Vitamin K2 Improves Anxiety and Depression but not Cognition in Rats with Metabolic Syndrome: a Role of Blood Glucose?

Silvia M. Gancheva 1  and Maria D. Zhelyazkova-Savova 1
  • 1 Department of Preclinical and Clinical Pharmacology, Medical University of Varna, Varna, Bulgaria

Abstract

Background: The metabolic syndrome is a socially important disorder of energy utilization and storage, recognized as a factor predisposing to the development of depression, anxiety and cognitive impairment in humans.

Aim: In the present study we examined the effects of vitamin K2 on the behavior of rats with metabolic syndrome and looked for relationships with the effects on blood sugar.

Materials and methods: Male Wistar rats were divided in four groups: a control group on a regular rat chow, a metabolic syndrome (MS) group fed a high-fat high-fructose diet, a control group treated with vitamin K2 and a MS group treated with vitamin K2. Vitamin K2 was given by gavage. At the end of the study (after 10 weeks) behavioral tests were performed and fasting blood glucose was measured. Anxiety was determined using the social interaction test and depression was assessed by the Porsolt test. Memory effects were estimated by the object recognition test. Correlations between fasting blood glucose and behavioral performance were analyzed.

Results: The rats from the MS group had elevated blood glucose. They had anxiety, depression and memory deficit. Vitamin K2 normalized blood glucose, reduced anxiety and depression, but did not improve memory. Time of social interaction (inverse index of anxiety) and memory recognition were negatively correlated with blood glucose in the untreated rats but the immobility time (measure of depression) was not. When vitamin K2-treated rats were added, the correlation of blood glucose with the time of social interaction was kept, but the one with the recognition memory was lost. It might be that the anxiolytic effect of vitamin K2 in this setting is at least partly due to its effects on blood glucose, while the anti-depressant effect is glucose-independent.

Conclusion: The present study demonstrated that vitamin K2 prevented the development of anxiety and depression, but did not improve the memory deficit caused by the dietary manipulation in an experimental model of metabolic syndrome. It might be that the anxiolytic effect of vitamin K2 is at least partly due to its effects on blood glucose, while the antidepressant effect is glucose-independent.

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  • 1. McElroy SL, Kotwal R, Malhotra S, et al. Are mood disorders and obesity related? A review for the mental health professional. J Clin Psychiatry 2004;65(5):634-51.

  • 2. Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. Int J Obesity 2010;34:407-19.

  • 3. Elias MF, Elias PK, Sullivan LM, et al. Obesity, diabetes and cognitive deficit: The Framingham heart study. Neurobiol Aging 2005;26(1):11-6.

  • 4. Thijssen H, Drittij-Reijnders M. Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4. Br J Nutr 1996;75:121-7.

  • 5. Schurgers L, Spronk H, Soute B, et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Blood 2007;109:2823-31.

  • 6. McCann J, Ames B. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr 2009;90(4):889-907.

  • 7. Pan Y, Jackson R. Dietary phylloquinone intakes and metabolic syndrome in US young adults. J Am Coll Nutr. 2009;28(4):369-79.

  • 8. Beulens J, van der A D, Grobbee D, et al. Dietary phylloquinone and menaquinones intakes and risk of type 2 diabetes. Diabetes Care 2010;33:1699-705.

  • 9. Ibarrola-Jurado N, Salas-Salvado J, Martinez-Gonzalez M, et al. Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of cardiovascular disease. Am J Clin Nutr 2012;96(5):1113-18.

  • 10. Sogabe N, Maruyama R, Baba O, et al. Effects of long-term vitamin K1 (phylloquinone) or vitamin K2 (menaquinone-4) supplementation on body composition and serum parameters in rats. Bone 2011;48(5):1036-42.

  • 11. Seyama Y, Kimoto S, Marukawa Y, et al. Comparative effects of vitamin K2 and estradiol on experimental arteriosclerosis with diabetes mellitus. Int J Vitam Nutr Res 2000;70(6):301-4.

