Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson's disease.
BACKGROUND
Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson's disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water-soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD.


RESULTS
We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway.


CONCLUSIONS
The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD.
Krithika
K
Muthukumaran
Samantha
S
Leahy
Kate
K
Harrison
Marianna
M
Sikorska
Jagdeep K
JK
Sandhu
Jerome
J
Cohen
Corrine
C
Keshan
Daniel
D
Lopatin
Harvey
H
Miller
Henryk
H
Borowy-Borowski
Patricia
P
Lanthier
Shelly
S
Weinstock
Chemistry & Biochemistry, University of Windsor, 401 Sunset Ave, Windsor, ON, Canada. spandey@uwindsor.ca.
Siyaram
S
Pandey
D000284:Administration, Oral; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005240:Feasibility Studies; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry; D010269:Paraquat; D010300:Parkinson Disease / Q000503:physiopathology* / Q000517:prevention & control*; D051381:Rats; D020318:Rats, Long-Evans; D017828:Rifabutin / Q000031:analogs & derivatives; D012995:Solubility; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D016896:Treatment Outcome; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D014815:Vitamins / Q000008:administration & dosage / Q000737:chemistry; D014867:Water / Q000737:chemistry
D018696:Neuroprotective Agents; D014815:Vitamins; D014867:Water; D014451:Ubiquinone; D017828:Rifabutin; C020754:herbimycin; C024989:coenzyme Q10; D010269:Paraquat