Ubisol-Q10 for Neurodegenerative Disease Treatment: History
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Subjects: Biochemistry & Molecular Biology
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Siyaram Pandey

It is well established and accepted that excessive oxidative stress is a key contributor to neurodegenerative diseases, driving interest in the development and application of redox therapies including the use of coenzyme-Q10 (CoQ10). However, in several human clinical trials, CoQ10 has failed to show efficacy, possibly due to poor tissue penetration and inability to deliver it parenterally. Ubisol-Q10 is a nanomicellar, water-dispersible formulation of CoQ10 that was created by combining CoQ10 with an amphiphilic and self-emulsifying molecule of polyoxyethanyl α-tocopheryl sebacate (PTS). This stable formulation is suitable for parenteral delivery and when tested at micromolar concentrations (well within FDA guidelines), it showed unprecedented neuroprotection, both in cellular models and animal models of chronic progressive neurodegeneration of both Parkinson’s and Alzheimer’s type. Systemic application of Ubisol-Q10 in drinking water stopped further progression of ongoing neurodegeneration as long as Ubisol-Q10 was provided. Mechanistically, this treatment with Ubisol-Q10 mobilized astroglia response in the CNS, quenched reactive oxygen species, prevented cell senescence, activated autophagy, reduced inflammation, and stabilized mitochondria. Importantly, these biochemical outcomes are accompanied by a significant improvement in behavioral deficits typically observed in animals with Parkinson’s and Alzheimer’s disease. Thus, Ubisol-Q10 is a promising candidate for developing a disease-modifying therapeutic intervention for neurodegenerative diseases that can be easily administered as drinking tonic.

  • progressive neurodegeneration
  • astroglia activation
  • oxidative stress
  • antioxidant
  • vitamin E
  • mitochondria

1. Introduction

Various mechanisms have been implicated in the progression of neurodegenerative processes. These include excessive oxidative stress, mitochondrial dysfunction, autophagy deficiencies, protein aggregation and misfolding, inflammation, excitotoxicity, cell death pathways, and loss of trophic support. However, none of these mechanisms have been proven to be a primary cause of neurodegenerative disorders [1][2][3]. This is likely because these pathogenic pathways are engaged at different stages of disease progression and are often a secondary manifestation of the disease process. Accordingly, no single drug and/or therapeutic approach to mitigate the neurodegeneration derived from various preclinical studies has been successful so far, but the needs are urgent and critically important.

It has long been recognized that CoQ10, a natural lipid soluble antioxidant and enzyme cofactor, possesses many molecular features that could play a role in neuroprotection. CoQ10 is an essential constituent of cell membranes where it controls cellular redox states as a critical cofactor of cellular oxidoreductases. Its function is essential for cellular homeostasis and viability. It can act as either a two electron or one electron carrier during the transition from fully oxidized (ubiquinone) to fully reduced (ubiquinol) forms. It is critical not only for mitochondrial electron transport chains and cellular energy production, but also for the function of many cellular oxidoreductases [4]. It is also a powerful antioxidant and free radical scavenger [5][6]. Although it is produced by cells, its content is low, decreasing with age or disease. The efforts to increase the cellular content through supplementation are mostly unsuccessful due to its lipophilic nature. Within the scientific communities, very significant efforts have been made to solubilize and increase the absorption/bioavailability of supplemented CoQ10. Multiple methods have been developed and tested and these include various approaches to emulsify and/or disperse CoQ10 and more recently methods to achieve water solubility which are extensively reviewed [7][8][9][10]. Most of these formulations have been shown to have an increased cellular absorption/bioavailability; however, none is suitable for parenteral delivery due to drawbacks of drug emulsions such as rate of dispensation, degree of emulsification, particle size, or drug precipitation from the formulation upon dispersion.

2. Standard Oil-Soluble Formulation of Coenzyme-Q10 in Neurodegenerative Diseases

A significant amount of work has been done with oil-soluble coenzyme-Q10 and many excellent reviews have been written on the subject focusing on general human health [11][12] and neurodegenerative diseases [13][14][15][16] such as Parkinson’s disease [17][18][19]. Oil-soluble coenzyme-Q10 has been studied as a potential therapeutic for many neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, among others [20]. The next section will briefly discuss previous results testing oil-soluble CoQ10 on these various neurodegenerative diseases.

