Users Online: 1713

Home Print this page Email this page Small font sizeDefault font sizeIncrease font size

Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts | Login 
     

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

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


Saveetha Medical College and Hospital, Thandalam, Chennai, Department of Pharmacology, Meenakshi Medical College and Research Institute, Enathur, Kancheepuram, Tamil Nadu, India

Date of Submission15-Aug-2011
Date of Acceptance16-Sep-2011
Date of Web Publication9-May-2012

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

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.95926

Rights and Permissions
   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.

Keywords: Coenzyme Q, diabetes, mitochondria, neuropathy, oxidative stress


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;2:80-3

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 Nov 20];2:80-3. Available from: http://www.ijnpnd.com/text.asp?2012/2/2/80/95926


   Introduction Top


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 Top


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 Top


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 Top


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.

 
   References Top

1.Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments.Diabetes Care 2010; 33:2285-293.  Back to cited text no. 1
    
2.Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy: A critical review for the end of the 20 th century. Diabetes Rev 1999;7:275-99.  Back to cited text no. 2
    
3.Singh RB, De Meester F, Wilczynska A, Wilson DW. The Brain- Gut Connection and Metabolic Syndrome.Int J Nutr Pharmacol Neurol Dis 2011;1:10-8.  Back to cited text no. 3
    
4.Schmidt Re. Neuropathology and pathogenesis of diabetic autonomic neuropathy. Int Rev Neurobiol 2002;50:257-92.  Back to cited text no. 4
    
5.Vasudevan K. Animal Models for Cardiovascular Diseases. Int J Nutr Pharmacol Neurol Dis 2011;1:10-8.  Back to cited text no. 5
    
6.Schalkwijk CG,Stehouwer CD.Vascular complications of diabetes mellitus: The role of endothelial function. Clin Sci 2005;109:143-59.  Back to cited text no. 6
    
7.Manoharan S, Umadevi S, Jayanthi S, Baskaran N. Antihyperglycaemic effect of Coscinium fenestratum and Catharanthus roseus in alloxan-induced diabetic rats. Int J Nutr Pharmacol Neurol Dis 2011;1:189-93.  Back to cited text no. 7
  Medknow Journal  
8.Drel VR, Mashtalir N, Ilnytska O, Shin J, Li F, Lyzogubov VV, et al. The Leptin-deficient (ob/ob) mouse: A new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes 2006;55:3343-55.  Back to cited text no. 8
    
9.Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004;25:612-28.  Back to cited text no. 9
    
10.Obrosova IG, Van Huysen C, Fathallah L, Cao XC, Greene DA, Stevenes MJ. An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. FASEB J 2002;16:123-5.  Back to cited text no. 10
    
11.Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005;54:1615-25.  Back to cited text no. 11
    
12.Nishikawa T, Araki E. Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antiox Redox Sig 2007;9:343-53.  Back to cited text no. 12
    
13.Nishikawa T, Edelstein D, Brownlee M. The missing link: A single unifying mechanism for diabetic complications. Kidney Int 2000;58: S26-30.  Back to cited text no. 13
    
14.Schmidt RE, Beaduet LN, Plurad SB, Dorsey DA. Axonal cytoskeletal/pathology in aged and diabetic human sympathetic automatic ganaglia. Brain Res 1997;769:375-83.  Back to cited text no. 14
    
15.Kamiya H, Zhangm W, Sima AA. Apoptotic stress is counterbalanced by survival elements preventing programmed cell death of dorsal root ganglions in subacute Type1 diabetic BB/Wor rats. Diabetes 2005;54:3288-95.  Back to cited text no. 15
    
16.Huang TJ, Sayers NM, Verkhratsky A, Fernyhough P. Neurotrophin-3 prevents mitrochondrial dysfunction in sensory neurons of streptozotocin-diabetic rats. Exp Neurol 2005;194:279-83.  Back to cited text no. 16
    
17.Huang TJ, Price SA, Chilton L, Calcutt NA, Tomlinson DR, Verkhratsky A, et al. Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes 2003;52:2129-36.  Back to cited text no. 17
    
18.Huang TJ, Verkhratsky A, Frenyhough P. Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinostide-3 kinase in adult sensory neurons. Mol Cell Neurosci 2005;28:42-54.  Back to cited text no. 18
    
19.Kruglikov I, Gryshchenko O, Shutov L, Kostyuk E, Kostyuk P, Voitenko N. Diabetes-induced abnormalities in ER calcium mobilization in primary and secondary nociceptive neurons. Pflugers Arch 2004; 448:395-401.  Back to cited text no. 19
    
20.Verkhratsky A, Frenyhough P. Mitochondrial malfunction and Ca2+ dyshomeostasis drive neuronal pathology in diabetes. Cell Calcium 2008;44:112-22.  Back to cited text no. 20
    
21.Huang TJ, Sayers NM, Frenyhough P, Verkhratsky A. Diabetes-induced alterations in calcium homeostasis in sensory neurons of streptozotocin-diabetic rats are restricted to lumbar ganglia and are prevented by neurotrophin-3. Diabetologia 2002;45:560-70.  Back to cited text no. 21
    
22.Nicholls DG. Budd SL. Mitochondrial and neuronal survival. Physiol Rev 2000;80:315-60.  Back to cited text no. 22
    
23.Nicholls DG. Mitochondrial dysfunction and glutamate excitotoxicty studied inprimary neuronal cultures. Curr Mol Med 2004;4:149-77.  Back to cited text no. 23
    
24.Nicholls DG. Mitochondrial and calcium signaling. Cell Calcium 2005;38:311-7.  Back to cited text no. 24
    
