For the first time ever, we have effectively established an animal model, using PQ, which accurately demonstrates the chronic and progressive neurodegeneration similar to that in PD patients. Compared to an acute model, our model effectively replicates PD by having slow, chronic degeneration of DA neurons in SNpc. However, progressive neurodegeneration has also been observed with continuous infusion of MPTP using an osmotic pump . The progressive loss was evident in our results over the observed time span, with a decreased number of neurons remaining at each subsequent time interval. Our model allows us to intervene with treatment at any point after the initiation of the disease. Due to this we were also able to demonstrate for the first time, that when Ubisol-Q10 is administered therapeutically it effectively halts the progression of the neurodegeneration, even at low dosages. After demonstrating the success Ubisol-Q10 has in protecting the neurons therapeutically, it was shown that this treatment needs to be continuous. Halting the administration of the treatment would result in a continuation of the neurodegeneration initiated by the PQ toxin during the injection regime. With bioavailability data, we were also able to show that Ubisol-Q10 is effective at increasing the CoQ10 levels in the brain. All of the results were supported using behavioural, histochemical, and biochemical methodology.
An animal model of PD was developed when the neurotoxin MPTP was found to cause PD like symptoms and loss of DA neurons by blocking complex I of the electron transport chain . MPTP establishes an acute model of PD, which is not realistic to the natural progression of the disease. Following this, it was found that environmental toxins, rotenone and PQ, can also block complex I of the electron transport chain. Further supported by epidemiological studies, a link between the use of these pesticides and the incidence of PD was established . The development of the PQ animal model of PD is more relevant than the acute MPTP model as it more effectively mimics PD in patients.
In previous research, a variety of dosages and injection regimes of PQ have been used in rat models of PD [14, 23]. The downfall of these PQ models was that they were not tested to ensure slow, progressive loss. However, progressive, continuous, and slow neuronal loss in the SNpc was tested and seen in our model during and after our 5 interpretational injection (1 every 5 days for 5 injections). Establishing this model is essential before testing any therapeutic treatment interventions as this is what characterizes PD in patients.
Additional research shows that the pathogenic mechanisms of PD are associated with mitochondrial dysfunction, oxidative stress and altered protein handling . The involvement of mitochondria is considered a key to cell death observed in PD in both sporadic and familial cases.
Previous experiments in our lab have shown that Ubisol-Q10 is effective in protecting neurons against toxic insult in vivo and can protect DA neurons if administered prophylactically, that is, even before exposure to the environmental toxin, PQ . However, PD is often not diagnosed until symptoms arise, which occurs when almost 50 – 60% neurons are lost.
Once the process is initiated by toxic insult, it is crucial to see if treatment administered therapeutically can halt further neurodegeneration. Ubisol-Q10 was tested therapeutically and it showed to have significant protection of the remaining DA neurons after both 4 weeks, and 8 weeks of treatment. This is one of the first experiments to show this. There are multiple explanations which could explain how Ubisol-Q10 protects the remaining neurons; initially it is plausible that the combined anti-oxidant nature of the two components of Ubisol-Q10 (CoQ10 and Vitamin E) could quench the levels of oxidative stress associated with the disease. It was shown that the carrier solution containing vitamin E alone did not have a significant effect on neuroprotection ( and data not shown). In other research, it’s been shown that lipid soluble CoQ10 (in high dosages) is an effective neuroprotective agent . Past research on Ubisol-Q10 has shown it to be effective in stabilizing the mitochondria through inhibiting Bax . Another hypothesis is that it could be protecting the mitochondria by increasing its overall energy output; as CoQ10 is naturally found in the electron transport chain.
Previous research using oil soluble CoQ10 as a treatment for PD made it into clinical trials in 2011, though failed in phase 2. In their pre-clinical work the oil-soluble CoQ10 treatment was tested prophylactically on MPTP induced mouse model [19, 25]. The oil soluble CoQ10 was shown to be effective, but only at high dosages. A possible explanation to the discontinuation of their clinical trial was because very large dosages (1,600 mg/kg/day) were required to show any neuroprotection. When this dosage is converted to a human dose (averaging 70 kg) they are required to take 112 g/day in order to obtain results, which is beyond the acceptable FDA approved dose for clinical trials (2.4 g). Therefore, in the clinical trial they were not receiving anywhere near the dose required to show positive results. However, our preclinical work, on our more accurate chronological model, treating both prophylactically and therapeutically has shown comparable neuroprotection but at a significantly lower dose (6 mg/kg/day). Therefore, if our dosage was converted for human treatment it would only be 0.42 g/day, which is not only lower then FDA approved amount for clinical trial (2.4 g) but also the approved maximum daily dosage for general supplement intake (1.2 g). Both the oil soluble CoQ10 and Ubisol-Q10 showed comparable bioavailability when administered, but in order to have comparable quantities in the brain the oil formulation needed to be given in a significantly higher dose .
The question remains why Ubisol-Q10 is more effective at lower doses than CoQ10. It is assumed that the water soluble composition makes absorption into the blood stream easier, therefore, making it possible to cross the blood brain barrier. It is evident in our bioavailability experiment that this formulation does shuttle CoQ10 into the brain, due to the increase of 35% after 3 hours. Though, the other significant finding was that once it is in the brain it does not accumulate. This means that there is no build-up of CoQ10 in the brain, which could be toxic to the neurons. The natural removal seen explains why when the treatment is withdrawn the effects are no longer sustained. Henceforth, in order to sustain neuroprotection the treatment must be continuous and in doing so neurotoxicity will not result. It is also important to note that the animals in this experiment were allowed to drink Ubisol-Q10 supplemented drinking water ad libitum and were not gavaged.
Our study has shown that the withdrawal of Ubisol-Q10 leads to continued neurodegeneration, which was triggered by the toxin during the injection period. Therefore, Ubisol-Q10 does not halt neurodegeneration by acting on the toxin, but rather by supporting the remaining neurons. This experiment was only conducted with sustained treatment over 8 weeks (with 1 month of treatment and a consecutive month of withdrawal). To ensure the results, more research needs to be conducted over longer time spans. Though the current data found supports sustained treatment regiments in order to withstand neurodegeneration. These findings were also supported by the behaviour data which shows that animals provided with Ubisol-Q10 treatment for a longer duration perform better throughout in the beam test compared to the animals where the treatment was withdrawn.