Accessible 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, 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.

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  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