Research Study on CQ10 Used for Neurodegenerative Diseases

Neurodegenerative diseases are a group of diseases caused by chronic and progressive degeneration of nervous tissue, including Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases often require high treatment costs and burden society and families heavily [1]. However, the cause of neurodegenerative diseases is still unclear, and effective treatments for these diseases are still lacking [2].

Coenzyme Q10 (CoQ10) is a fat-soluble organic compound. It is a powerful antioxidant in cell membranes and lipoproteins, and an important component of the electron transport chain, playing an important role in the process of oxidative phosphorylation in mitochondria. Although the FDA does not approve CoQ10 for the treatment of any disease, it is widely used as a dietary supplement in over-the-counter drugs and is recommended by doctors and experts. It is constantly being studied as an adjuvant treatment for various medical conditions [ 3]. CoQ10's antioxidant, anti-inflammatory, and anti-apoptotic properties may be useful in the treatment of neurodegenerative diseases. Therefore, this article mainly summarizes the therapeutic effects of CoQ10 on neurodegenerative diseases as follows.

Ⅰ. CoQ10

1. Introduction of CQ10

Coenzyme is the general term for a large class of organic cofactors. It is a necessary factor for enzymes to catalyze redox reactions, group transfers and isomerization reactions. CoQ is a class of fat-soluble quinone compounds that exist on the inner mitochondrial membrane and are widely found in living organisms [4]. CoQ from different species has different numbers of isoprenoid units in the side chain. Human and mammals have 10 isoprenoid units, so it is called CoQ10 [5].

CoQ10 is the only fat-soluble antioxidant in the human body. Cellular biosynthesis and dietary sources are the main sources of CoQ10 in the human body. The synthesis of the CoQ10 molecule synthesis includes three main steps, namely the synthesis of the benzoquinone structure from 4-hydroxybenzoate (derived from tyrosine or phenylalanine), the synthesis of the polyisoprenoid side chain from acetyl coenzyme A (CoA) via the methylmalonic acid pathway, and the condensation of these two structures to form CoQ10 [6].

CoQ10 exists in two forms: the oxidized form (ubiquinone) and the reduced form (ubiquinol). The two forms can be converted into each other in the body, but they differ in their main functions. Ubiquinone is mainly used to increase energy levels at the cellular level, while ubiquinol plays an important role in antioxidant protection. Both are involved in the mitochondrial electron transport chain (ETC) and are converted in the body. Ubiquinone is generated from ubiquinol by electron transfer from mitochondrial complexes I and II, while complex III oxidizes ubiquinol back to ubiquinone [7].

There are also differences in the distribution of the two forms of CoQ10 in human tissues. In organs such as the heart, kidneys and liver, ubiquinone accounts for a relatively high proportion, while in the brain and lungs ubiquinol accounts for a relatively high proportion [8], which may be related to its redox reactions. Biglan et al. [9] reported a comparison of the bioavailability of ubiquinol and ubiquinone. CoQ10 supplements provide CoQ10 as ubiquinone or ubiquinol, and the bioavailability of a given CoQ10 supplement depends on the lipid vehicle it is dissolved in [10]. Zhang et al. [11] showed that ubiquinol is a better supplement than ubiquinone for improving CoQ10 status in elderly men. However, most clinical trials have been designed with ubiquinone supplements, rather than the more absorbable and more effective antioxidant ubiquinol.

CoQ10 plays an important role in cellular energy production within the mitochondrial respiratory chain. It also protects DNA from oxidative damage, as well as having anti-inflammatory, anti-apoptotic, and protective vascular endothelial, cholesterol metabolism, and maintenance of lysosomal pH functions [3]. As a redox carrier, CoQ10 has the ability to continuously oxidize and reduce, and is involved in different cellular processes. For example, CoQ10 is considered an essential cofactor for mitochondrial complexes essential cofactor, which is essential for the production of adenosine triphosphate (ATP) in about 95% of human cells [12]. CoQ10 transfers electrons from mitochondrial complexes I or II to complex III. Therefore, CoQ10 acts as an electron transfer carrier in the mitochondrial respiratory chain, thereby participating in the production of cellular energy [13].

CoQ10 can protect DNA from oxidative damage in two main ways: the antioxidant properties of CoQ10 itself and the activation of DNA repair enzyme activity by CoQ10. Reactive oxygen species (ROS) formed in cells can damage lipids, proteins and DNA. Mitochondria are considered to be the main source of ROS in cells, and are therefore vulnerable to oxidative damage. To counteract this harmful effect, mitochondria have a system of antioxidant compounds, of which CoQ10 is one [14]. CoQ10 is an endogenously synthesized membrane antioxidant that prevents lipid peroxidation in most subcellular membranes.