2.1. Parkinson’s Disease

Mitochondrial dysfunction and excessive reactive oxygen species (ROS) have been shown to be major factors in the development of Parkinson’s disease. Initially, Beal et al. used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and demonstrated the mitigation of MPTP-induced loss of striatal dopamine and dopaminergic axons in mice treated with 200 mg/kg/day CoQ10 in their diet (Table 1) [21]. Further investigation by this group using a formulation of CoQ10 with surfactant (Tishcon CoQ10) demonstrated significant neuroprotection at doses of 1600 mg/kg/day in MPTP mice [22]. Administration of normal oil-soluble CoQ10 at 1600 mg/kg/day through diet significantly reduced the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) while preventing the formation of α-synuclein aggregates in dopaminergic neurons [22]. Combining CoQ10 (1% of diet) with creatine (2% of diet), shown to protect against excitotoxicity and β-amyloid toxicity in vitro [23], researchers demonstrated additive neuroprotective effects against MPTP neurotoxicity in mice [24]. This combination was able to reduce lipid peroxidation, the accumulation of α-synuclein in SNpc neurons, and dopaminergic neuron loss in vivo. Examining various antioxidants on a Drosophila model of Parkinson’s disease, Faust et al. found no neuroprotection following CoQ10 supplementation at very high doses of 100 mg/mL in their drinking water (Table 1) [25]. This group obtained approval for a clinical trial using the Tishcon CoQ10 formulation; however, the maximum dose given to the patient as approved by the FDA was far lower than that reported in the in vivo work. Therefore, it is not surprising that this formulation did not show any significant effects in patients [26]. A formulation with bioavailability and efficacy at FDA-approved doses should be evaluated and advanced to a clinical study.

Table 1. Summary of recent research progress made with various formulations of coenzyme-Q10.

