title: 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.
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.forename: Simon
authors.initials: S
authors.lastname: Chiu
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Terpstra
authors.forename: Yves
authors.initials: Y
authors.lastname: Bureau
authors.forename: Jirui
authors.initials: J
authors.lastname: Hou
authors.forename: Hana
authors.initials: H
authors.lastname: Raheb
authors.forename: Zack
authors.initials: Z
authors.lastname: Cernvosky
authors.forename: Vladimir
authors.initials: V
authors.lastname: Badmeav
authors.forename: John
authors.initials: J
authors.lastname: Copen
authors.forename: Mariwan
authors.initials: M
authors.lastname: Husni
authors.forename: Michael
authors.initials: M
authors.lastname: Woodbury-Farina
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects*; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D055786:Gene Knockout Techniques; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy*; D011596:Psychomotor Disorders / Q000188:drug therapy*; D011897:Random Allocation; D051381:Rats
chemical_list: D056572:Histone Deacetylase Inhibitors; D018697:Nootropic Agents; D006655:Histone Deacetylases; D003474:Curcumin