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.

In an attempt to improve the bioavailability of CoQ₁₀, Park et al. used direct intrastriatal delivery of oil-soluble CoQ₁₀ ^[38][27]. 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][27]. 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][28,29]. 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][30,31,32]. 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][30]. 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][33]. It was also shown that CoQ₁₀ can stabilize the membrane of neuronal cells following Aβ-induced alterations in membrane potential ^[29][33]. 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][34].

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][30]. 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][35]. 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][36] with mitochondrial dysfunction and increased oxidative stress playing crucial roles in its pathogenesis ^[52][53][37,38]. 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][38]. 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][39]. 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][40]. 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][40]. 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][41]. Examining weight loss, a common feature of HD patients and R6/2 transgenic mice ^[54][42], CoQ₁₀ alone demonstrated drastic improvements, even compared to the combined treatment ^[34][41]. It could be that HD-associated weight loss occurs as a result of energy metabolism defects which are being ameliorated by CoQ₁₀ ^[34][41]. 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][43]. 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][43]. 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][44]. Mutations in superoxide dismutase (SOD1) commonly associated with ALS implicate the role of oxidative stress in its pathogenesis ^[55][45]. 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][39]. 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][46], mitochondrial dysfunction of motor neurons has been observed ^[57][47]. 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][39]. Unfortunately, similar studies on SOD1^G93A mice demonstrated no effect on disease progression following oral supplementation of 200 mg/kg/day CoQ₁₀ (Table 1) ^[31][44]. 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][48,49]. 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][50].

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][51]. This results in protein misfolding, dysfunction and aggregation resulting in neuronal cell death ^[36][60][51,52]. 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][53]. Patients with MSA often display oligodendrocytes containing α-synuclein aggregates and neurons containing apoptotic proteins ^[61][62][54,55]. Furthermore, decreased levels of CoQ₁₀ have been observed in the cerebellum of MSA patients ^[63][56]. 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][53].