Neurodegenerative
Disease		 Model Effective
Dose		 Mode of Administration Major Outcomes Reference
Oil-Soluble CoQ10 Alzheimer’s Disease In-Vivo (Mice) 10 g/kg diet Oral - Protection against neurotoxicity & oxidative stress
- Mitochondrial stabilization
- Reduced Aβ plaques
- Improved cognitive performance		 Wadsworth 2008 [27]
In-Vitro 6.25 µM Media Supplementation Wadsworth 2008 [27]
In-Vivo (Mice) 0.4% or 2.4% Oral Dumont 2011 [28]
In-Vitro 10 µM Media Supplementation Sadli 2013 [29]
Amyotrophic Lateral Sclerosis (ALS) In-Vivo (Rats & Mice) 200 mg/kg/ day Oral - Anti-oxidative effects
- Preserved mitochondrial function
- Increased lifespan		 Matthews 1998 [30]
In-Vivo (Mice) 200 mg/kg/day (no effect) Oral (Gavage) Lucchetti 2013 [31]
Frontotemporal Dementia In-Vivo (Mice) 0.5% of Diet Oral - Improved behaviour & survival Elipenahli 2012 [32]
Huntington’s Disease In-Vivo (Rats) 200 mg/kg/day Oral - Improved motor performance & survival
- Delayed weight loss
- Prevented striatal neuron intranuclear inclusion formation
- Slowed striatal neuron atrophy
- Reduced HTT aggregate formation
- Reduced oxidative damage		 Matthews 1998 [30]
In-Vivo (Mice) 400 mg/kg/day Oral Ferrante 2002 [33]
In-Vivo (Mice) 0.2% of Diet Oral Stack 2006 [34]
In-Vivo (Mice, Rats) 1600–2000 mg/kg/day Oral Yang 2009 [24]
In-Vivo (Mice) 0.2% of Diet Oral Hickey 2012 [35]
Machado-Joseph Disease In-Vitro 10 µM, 30 µM, 90 µM Media Supplementation - Improved cell viability & reduced apoptosis
- Prevented ATX3 protein aggregation		 Lopes-Ramos 2016 [36]
Multiple-System Atrophy In-Vitro 25 µM Media Supplementation - Improved oxidative metabolism
- Reduced apoptosis		 Nakamoto 2018 [37]
Parkinson’s Disease In-Vivo (Mice) 200 mg/kg/day Oral - Dopaminergic neurons saved in striatum and SNpc
- Clearance of α-synuclein aggregates
- Limited oxidative damage
- Reduced pro-inflammatory cytokines		 Beal 1998 [21]
In-Vivo (Mice) 200–1600 mg/kg/day Oral Cleren 2008 [22]
In-Vivo (Mice) 1% of Diet Oral Yang 2009 [24]
In-Vivo (Drosophila) 100 mg/mL (no effect) Oral Faust 2009 [25]
In-Vivo (Rats) 25 µg/mL Intrastriatal Injection Park 2020 [38]
Ubisol-Q10 Alzheimer’s Disease In-Vitro 50 µg/mL Media Supplementation - Inhibited oxidative stress
- Upregulated autophagy
- Maintained MMP
- Reduced cell cycle arrest protein expression
- Prevented SIPS onset
- Inhibited apoptosis
- Improved memory
- Reduced hippocampal neurodegeneration
- Cleared Aβ plaques
- Increased astrocyte activity
- Reduced microglial activity		 Ma 2014 [39]
In-Vivo (Mice) 6 mg/kg/day Oral Muthukumaran 2018 [40]
In-Vivo (Mice) 50 µg/mL Oral Vegh 2019 [41]
In-Vitro 50 µg/mL Media Supplementation Vegh 2019 [41]
Parkinson’s Disease In-Vivo (Rats) 50 µg/mL Oral - Reduced oxidative stress
- Maintained ATP generation
- Stabilized mitochondrial membrane
- Prevented loss of dopaminergic neurons
- Activated pro
-survival astrocytes
- Ameliorated motor dysfunction		 Somayajulu-Nitu 2009 [42]
In-Vivo (Mice) 6 mg/kg/day Oral Muthukumaran 2014 [43]
In-Vivo (Rats) 6 mg/kg/day Oral Muthukumaran 2014 [44]
In-Vivo (Mice) 3 mg/kg/day Oral Sikorska 2014 [45]

In an attempt to improve the bioavailability of CoQ10, Park et al. used direct intrastriatal delivery of oil-soluble CoQ10 [38]. Using 6-hydroxydopamine (6-OHDA)-induced Parkinson’s rats, they compared the progression of cell death in the substantia nigra (SN) region of the brain between the rats receiving intrastriatal CoQ10 and rats receiving oral administration of CoQ10 at significantly higher doses. Results indicated increased tyrosine hydroxylase expression in the striatum and SN as well as a reduction in TNF-α, a pro-inflammatory cytokine, following intrastriatal delivery of CoQ10 [38]. This demonstrates the targeting and amelioration of two critical Parkinsonian pathologies, those being the loss of tyrosine hydroxylase positive neurons in the SN and neuroinflammation. These results indicated considerable neuroprotection at doses significantly lower than what is seen with oral delivery of oil-soluble CoQ10 (Table 1). Furthermore, this study helps demonstrate the importance of increasing the bioavailability of CoQ10 as it can result in significantly improved neuroprotection. Although it gave good results, intrastriatal injections are not a conceivable way to treat patients.

2.2. Alzheimer’s Disease

Oxidative stress and mitochondrial dysfunction are also critical causative features of Alzheimer’s disease development [46][47]. Researchers have investigated the therapeutic properties of oil-soluble coenzyme-Q10 both in vitro and in vivo. MC65 cells are a human neuroblastoma cell line expressing residues of the amyloid precursor protein (APP), commonly cleaved by secretases to form amyloid-β plaques in AD patients [27][48][49]. Woodworth et al. used hydrophobic CoQ10 solubilized in ethanol in MC65 cells and demonstrated the neuroprotective effects with a dose of 6.25 µM (around 5 mg/mL, a relatively high dose) against neurotoxicity and oxidative stress (Table 1) [27]. Another research group examined the effects of 10 µM CoQ10 (dissolved in acetone) against Aβ- and zinc-induced mitochondrial dysfunction in M17 human neuroblastoma cells (Table 1). They demonstrated CoQ10′s ability to restore zinc-mediated cellular dysfunction and provide neuroprotection against the associated mitochondrial dysfunction [29]. It was also shown that CoQ10 can stabilize the membrane of neuronal cells following Aβ-induced alterations in membrane potential [29]. Furthermore, in vitro application of CoQ10 has reported its ability to prevent the accumulation of the characteristic Aβ aggregates and thus inhibit its toxicity [50].

