Folic Acid and Coenzyme Q10 Ameliorate Cognitive Dysfunction in the Rats with Intracerebroventricular Injection of Streptozotocin

Document Type : Original Article

Authors

1 Department of Basic Sciences, Isfahan Payame Noor University, Isfahan, Iran

2 Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Biosensor Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran

4 Department of Basic Sciences, Islamic Azad University Khorasgan Branch, Isfahan, Iran

Abstract

Objective(s)
The present study aimed to investigate the effects of a fat soluble antioxidant, coenzyme Q10 (CoQ10) and folic acid on learning and memory in the rats with intracerebroventricular injection of streptozotocin (ICV-STZ), an animal model of sporadic type of Alzheimer's disease.
Materials and Methods
The lesion groups were injected bilaterally with ICV-STZ (1.5 mg/kg b.wt., in normal saline). In the treated groups, rats received folic acid (4 mg/kg; i.p.) or CoQ10 (10 mg/kg; i.p.), either alone or together, for 21 days. Passive avoidance learning test was used for evaluation of learning and memory.
Results
The results showed that learning and memory performance was significantly impaired in the rats with ICV-STZ (P< 0.001), however CoQ10 and folic acid, either alone or together, prevented impairments significantly (P< 0.001), as there was not any significant difference between these treated lesion groups and control group.
Conclusion
The present results suggest that CoQ10 and folic acid have therapeutic and preventive effects on cognitive impairments in Alzheimer’s disease.
 

