International Journal of Nutrition, Pharmacology, Neurological Diseases

REVIEW ARTICLE
Year
: 2012  |  Volume : 2  |  Issue : 2  |  Page : 80--83

The beneficial effect of Coenzyme Q in diabetic neuropathy: An overview


Justin Prashanth, AC Jesudoss Prabhakaran 
 Saveetha Medical College and Hospital, Thandalam, Chennai, Department of Pharmacology, Meenakshi Medical College and Research Institute, Enathur, Kancheepuram, Tamil Nadu, India

Correspondence Address:
A C Jesudoss Prabhakaran
Department of Pharmacology, Meenakshi Medical College and Research Institute, Enathur, Kancheepuram - 631 552, Tamil Nadu
India

Abstract

One of the most common complications in diabetes mellitus, which has a multifaceted pathogenesis, is neuropathy. The implication of various researchers points toward the oxidative stress occurring in the mitochondria, which plays a central role in the development of this complication. Coenzyme Q is an important factor contributing to mitochondrial bioenergetics. The hypothesis of Coenzyme Q in the management of diabetic neuropathy is reviewed in this article.



How to cite this article:
Prashanth J, Jesudoss Prabhakaran A C. The beneficial effect of Coenzyme Q in diabetic neuropathy: An overview.Int J Nutr Pharmacol Neurol Dis 2012;2:80-83


How to cite this URL:
Prashanth J, Jesudoss Prabhakaran A C. The beneficial effect of Coenzyme Q in diabetic neuropathy: An overview. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Sep 16 ];2:80-83
Available from: http://www.ijnpnd.com/text.asp?2012/2/2/80/95926


Full Text

 Introduction



Neuropathies are characterized by progressive loss of function of nerve fibers. The accepted definition of peripheral diabetic neuropathy is the presence of chronic symmetrical symptoms and/ or signs of sensory motor dysfunction developing on a background of longstanding hyperglycemia. [1] Saturation of the normal glycolytic pathway occurs when there is an increase in the intracellular glucose levels during sustained hyperglycemia. The extra glucose is converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase through the polyol pathway. [2] The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids, results in advanced glycation end-products that may have a role in disrupting the neuronal integrity and repair mechanisms through interference with the nerve cell metabolism and axonal transport. [3] Although there is no pathogonomonic feature of this disease on histopathology, neurodegeneration is visible in the long axons in diabetic neuropathy. The distal dying-back of the axons and axonal dystrophy are the major features seen in the pathologenesis of the nervous system. [4] However, pharmacological intervention targeting one or more of these mechanisms may prove successful.

 Pathogenesis of Diabetic Neuropathy



The mechanism of oxidative stress caused by microangiopathy is responsible for diabetic neuropathy. This is evident by various studies in animal models of both Type I and II diabetes, [5],[6] where higher levels of the reactive oxygen species (ROS), lipid peroxidation, and protein nitrosylation, and lower levels of ascorbates and glutathione have been observed. [7],[8]

This is evident by the fact that antioxidants such as α-lipoic acid and γ-linolenic acid are frequently used by clinicians in the management of diabetic neuropathy. [9],[10]

Various pathways involved in the pathophysiology of diabetic complications arise from mitochondrial dysfunction. The abnormalities in the structure of the mitochondria of the nerves, heart, muscles, and kidneys, of both clinical and animal models are seen in both Type I and Type II diabetes. [11] Mitochondrial electron transport chain [ETC] activity is enhanced during sustained hyperglycemia and leads to mitochondrial hyperpolarization with elevated ROS production. [12] The partial reduction of oxygen to superoxide in the proximal ETC occurs when there is increased electron availability, due to high ROS production, which subsequently induces neurodegeneration. [13]

The apoptosis that occurs during sustained hyperglycemia through the mitochondrial pathway in cultured embryonic sensory neurons, [9] is not observed in either animal or human models of diabetes. [14],[15] The sensory neuronal mitochondria respond differently from endothelial cells in persistent hyperglycemia, in the diabetic animal models. [16],[17] Even as the mitochondrial inner membrane is depolarized in hyperglycemia, the endothelial cells exhibit hyperpolarization. Low-dose insulin and neurotropin-3, a neurotropic growth factor, prevent this depolarization through a PI3K-dependent pathway, [18] rather than a glucose-dependent mechanism. The studies reveal that persistent hyperglycemia is unable to cause apoptosis and oxidative stress directly in adult sensory neurons, unlike in embryonic neurons and endothelial cells. [19] This implicated our search for other mechanisms or pathways by which neuronal damage occurs in diabetes mellitus.

Many studies report the association of impaired calcium homeostasis in diabetes mellitus. [20] It is very prominent and severe in neurons with long axons, [21] that is, lumbar dorsal root ganglion neurons, which are affected early in human diabetic neuropathy. Mitochondrial buffering of calcium ions is deranged in diabetes and high intramitochondrial calcium ion levels can cause inner membrane depolarization. [22] These high intramitochondrial calcium ion levels can also promote oxidative stress by stimulating ROS production. [23],[24],[25] This occurs through the Krebs cycle where calcium ions activate pyruvate dehydrogenase [26] and adenine nucleotide translocase, [27] to enhance nicotinamide adenine dinucleotide hydride (NADH) and adenosine triphosphate (ATP) production, respectively. Thus, mitochondria work faster with calcium ions, consuming more oxygen and producing enhanced ROS output. Ultimately they are associated with a higher metabolic rate. [28],[29]