Interestingly, in vivo studies with oral supplementation of 10 g/kg diet of CoQ10 have shown antioxidative effects in the brains of wild-type mice; however, the levels of mitochondrial CoQ10 were not increased in their brains casting doubt about the blood-brain-barrier permeability and brain bioavailability (Table 1) [27]. Furthermore, using a Tg19959 transgenic mouse model of AD, Dumont et al. showed that oral CoQ10 supplementation reversed AD pathologies through the reduction of oxidative stress and Aβ42 levels, while improving cognitive performance (Table 1) [28]. Overall, researchers have shown the neuroprotective efficacy of CoQ10 and its ability to target multiple pathologies associated with Alzheimer’s disease. Unfortunately, the daily CoQ10 intake required to show this efficacy is very high and cannot be translated to human patients. If an improved formulation were created that can increase bioavailability particularly in the brain, it could permit the use of more biologically relevant doses experimentally and clinically to treat AD.

2.3. Huntington’s Disease

Huntington’s disease (HD) occurs due to neurodegeneration in the striatum [51] with mitochondrial dysfunction and increased oxidative stress playing crucial roles in its pathogenesis [52][53]. Furthermore, the misfolding and aggregation of the Huntington (HTT) protein indicates that a supplement which can improve mitochondrial function and eliminate oxidative stress while activating autophagy may be beneficial in the treatment of HD [53]. Specifically, Matthews et al. found that oral supplementation of 200 mg/kg/day CoQ10 was effective in reducing 3-NP associated neurotoxicity in rat models of HD (Table 1) [30]. In transgenic mouse models of HD, 400 mg/kg/day CoQ10 supplementation was shown to significantly increase survival while influencing disease progression as well (Table 1) [33]. CoQ10 intake led to improved motor performance, mitigated the formation of striatal neuron intranuclear inclusions, delayed reductions in body weight, and slowed neuronal and gross brain atrophy in the striatum [33]. Combining a diet of 0.2% CoQ10 and minocycline, Stack et al. demonstrated improved survival, behavioral performance, and improved biochemical pathologies including brain atrophy, neuronal atrophy, and HTT aggregation compared to either treatment alone in R6/2 transgenic mice (Table 1) [34]. Examining weight loss, a common feature of HD patients and R6/2 transgenic mice [54], CoQ10 alone demonstrated drastic improvements, even compared to the combined treatment [34]. It could be that HD-associated weight loss occurs as a result of energy metabolism defects which are being ameliorated by CoQ10 [34]. Other combinatorial studies examined high oral doses of CoQ10 in combination with creatine on a 3-NP rat model of HD and R6/2 transgenic mice (Table 1) [24]. Additive neuroprotective effects were observed whereby striatal lesion volume decreased, glutathione homeostasis was maintained, and oxidative damage was attenuated following 3-NP administration. The expected increase in motor performance and survival were demonstrated in the R6/2 transgenic mice [24]. Unfortunately, the dosing used in this experiment is extremely high and unrealistic for humans corresponding to approximately 1 kg of CoQ10 per day for a 62 kg individual (the average weight worldwide). As a model of the more common middle-age onset form of HD, Hickey et al. used CAG140 knock-in mice to better demonstrate the progressive nature of the disorder. Feeding the mice with 0.2% or 0.6% CoQ10 in their diet (Table 1), they observed improvements in behavior deficits without blocking huntingtin protein aggregation in the striatum [35]. If another formulation were able to more readily cross the blood-brain-barrier increasing bioavailability in the brain, this could aid in the clearance of these protein aggregates. Interestingly, they found more benefits using the lower dose of 0.2% compared to 0.6%. Furthermore, 0.2% CoQ10 led to deleterious effects in WT mice whereby open field rearing and activity and rotarod performance were reduced; however, the absence of these deleterious effects in the mutant mice along with the outstanding safety profile of CoQ10 in humans may render this result insignificant [35]. Overall, the antioxidant and mitochondrial stabilizing properties of CoQ10 make it an excellent candidate to treat the progression of Huntington’s disease if clinically relevant doses can be achieved.