CoQ10 can reduce the production of superoxide in mitochondria by improving the electron transfer efficiency of complexes I and II in the electron transport chain. It also has an antioxidant effect by scavenging free radicals and reducing lipid peroxidation at the level of the plasma membrane [15]. At the same time, in addition to its own antioxidant effect, CoQ10 can also enhance and regenerate the antioxidant effects of other antioxidants such as vitamin E and ascorbic acid.

For example, CoQ10 can reduce the α-tocopheryl radical produced by vitamin E when scavenging free radicals, thereby regenerating vitamin E [16]. CoQ10 can also bind to low density lipoprotein (LDL) and very low density lipoprotein (VLDL) to prevent lipid peroxidation damage, and reduces the production of oxidatively modified LDL (OX-LDL) [17]. OX-LDL consumes nitric oxide (NO), an important vasodilator. In other words, CoQ10 reduces NO consumption by stabilizing LDL, which reduces peripheral vascular resistance, suggesting that CoQ10 can protect the vascular endothelium [18].

2. CoQ10 In Disease Treatment/Adjuvant Therapy

CoQ10 is involved in the electron transport chain and aerobic respiration in mitochondria, and its antioxidant properties form the basis of its clinical application. On the other hand, CoQ10 may also affect gene expression, which may explain its effect on the metabolism of entire tissues [19]. Since CoQ10 is involved in ATP synthesis, it affects the function of all cells in the body, especially cells with high energy requirements. Therefore, it is essential for all tissues and organs, and abnormalities in CoQ10 may lead to the development of related diseases.

CoQ10 deficiency is caused by autosomal recessive mutations and includes primary and secondary CoQ10 deficiency [12]. These diseases usually begin in the neonatal period and are accompanied by neonatal respiratory distress or respiratory insufficiency, seizures, hypertrophic cardiomyopathy, elevated serum lactate, or lactic acidosis. Cranial imaging can reveal various lesions such as brain or cerebellum dysplasia, brain atrophy, and basal ganglia lesions. The disease can be treated by supplementing exogenous CoQ10, but most have a poor prognosis [20].

At least 10 genes are required for the biosynthesis of functional CoQ10, and mutations in any of these genes can lead to a deficiency in CoQ10 status [21]. Previous literature has reported that primary CoQ10 deficiency is mainly related to the COQ4 gene. Case reports have shown that this gene can undergo missense mutations, frame-shift mutations, splicing mutations, nonsense mutations and deletion mutations, while c.370G>A has only been found in children in southern China [20]. Many diseases associated with its deficiency, such as mitochondrial diseases, fibromyalgia, cardiovascular disease, diabetes, and periodontal disease, etc. [22], can also be relieved by supplementing CoQ10.

Endogenous CoQ10 levels are determined by the rate of production and consumption in the body, and these levels may change in disease states. It has been shown that cardiovascular disease and degenerative muscle disease affect endogenous CoQ10 levels. In addition, oxidative stress plays a central role in the pathogenesis of cardiovascular disease, and heart failure is often characterized by changes in the energy consumption state in mitochondria. Both are related to low endogenous CoQ10 levels and lead to myocardial contractile dysfunction [4]. CoQ10 can also improve the functional capacity, endothelial function, and left ventricular contractility of patients with congestive heart failure [23].

A 2017 meta-analysis of 14 randomized controlled trials (2,149 participants) showed that CoQ10 users had higher exercise capacity and lower mortality compared to the placebo group [24]. In summary, CoQ10 supplements can improve cardiovascular function by increasing energy production, improving myocardial contractility and their potent antioxidant activity, especially preventing the oxidation of LDL [23].

In addition, CoQ10 may also have anticancer effects by stimulating the immune system, slow down the progression of PD, and protect against the cardiotoxicity of anthracyclines [25-26]; and when supplemented with standard psychiatric drug therapy, CoQ10 seems to reduce depressive symptoms in patients with bipolar disorder [27]. Although some preliminary studies suggest that CoQ10 may be effective in treating these diseases, the results are still unclear and require further testing.

