderoM, et al. Histone deacetylase inhibitors prevent oxidative neuronal death. Independent of expanded polyglutamine repeats via an sp1-dependent pathway. Proc Natl Acad Sci USA2003;100:42816.10.1073/pnas.0737363100Search in Google Scholar PubMed PubMed Central

38. SteffanJS, BodaiL, PallosJ, PoelmanM, McCampbellA, ApostolBL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in drosophila. Nature2001;413:73943.Search in Google Scholar

39. SookramC, TanM, DayaR, HeffernanS, MishraRK. Curcumin prevents haloperidol-induced development of abnormal oro-facial movements: possible implications of Bcl-XL in its mechanism of action. Synapse2011;65:78894. DOI:10.1002/syn.20905. Epub ahead of print 21 Mar 2011.Search in Google Scholar

40. RavindranJ, PrasadS, AggarwalBB. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively?AAPS J2009;11:495510.10.1208/s12248-009-9128-xSearch in Google Scholar PubMed PubMed Central

41. MarFarlaneM. Cell death pathways – potential therapeutic targets. Xenobiotica2009;39:61624.10.1080/00498250903137990Search in Google Scholar PubMed

42 DoubleKL, ReyesS, WerryEL, HallidayGM. Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions?Prog Neurobiol2010;92:31629.10.1016/j.pneurobio.2010.06.001Search in Google Scholar PubMed

43. GoldmanSA, ChenZ. Perivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci2011;14:13829.10.1038/nn.2963Search in Google Scholar PubMed PubMed Central

44. DongS, ZengQ, MitchellES, XiuJ, DuanY, LiC, et al. Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity. PLoS One2012;7:e31211. Epub ahead of print 16 Feb 2012.10.1371/journal.pone.0031211Search in Google Scholar PubMed PubMed Central

45. LiS, SunY, ZhaoX, PuXP. Expression of the Parkinsons disease protein DJ-1 during the differentiation of neural stem cells. Brain Res2012;1468:8493.10.1016/j.brainres.2012.05.022Search in Google Scholar PubMed

46. MaDK, MarchettoMC, GuoJU, MingG, GageFH, SongH. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci2010;13:133844.10.1038/nn.2672Search in Google Scholar PubMed PubMed Central

47. DawsonTM, KoHS, DawsonVL. Genetic animal models of Parkinson’s disease. Neuron2010;66:64661.10.1016/j.neuron.2010.04.034Search in Google Scholar PubMed PubMed Central

48. ChandranJS, LinZ, ZapataA, HokeH, ShimojiM, MooreS, et al. Progressive behavioral deficits in DJ-1 deficient mice are associated with normal nigrostriatal function. Neurobiol Dis2008;29:50514.10.1016/j.nbd.2007.11.011Search in Google Scholar PubMed PubMed Central

49. KitadaT, TongY, GautierCA, ShenJ. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem2009;111:696702. Epub ahead of print 19 Aug 2009.10.1111/j.1471-4159.2009.06350.xSearch in Google Scholar PubMed PubMed Central

50. ChesseletMF. In vivo alpha-synclein overexpression in rodents: a useful model of Parkinson’s disease?Exp Neurol2008;209:227.10.1016/j.expneurol.2007.08.006Search in Google Scholar PubMed PubMed Central

51. DecressacM, MattssonB, LundbladM, WeikopP, BjorklundA. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of alpha-synclein in midbrain dopamine neurons. Neurobiol Dis2012;45(3):93953.10.1016/j.nbd.2011.12.013Search in Google Scholar PubMed

52. TatsunoriM, SayuriM, YuiS, TakashiM, SadahiroA, EtsuroO, et al. The I2020T leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol Neurodegener2012;7:1.10.1186/1750-1326-7-15Search in Google Scholar PubMed PubMed Central

53. Ramos-CabrerP, CamposF. Liposomes and nanotechnology in drug development focus on neurological targets. Int J Nanomedicine2013;8:95160.10.2147/IJN.S30721Search in Google Scholar PubMed PubMed Central

54. TeleseF, GamlielA, Skowronska-KrawczykD, Garcia-BassetsI, RosenfeldMG. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron2013;77:60623.10.1016/j.neuron.2013.01.034Search in Google Scholar PubMed PubMed Central

  1. Preliminary results of the study were presented at 16th International Congress of Parkinson’s Disease and Movement Disorders, Dublin, Ireland June 17–21, 2012. Abstract was published in Journal of Movement Disorder Volume 27, Suppl 1:1304. Results were also presented at the International Congress of Cultivating Natural Bioactives, July 9–11, sponsored by University of Western Ontario, London, Ontario, Canada.

    Simon Chiu, Kristen J. Terpstra, Yves Bureau and Jirui Hou contributed equally to this work.

Received: 2013-06-05
Accepted: 2013-09-10
Published Online: 2013-11-07

©2013 by Walter de Gruyter Berlin / Boston

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