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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.
J Complement Integr Med. 2013 Nov 07; 10JC

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.

Authors

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Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24200537

Citation

Chiu, Simon, et al. "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." Journal of Complementary & Integrative Medicine, vol. 10, 2013.
Chiu S, Terpstra KJ, Bureau Y, et al. 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. J Complement Integr Med. 2013;10.
Chiu, S., Terpstra, K. J., Bureau, Y., Hou, J., Raheb, H., Cernvosky, Z., Badmeav, V., Copen, J., Husni, M., & Woodbury-Farina, M. (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. Journal of Complementary & Integrative Medicine, 10. https://doi.org/10.1515/jcim-2013-0020
Chiu S, et al. 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. J Complement Integr Med. 2013 Nov 7;10 PubMed PMID: 24200537.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chiu,Simon, AU - Terpstra,Kristen J, AU - Bureau,Yves, AU - Hou,Jirui, AU - Raheb,Hana, AU - Cernvosky,Zack, AU - Badmeav,Vladimir, AU - Copen,John, AU - Husni,Mariwan, AU - Woodbury-Farina,Michael, Y1 - 2013/11/07/ PY - 2013/06/05/received PY - 2013/09/10/accepted PY - 2013/11/9/entrez PY - 2013/11/10/pubmed PY - 2015/4/9/medline JF - Journal of complementary & integrative medicine JO - J Complement Integr Med VL - 10 N2 - 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. SN - 1553-3840 UR - https://www.unboundmedicine.com/medline/citation/24200537/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_ L2 - https://www.degruyter.com/document/doi/10.1515/jcim-2013-0020 DB - PRIME DP - Unbound Medicine ER -