2.4. Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is another neurodegenerative disease characterized by progressive muscle weakness and atrophy, as well as the loss of motor neurons [31]. Mutations in superoxide dismutase (SOD1) commonly associated with ALS implicate the role of oxidative stress in its pathogenesis [55]. As a result, coenzyme-Q10 with its antioxidant and neuroprotective abilities may serve as a potential therapeutic to halt the progression of ALS. Using transgenic rat models of ALS, oral supplementation of 200 mg/kg/day of CoQ10 (Table 1) led to a subsequent increase in coenzyme-Q9 and coenzyme-Q10 in the cerebral tissues and increases in mitochondrial CoQ10 concentrations [30]. In a transgenic mouse model of familial ALS containing a point mutation in the SOD1 gene, known to lead to motor neuron degeneration in ALS patients [56], mitochondrial dysfunction of motor neurons has been observed [57]. However, oral supplementation of CoQ10 resulted in antioxidant effects and preserved mitochondrial function in SOD1-mutated transgenic mice resulting in an overall increase in their lifespan [30]. Unfortunately, similar studies on SOD1G93A mice demonstrated no effect on disease progression following oral supplementation of 200 mg/kg/day CoQ10 (Table 1) [31]. As endogenous CoQ10 levels are significantly increased in these ALS mice in an attempt toward a protective antioxidant state, it could be that the supplementation of exogenous CoQ10 has little to no additional effects on CoQ10 levels in the brain. However, if the bioavailability of CoQ10 is improved, it could allow for important neuroprotection in the Central Nervous System (CNS) of ALS models and patients providing a potential therapeutic treatment.

2.5. Other Neurodegenerative Diseases

Various other neurodegenerative diseases present similar hallmarks to the aforementioned conditions including oxidative stress and mitochondrial dysfunction, ultimately resulting in neuronal death. Frontotemporal dementia is characterized by progressive atrophy of the frontal and temporal lobes as well as neurofibrillary tangles (NFT) [58][59]. Using P301S mice containing a mutation in the tau protein, resulting in NFT generation and tau hyperphosphorylation, Elipenahli et al. demonstrated improved survival and behavior without significantly affecting tau hyperphosphorylation levels following supplementation of CoQ10 comprising 0.5% of the mouse diet (Table 1) [32].

Machado-Joseph Disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by Cytosine-Adenine-Guanine (CAG) triplet repeat expansions which result in an expanded polyglutamine tract in the ataxin-3 (ATX3) protein [36]. This results in protein misfolding, dysfunction and aggregation resulting in neuronal cell death [36][60]. Using PC12 cells transfected with expanded ATX3 as a model of MJD, treatment with 10µM CoQ10 was shown to improve cell viability, reduce the percentage of apoptotic cells, and prevent ATX3 protein aggregation ultimately ameliorating MJD-like pathologies (Table 1).

Multiple System Atrophy (MSA) is another neurodegenerative disease which is characterized by autonomic failure with combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction [37]. Patients with MSA often display oligodendrocytes containing α-synuclein aggregates and neurons containing apoptotic proteins [61][62]. Furthermore, decreased levels of CoQ10 have been observed in the cerebellum of MSA patients [63]. As a result, Nakamoto et al. obtained induced pluripotent stem cells (iPSCs) from MSA patients and differentiated them into neurons. These cells were then supplemented with 25µM CoQ10 (Table 1) and showed improved mitochondrial oxidative metabolism and reduced amounts of apoptosis [37].

This entry is adapted from the peer-reviewed paper 10.3390/antiox10050764

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