Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease.
Although the support for the use of antioxidants, such as coenzyme Q(10) (CoQ(10)), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ(10) is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ(10) (Ubisol-Q(10)) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q(10) was delivered in drinking water. Prophylactic application of Ubisol-Q(10), started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q(10) group by day 28). Therapeutic application of Ubisol-Q(10), given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q(10) concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ(10)/kg body weight/day, showing clearly that high doses of CoQ(10) were not required to deliver these effects. Furthermore, the Ubisol-Q(10) treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q(10) was capable of halting the neurodegeneration already in progress; however, to maintain it a continuous supplementation of Ubisol-Q(10) was required. The pathologic processes initiated by MPTP resumed if supplementation was withdrawn. We suggest that in addition to brain delivery of powerful antioxidants, Ubisol-Q(10) might have also supported subcellular oxidoreductase systems allowing them to maintain a favorable cellular redox status, especially in astroglia, facilitating their role in neuroprotection. Based on this data further clinical testing of this formulation in PD patients might be justifiable.
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Marianna
M
Sikorska
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Patricia
P
Lanthier
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Harvey
H
Miller
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Melissa
M
Beyers
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Caroline
C
Sodja
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Bogdan
B
Zurakowski
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada.
Sandhya
S
Gangaraju
Department of Chemistry and Biochemistry, University of Windsor Essex Hall, Windsor, Ontario, Canada.
Siyaram
S
Pandey
Department of Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa, Ontario, Canada. Electronic address: jagdeep.sandhu@nrc.ca.
Jagdeep K
JK
Sandhu
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001253:Astrocytes / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008823:Micelles; D053758:Nanoparticles; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000975:Antioxidants; D008823:Micelles; D018696:Neuroprotective Agents; D014451:Ubiquinone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C024989:coenzyme Q10
Antioxidant; Astroglia activation; Motor function; Neuroprotection; Oxidative stress; Vitamin E