The central position of mitochondria in neuronal cells with altered function and structure is as observed in studies pertaining to the pathogenesis of diabetic neuropathy. Inhibition of oxidative phosphorylation and shifting of glucose metabolism to anaerobic glycolysis (Crabtree effect) occurs during sustained hyperglycemia. [30] This Crabtree effect occurs through the AMP-activated protein kinase, and the PPAR-a activator 1 pathway is also considered to be the mechanism of development of neuropathy. This allows the mitochondrial damage to go unchecked by reducing the need for an effective mitochondrial proteome. The enhanced ROS leads to a vicious cycle in the mitochondria, by increasing lipid peroxidation, a change in mitochondrial trafficking, and finally mitochondrial fragmentation. This leads to a fall in ATP production in the cell and neuronal damage. [31]

 Coenzyme Q and Diabetic Neuropathy



The Coenzyme Q (Co Q) was discovered by Crane and his colleagues, in 1957, in beef cardiac mitochondria. [32] The Co Q is also called as ubiquinone due its widespread distribution in the human body as nutrients and aids the mitochondria in the complex process of transforming food into ATP to provide energy for the cell to function. This nutrient deficiency is found to be the cause of various health-related disease conditions, as discussed in this study. CoQ or ubiquinone is also widely distributed in plants, animals, and microorganisms. Its homologs are classified based on their isoprenoid units (Q-n). The number, Q-n, refers to the amount of isoprenoid units attached to the 6-position on the benzoquinone ring of the coenzyme Q moiety. The Coenzyme Q is a soluble fat quinine and is crucial in an optimal biological function. Coenzyme Q is chemically a quinone, with the structure of 2,3-diamethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone and it was first isolated from bovine heart mitochondria. It is often abbreviated at times to CoQ10, where 10 refers to the number of isoprenyl chemical subunits in its tail. As it is found virtually in all human cells, it is also known as ubiquinone. This review will focus on the literature to enrich the understanding of the complex interactions among CoQ10, mitochondrial bioenergetics in the pathogenesis of diabetic neuropathy. When CoQ10 is reduced to act as an antioxidant, it combats free radicals, prevents lipid peroxidation, and protects mitochondrial DNA. Another field of study is related to the antioxidant property of CoQ10, which is useful in the treatment of migraine, where inflammatory components produce ROS leading to over-consumption of CoQ. The energy carrier function of CoQ10 is directly dependent on its antioxidant activity. The primary role of CoQ10 is to facilitate an electron transfer between the redox components of the electron transport chain in order to create a proton gradient across the inner mitochondrial membrane, thereby increasing ATP production, which ensures optimal mitochondrial bioenergetics. [33],[34]

CoQ10 is found to be deficient in periodontal diseases and the CoQ10 supplement leads to a rapid cure and prevents a relapse. [35] In heart and liver, the cells contain more mitochondria per cell for their energy, and have the greatest amount of CoQ10. The withdrawal of CoQ10 supplementation may precipitate congestive heart failure in patients who were previously benefited by taking CoQ. [36],[37] Certain lipid-lowering drugs like statins and gemfibrosil as well as oral hypoglycemic drugs like tolazamide and glyburide cause a decrease in the production of CoQ10 from the liver and decrease the effects of CoQ10 supplementation. [38] Therefore, such prescriptions should always be accompanied with CoQ10 preparations to prevent heart failure. The beta-blockers too can inhibit the CoQ10-dependent reactions in the cell. [39] The patients taking beta-blockers for hypertension and coronary artery diseases may also be observed for any deterioration in their cardiac function. In a placebo controlled, multi-center clinical trial, researchers found that the rate of disease progression in early Parkinson's disease slowed down after supplementation of CoQ10 in the diet. [40]

CoQ10 is being used in other clinical conditions also. One study discusses the mechanism of inhibition of ultraviolet-B induced wrinkles in vivo and in vitro. [41] CoQ has been administered in Down's syndrome to counteract the oxidative imbalance present in this condition. [42] Many studies have highlighted the antiangiogenic and hypolipidemic activities of CoQ10 supplementation in breast cancer, when undergoing tamoxifen therapy. [43]

Neurodegenerative disorders, cancer, cardiovascular diseases, and diabetes mellitus exhibit altered levels of ubiquinone, indicating their likely crucial role in the pathogenesis and cellular mechanisms of these ailments. [44] CoQ10 is found to be rich in the heart, liver, and meat of beef, lamb, pork, and fish. The richest vegetable sources of CoQ10 are spinach, broccoli, peanuts, wheat germ, and whole grains. Increasing the antioxidant activity and ensuring mitochondrial protection in the body can be achieved by supplementing CoQ10, as dietary sources are limited due to the decreasing efficacy of exogenous CoQ during the process of cooking. [45] The supplementation is usually done by pharmacological means to prevent mitochondrial damage and for the development of neuropathy in patients with diabetes mellitus. No clinical studies have been conducted on this aspect of diabetic neuropathy, but the logic is tempting. When the CoQ10 levels are enhanced at the cellular level, the ROS production can be suppressed and thereby neuronal health restored.

 Conclusion



The hypothesis of supplementation of CoQ10 has a scientific rationale and the patients suffering from diabetic neuropathy will definitely be greatly benefited if it is prescribed as an adjuvant. Large studies are required to prove the effect of CoQ10 in the prevention of a neuropathic complication in diabetes mellitus. This molecule lacks patent protection and keeps away the major sponsors from funding such studies.

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