Ⅱ. Basic Research on COQ10 in Neurodegenerative Diseases

Neurodegenerative diseases are a group of diseases caused by chronic and progressive degeneration of nerve tissue [28]. At present, the cause of neurodegenerative diseases is not clear. Aging is the main risk factor for genetic and sporadic neurodegenerative diseases [29], and there is still a lack of effective treatments for these diseases. In the treatment of these diseases, although the damage that has occurred cannot be reversed, measures can be taken to prevent or slow down further nerve damage. Currently, neuroprotective agents such as calcium antagonists (e.g. nimodipine, nicardipine, flunarizine), glutamate antagonists (e.g. eliprodil), gamma-aminobutyric acid receptor agonists, and free radical scavengers (e.g. vitamin E, vitamin C, glutathione mannitol) can be used.

The amount of CoQ10 in the human body decreases with age. Generally, the synthesis capacity peaks at the age of 20, reaching 500 to 1,500 mg. Afterward, with age, the synthesis capacity gradually decreases, so that by the age of 50, the amount synthesized is only 75% of that at the age of 20, and by the age of 80, the amount synthesized is only 50% of that at the age of 20. Therefore, the decline in CoQ10 levels during the aging process may be one of the factors in the development of chronic diseases in the elderly [30]. Since CoQ10 is not only an antioxidant but also participates in cellular processes, proper intake of CoQ10 is important for slowing down cellular aging and improving cellular activity [31].

In addition, a study obtained 113 human ubiquinone-binding proteins from Swiss-Prot. Pathway enrichment analysis of these proteins revealed a high correlation with neurodegenerative diseases [32]. In another study, a fixed-effect meta-analysis was performed in two independent cross-sectional cohorts from northern Germany to identify common genetic variants influencing serum CoQ10 levels.

The study included 1,300 subjects, and the authors identified the genome-wide significant susceptibility loci rs9952641 and rs933585, which correspond to the COLEC12 and NRXN-1 genes, respectively. Both genes have been previously reported to be associated with neuronal diseases, such as Alzheimer's disease. loci rs9952641 and rs933585, which correspond to the COLEC12 and NRXN-1 genes, respectively. Both genes have previously been reported to be associated with neuronal diseases such as Alzheimer's disease, autism, and schizophrenia. This study showed that serum CoQ10 levels are associated with common genetic loci associated with neuronal diseases [33]. Therefore, CoQ10 may alleviate the symptoms of patients with neurodegenerative diseases.

Ⅲ. Clinical Studies on the Treatment of Neurodegenerative Diseases With CoQ10

1. AD: Wadsworth et al. [34] conducted an AD-related experimental study based on the hypothesis that AD is caused by oxidative damage and mitochondrial dysfunction, using CoQ10 as a mitochondrial antioxidant. It was found that exogenous CoQ10 supplementation can protect MC65 neuroblastoma cells from the neurotoxicity induced by the C-terminal fragment of amyloid precursor protein. This effect is concentration-dependent. In animal experiments, CoQ10 supplementation via the diet for one month in 11-month-old female C57BL/6 mice was found to significantly inhibit brain protein carbonyl levels, indicating reduced oxidative damage.

In clinical trials, Karakahya et al. [35] treated 30 AD patients with topical CoQ10 for 6 months. To achieve greater bioavailability and a longer duration of action, the authors administered the drug intravitreally. They found that CoQ10 improved the loss of retinal ganglion cells (RGCs) associated with AD. Due to the short duration of the drug administration, the researchers did not report changes in the cognitive symptoms of the patients.

In addition, another study treated 78 patients with mild to moderate AD with 400 mg of CoQ10 three times a day for 16 weeks. The efficacy was evaluated using oxidative stress markers and cognitive function scores. The study found that CoQ10 treatment did not affect the levels of cerebrospinal fluid biomarkers associated with amyloid or tau pathology [36]. At present, the results of CoQ10 treatment in AD are inconsistent, which may be related to the choice of CoQ10 supplements, different administration methods, different trial administration times, and the fact that the large molecular weight makes it difficult to cross the blood-cerebrospinal fluid barrier to reach neuronal mitochondria. Therefore, there is still controversy about the therapeutic effect of CoQ10 on AD.

2.PD: Cooper et al. [37] demonstrated in cell experiments that CoQ10 can be used to treat neural cells derived from induced pluripotent stem cells of patients with familial PD and high-risk individuals, and found that CoQ10 causes changes in the pathophysiology of cells associated with mitochondrial dysfunction.