Keywords


1. Flynn BL, Ranno AE. Pharmacologic management of Alzheimer disease, Part II: Antioxidants, antihypertensives, and ergoloid derivatives. Ann Pharmacother 1999; 33:188-197.
2.  Li X, Yuan HF, Quan QK, Wang JJ, Wang NN, Li M. Scavenging effect of Naoerkang () on amyloid beta-peptide deposition in the hippocampus in a rat model of Alzheimer's disease. Chin J Integr Med  2011; 17(11):847-53.
3. Herring A, Ambrée O, Tomm M, Habermann H, Sachser N, Paulus W, et al. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol  2009; 216:184-192.
4. Robert R, Dolezal O, Waddington L, Hattarki MK, Cappai R, Masters CL, et al. Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers. Protein Eng Des Sel  2009; 22:199-208.
5. Holscher C, Gengler S, Gault VA, Harriott P, Mallot HA. Soluble beta-amyloid [25-35] reversibly impairs hippocampal synaptic plasticity and spatial learning. Eur J Pharmacol 2007; 561:85-90.
6. Sharma M, Gupta YK. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci  2001; 68:1021-1029.
7. Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR. Protein oxidation in the brain in Alzheimer's disease. Neuroscience 2001; 103:373-383.
8. Gutteridge JM. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1995; 41:1819-1828.
9. Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, et al. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav Brain Res 2006; 171:9-16.
10. Ishrat T, Parveen K, Khan MM, Khuwaja G, Khan MB, Yousuf S, et al. Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer's type. Brain Res 2009; 1281:117-127.
11. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta 1995; 1271:195-204.
12. Tsuneki H, Sekizaki N, Suzuki T, Kobayashi S, Wada T, Okamoto T, et al. Coenzyme Q10 prevents high glucose-induced oxidative stress in human umbilical vein endothelial cells. Eur J Pharmacol  2007; 566:1-10.
13. McDonald SR, Sohal RS, Forster MJ.Concurrent administration of coenzyme Q10 and alpha-tocopherol improves learning in aged mice. Free Radic Biol Med  2005; 38:729-736.
14. Lass A, Sohal RS. Electron transport-linked ubiquinone-dependent recycling of alpha-tocopherol inhibits autooxidation of mitochondrial membranes. Arch Biochem Biophys 1998; 352:229-236.
15. Dumont M, Kipiani K, Yu F, Wille E, Katz M, Calingasan NY, et al.  Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 2011; 27:211-223.
16. Vranesić-Bender D. The role of nutraceuticals in anti-aging medicine. Acta Clin Croat  2010; 49:537-544.
17. Shinde S, Patil N, Tendolkar A. Coenzyme Q10: A review of essential functions. Internet J Nutr Wellness  2005; 1(2). ISSN: 1937-8297.
18. Folkers K. Relevance of the biosynthesis of coenzyme Q10 and the four bases of DNA as a rationale for the molecular causes of cancer and a therapy. Biochem Biophys Res Commun 1996; 224:358-61.
19. Kamen B. Folate and antifolate pharmacology. Semin Oncol 1997; 24:S18-30-S18-39.
20. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346:476-483.
21. Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, Pietinen P, Barrett MJ, Taylor PR, et al. Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine. Cancer Epidemiol Biomarkers Prev  2003; 12:1271-1272.
22. Reynolds EH.Mental effects of anticonvulsants, and folic acid metabolism. Brain 1968; 91:197-214.
23. Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med  2001; 30:1390-1399.
24. Singh R, Kanwar SS, Sood PK, Nehru B. Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brain. Cell Mol Neurobiol  2011; 31:83-91.
25. Bottiglieri T, Reynolds EH, Laundy M. Folate in CSF and age. J Neurol Neurosurg Psychiatry  2000; 69:562.
26. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998; 55:1449-1455.
27. Isobe C, Abe T, Terayama Y. Increase in the oxidized/total coenzyme Q-10 ratio in the cerebrospinal fluid of Alzheimer's disease patients. Dement Geriatr Cogn Disord  2009; 28:449-454.
28. Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998; 112:1199-1208.
29. Ponce-Lopez T, Liy-Salmeron G, Hong E, Meneses A. Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model. Brain Res  2011; 1426:73-85.
30. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5th ed. San Diego: Elsevier Academic Press; 2005.
31. Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M.  Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology  2007; 52:836-843.
32. Duelli R, Schröck H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994; 12:737-743.
33. Nitsch R, Hoyer S. Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett  1991; 128:199-202.
34. Blokland A, Jolles J. Spatial learning deficit and reduced hippocampal ChAT activity in rats after an ICV injection of streptozotocin. Pharmacol Biochem Behav 1993; 44:491-494.
35. Hoyer S, Lannert H. Inhibition of the neuronal insulin receptor causes Alzheimer-like disturbances in oxidative/energy brain metabolism and in behavior in adult rats. Ann N Y Acad Sci 1999; 893:301-303.
36. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 1997; 23:134-147.
37. Liu R, Liu IY, Bi X, Thompson RF, Doctrow SR, Malfroy B, et al. Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics. Proc Natl Acad Sci USA 2003; 100:8526-8531.
38. Morrison JH, Hof PR. Life and death of neurons in the aging brain. Science 1997; 278:412-419.
39. Beal MF. Therapeutic effects of coenzyme Q10 in neurodegenerative diseases. Methods Enzymol  2004; 382:473-487.
40. Rauscher FM, Sanders RA, Watkins JB. Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 2001; 15:41-46.
41. Durand P, Fortin LJ, Lussier-Cacan S, Davignon J, Blache D. Hyperhomocysteinemia induced by folic acid deficiency and methionine load--applications of a modified HPLC method. Clin Chim Acta 1996; 252:83-93.
42. Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev 2002; 1:95-111.
43. Blundell G, Jones BG, Rose FA, Tudball N. Homocysteine mediated endothelial cell toxicity and its amelioration. Atherosclerosis 1996; 122:163-172.
44. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000; 20:6920-6926.
45. Singh R, Kanwar SS, Sood PK, Nehru B. Beneficial effects of folic Acid on enhancement of memory and antioxidant status in aged rat brain. Cell Mol Neurobiol 2011; 31:83-91.
46. Barber DA, Harris SR. Oxygen free radicals and antioxidants: a review. Am Pharm 1994; NS34:6-35.
47. Fridovich I. Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol 1983; 23:239-257.
48. Chen S, Liu AR, An FM, Yao WB, Gao XD.Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4. Age (Dordr)  2011.
49. Agrawal R, Tyagi E, Shukla R, Nath C.Insulin receptor signaling in rat hippocampus: a study in STZ (ICV) induced memory deficit model. Eur Neuropsychopharmacol  2011; 21:261-273.