Article

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

BMC Neuroscience (Impact Factor: 2.67). 01/2014; 15(1):21. DOI: 10.1186/1471-2202-15-21
Source: PubMed

ABSTRACT

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.
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 To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway.
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.

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Available from: Marianna Sikorska, Mar 14, 2014
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    • "In these experiments, mice received on average 6 mg CoQ 10 /kg/day, similar to the concentrations previously used in rats and mice [15] [16]. In the later studies we show that the neuroprotection correlated with the brain penetration of CoQ 10 [15] [16]. We have also ruled out a possibility that this neuroprotection was due to an interaction between CoQ 10 and MPTP preventing the generation of the neurotoxic MPP+. "
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    ABSTRACT: Introduction: Parkinson's disease arises from a combination of environmental and genetic risk factors. At present neither the curative nor preventative therapies are available; hence, there is an urgent need to develop reliable animal models to facilitate their development. Water soluble nanomiceller formulation of CoQ10 (Ubisol-Q10) has shown neuroprotection against neurotoxin on human neuronal cells. We have combined the genetic deficiency of DJ-1/PARK7 mice with MPTP exposure and develop a genetic susceptibility model of PD and evaluated the neuroprotective efficacy of (Ubisol-Q10). Methods: Transgenic mice with DJ-1 deficiency (DJ-1/PARK7) were given either water or Ubisol-Q10 prophylactically at a dose of 6 mg/kg/day added directly to a drinking water for one month followed challenged with MPTP injections while keeping the same drinking water regiments. Four weeks after the last injection we evaluated neuroprotective efficacy of Ubisol-Q10 in DJ-1/MPTP model of PD using histochemical and behavioral readouts. Results: We confirmed genetic susceptibility to MPTP and showed that prophylactic oral treatment with Ubisol-Q10 significantly offset the neurotoxicity and ameliorated motor dysfunction, otherwise correlated with the MPTP injury. Conclusion: Ubisol-Q10 protects against MPTP-induced neurodegeneration and motor dysfunction in DJ-1 deficient mice. Ubisol-Q10 might be a treatment prospect for people genetically predisposed to PD as well as with sporadic PD.
    Full-text · Article · Jul 2014 · Journal of Parkinson's Disease
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    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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.
    Full-text · Article · Jan 2014 · BMC Neuroscience
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    ABSTRACT: Although the support for the use of antioxidants, such as coenzyme Q10 (CoQ10), 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 CoQ10 is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ10 (Ubisol-Q10) 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-Q10 was delivered in drinking water. Prophylactic application of Ubisol-Q10, started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q10 group by day 28). Therapeutic application of Ubisol-Q10, 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-Q10 concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ10/kg body weight/day, showing clearly that high doses of CoQ10 were not required to deliver these effects. Furthermore, the Ubisol-Q10 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-Q10 was capable of halting the neurodegeneration already in progress; however, to maintain it a continuous supplementation of Ubisol-Q10 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-Q10 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.
    Full-text · Article · Apr 2014 · Neurobiology of aging
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