In experiments using the PD mouse model, it was found that when supplemented with 200 mg/(kg·d) CoQ10, the plasma CoQ10 concentration of mice supplemented with reduced CoQ10 was higher than that of oxidized CoQ10, indicating that reduced CoQ10 is more effective as a supplement than oxidized CoQ10 [38]. In clinical trials, in a double-blind clinical trial, 300 mg of reduced CoQ10 per day can improve the tremor symptoms of PD patients by reversing mitochondrial abnormalities for 48 or 96 weeks, which is more effective than the placebo group [39].

Another meta-analysis including 899 PD patients found that CoQ10 was well tolerated compared to the placebo group, but was not superior to placebo in terms of motor symptoms [40]. In addition, a study aimed to determine whether a range of CoQ10 doses is safe and well tolerated and whether it can slow the functional decline of PD.

A multi-center randomized controlled double-blind dose-ranging trial was conducted. In the trial, 654 patients were given 300, 6 00, 1 200 mg/d of CoQ10 or placebo, with a follow-up period of 16 months. The results showed that CoQ10 was safe and well tolerated at a dose of 1 200 mg/d. Compared with placebo subjects, CoQ10 subjects had a lower probability of disability, and the effect was best in subjects receiving the highest dose. CoQ10 seems to slow the gradual deterioration of PD function, but these results need to be confirmed in larger studies [41].

In a study investigating the combined treatment of creatine and CoQ10 for PD, 75 patients were randomly assigned to treatment groups and evaluated after 12 or 18 months of treatment. The results showed that combined treatment with creatine and CoQ10 can delay the decline in cognitive function in PD patients and reduce plasma PL levels [42]. According to the results of current clinical studies, although CoQ10 has a certain effect on mitochondrial dysfunction and oxidative stress mechanisms in PD, mitochondrial oxidative stress damage may be the result of multiple neurodegenerative mechanisms rather than the primary cause of the disease. Therefore, interventions targeting this mechanism may not have significant clinical benefits.

3. Huntington disease (HD): There is evidence that early oxidative stress in HD is accompanied by mitochondrial dysfunction, which exacerbates each other and leads to energy deficiency [43]. Therefore, CoQ10 may be used in the treatment of HD. Animal experiments have found that in the R6/2 transgenic mouse model of HD, oral administration of CoQ10 or the NMD antagonist remacemide can significantly prolong survival and delay the development of motor deficits, weight loss, brain atrophy, and neuronal inclusions. The combined treatment of CoQ10 and remacemide was more effective than the use of each agent alone, increasing the survival rate of R6/2 and N171-82Q mice by 32% and 17%, respectively. Magnetic resonance imaging showed that the combined treatment significantly reduced ventricular enlargement in vivo [44].

A multicenter randomized double-blind controlled trial recruited 609 patients with early-stage HD from 48 sites in the United States, Canada, and Australia. The patients were randomly assigned to receive either CoQ10 2,400 mg/d or placebo. The primary and secondary outcome measures were not statistically different between the treatment groups after 60 months of follow-up. Throughout the study, CoQ10 was generally safe and well tolerated, and it cannot be proven that the use of CoQ10 can slow down the disease progression of HD [45].

Ⅳ.Summary and Outlook

CoQ10 deficiency patients have shown clinical improvement through oral CoQ10 supplementation, but for neurodegenerative patients, only partial relief of brain symptoms has been observed, which may be due to irreversible structural brain damage before treatment and poor permeability of CoQ10 across the blood-brain barrier. At the same time, patients with neurodegenerative diseases may have other diseases that affect the absorption of CoQ10 supplements, which in turn leads to insignificant results after taking them. Therefore, given the complexity of neurodegenerative diseases and comorbidities, single-drug or single-targeted treatment methods may not be sufficient, and a more comprehensive approach or combined treatment strategy may be required.

On the other hand, idebenone, a CoQ10 analogue, is an antioxidant compound with well-established clinical safety and is currently used to treat ataxia and AD [46]. In the future, new drug designs can be considered based on the binding sites of CoQ10 to overcome the bottlenecks of its low absorption rate in the human body and blood-brain barrier.

At the same time, CoQ10 exists in reduced and oxidized states in the human body. Since the normal brain contains high levels of panthenol, supplementing with panthenol may have a better effect on neurodegenerative diseases. Therefore, the chemical state of CoQ10 should be considered in the drug design for patients with neurodegenerative diseases. However, the oxidizable nature of CoQ10 in the air needs to be taken into account. The physiological mechanism of CoQ10 in treatment can be considered based on its site and pathway, and its role in the pathogenesis of neurodegenerative diseases can be further explored.

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