25.Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD. Calcium and mitochondria. FEBS Lett 2004;567:96-102.  Back to cited text no. 25
    
26.VoetD, VoetJG. Biochemistry. 3 rd ed. New York: John Wiley and Sons, Inc.; 2004. p. 615.  Back to cited text no. 26
    
27.Gunter TE, Buntinas L, Sparagana G, Eliseev R, Gunter K. Mitochondrial calcium transport: Mechanisms and functions. Cell Calcium 2000;28:285-96.  Back to cited text no. 27
    
28.Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004;287:817-33.  Back to cited text no. 28
    
29.Coatesworth W, Bolsover S. Spatially organized mitochondrial calcium uptake through a novel pathway in chick neurons. Cell Calcium 2006;39:217-25.  Back to cited text no. 29
    
30.Ibsen HK. The Crabtree effect: A review. Cancer Res 1961;21:829-41.  Back to cited text no. 30
    
31.Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondrial and promotes their autophagy. J Cell Biol 2008;183:795-803.  Back to cited text no. 31
    
32.Bliznakov EG, Chopra RK, Bhagavan HN. Coenzyme Q10 and neoplasia: Overview of experimental and clinical evidence. In: Bagchi D, Preuss HG, editor. Phytopharmaceuticals in Cancer Chemoprevention. Boca Raton: CRC Press; 2004. p. 599-622.  Back to cited text no. 32
    
33.Bentinger M, Tekle M, Dallner G. Coenzyme Q-biosynthesis and functions. Biochem Biophys Res Commun 2010;396:74-9.  Back to cited text no. 33
    
34.Fernandez-Ayala DJ, Lopenz-Lluch G, Gracia-Valdes M, Arroyo A, Navas P. Specificity of coenzyme Q 10 for a balanced function of respiratory chain and endogenous ubiquinone biosynthesis in human cells. Biochem Biophys Acta 2005;1706:174-86.  Back to cited text no. 34
    
35.Prakash S, Sunitha J, Hans M.Role of coenzyme Q(10) as an antioxidant and bioenergizer in periodontal diseases. Indian J Pharmacol 2010;42:334-7.  Back to cited text no. 35
[PUBMED]  Medknow Journal  
36.Felker GM. Coenzyme Q10 and statins in heart failure: The dog that didn't bark. J Am Coll Cardiol 2010;56:1205-6.  Back to cited text no. 36
    
37.Sarma S, Gheorghiade M. Nutritional assessment and support of the patient with acute heart failure. Curr Opin Crit Care 2010;16:413-8.  Back to cited text no. 37
    
38.Kaikkonen J, Nyyssönen K, Tuomainen TP, Ristonmaa U, Salonen JT. Determinants of plasma coenzyme Q10 in humans. FEBS Lett 1999;443:163-6.  Back to cited text no. 38
    
39.Pepping J. Coenzyme Q. Am J Health Syst Pharm 1999;56:519-21.  Back to cited text no. 39
    
40.Shults CW, Oakes D, Kieburtz K, Beal F, Haas R, Plumb S, et al. Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline. Arch Neurol 2002;59:1541-50.  Back to cited text no. 40
    
41.Pravst I, Zmitek K, Zmitek J. Coenzyme Q10 contents in foods and fortification strategies. Crit Rev Food Sci Nutr 2010;50:269-80.  Back to cited text no. 41
    
42.Inui M, Ooe M, Fujii K, Matsunaka H, Yoshida M, Ichihashi M. Mechanisms of inhibitory effects of CoQ10 on UVB-induced wrinkle formation in vitro and in vivo. Biofactors 2008;32:237-43.  Back to cited text no. 42
    
43.Sachdanandam P. Antiangiogenic and hypolipidemic activity of coenzyme Q10 supplementation to breast cancer patients undergoing Tamoxifen therapy. Biofactors 2008;32:151-9.  Back to cited text no. 43
    
44.Malchir P, Van Overmeirc L, Boland A, Samon E, Pietard L, Seutin V. Coenzyme Q 10: Biochemistry, pathophysiology of its deficiency and potential benefit of an increased intake. Rev Med Liege 2005;60:45-51.  Back to cited text no. 44
    
45.Pravst I, Zmitek K, Zmitek J. Coenzyme Q10 contents in foods and fortification strategies. Crit Rev Food Sci Nutr 2010;50:269-80.  Back to cited text no. 45
    



This article has been cited by
1 Alpha-lipoic acid and coenzyme Q10 combination ameliorates experimental diabetic neuropathy by modulating oxidative stress and apoptosis
Nasrin Sadeghiyan Galeshkalami,Mohammad Abdollahi,Rezvan Najafi,Maryam Baeeri,Akram Jamshidzade,Reza Falak,Mohammad Davoodzadeh Gholami,Gholamreza Hassanzadeh,Tahmineh Mokhtari,Shokoufeh Hassani,Mahban Rahimifard,Asieh Hosseini
Life Sciences. 2018;
[Pubmed] | [DOI]
2 A histological and morphometric study of the sciatic nerve in experimentally induced male diabetic rabbits and the potential neuroprotective role of coenzyme Q10
Dalia A. Mandour
The Egyptian Journal of Histology. 2015; 38(4): 804
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Introduction
    Pathogenesis of ...
    Coenzyme Q and D...
   Conclusion
    References

 Article Access Statistics
    Viewed4594    
    Printed193    
    Emailed0    
    PDF Downloaded241    
    Comments [Add]    
    Cited by others 2    

Recommend this journal