  • 12. Mukai K, Itoh S, Morimoto H. Stopped-flow kinetic study of vitamin E regeneration reaction with biological hydroquinones (reduced forms of ubiquinone, vitamin K, and tocopherolquinone) in solution. J Biol Chem 1992;267:22277-81.

  • 13. Westhofen P, Watzka M, Marinova M, et al. Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function. J Biol Chem 2011;286(17):15085-94.

  • 14. Li J, Lin J, Wang H, et al. Novel role of vitamin K in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci 2003;23(13):5816-26.

  • 15. Josey B, Inks E, Wen X, et al. Structure-activity relationship study of Vitamin K derivatives yields highly potent neuroprotective agents. J Med Chem 2013;56(3):1007-22.

  • 16. Allison A. The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease. Med Hypotheses 2001;57(2):151-5.

  • 17. Gancheva S, Zhelyazkova-Savova M, Galunska B, et al. Experimental models of metabolic syndrome in rats. Scr Sci Med 2015;47(2):23-30.

  • 18. Fluttert M, Dalm S, Oitzl M. A refined method for sequential blood sampling by tail incision in rats. Laboratory Animals 2000;34:372-8.

  • 19. File SE, Hyde JRG. Can social interaction be used to measure anxiety? Br J Pharmacol 1978;62:19-24.

  • 20. Porsolt RD. Animal model of depression. Biomedicine 1979;30(3):139-40.

  • 21. Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res 2010;215:244-54.

  • 22. Sakamoto N, Nishiike T, Iguchi H, et al. Possible effects of one week vitamin K (menaquinone-4) tablets intake on glucose tolerance in healthy young male volunteers with different descarboxy prothrombin levels. Clin Nutr 2000;19:259-63.

  • 23. Sardinha A, Nardi AE. The role of anxiety in metabolic syndrome. Expert Rev Endocrinol Metab 2012; 7(1):63-71.

  • 24. Lykouras L, Michopoulos J. Anxiety disorders and obesity. Psychiatriki 2011;22(4):307-13.

  • 25. Murphy M, Mercer JG. Diet-regulated anxiety. Int J Endocrinol 2013;2013:701967.

  • 26. Lalanza JF, Caimari A, del Bas JM, et al. Effects of a post-weaning cafeteria diet in young rats: metabolic syndrome, reduced activity and low anxiety-like behaviour. PLoS ONE 2014;9(1):e85049.

  • 27. Warneke W, Klaus S, Fink H, et al. The impact of cafeteria diet feeding on physiology and anxiety-related behaviour in male and female Sprague-Dawley rats of different ages. Pharmacol Biochem Behav 2014;116:45-54.

  • 28. Gupta D, Radhakrishnan M, Kurhe Y. Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice. Metabolic Brain Dis 2014;29(3):737-46.

  • 29. Buchenauer T, Behrendt P, Bode FJ, et al. Diet-induced obesity alters behavior as well as serum levels of corticosterone in F344 rats. Physiol Behav 2009;98:563-9.

  • 30. Souza CG, Moreira JD, Siqueira IR, et al. Highly palatable diet consumption increases protein oxidation in rat frontal cortex and anxiety-like behavior. Life Sci 2007;81:198-203.

  • 31. Anderson RJ, Grigsby AB, Freedland KE, et al. Anxiety and poor glycemic control: a meta-analytic review of the literature. Int J Psychiatry Med 2002;32(3):235-47.

  • 32. McIntyre RS, Soczynska JK, Konarski JZ, et al. Should depressive syndromes be reclassified as “metabolic syndrome type II”? Ann Clin Psychiatry 2007;19(4):257-64.

  • 33. Berk M, Williams LJ, Jacka FN, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 2013;11:200.

  • 34. Juanola-Falgarona M, Salas-Salvadó J, Estruch R, et al. Association between dietary phylloquinone intake and peripheral metabolic risk markers related to insulin resistance and diabetes in elderly subjects at high cardiovascular risk. Cardiovasc Diabetol 2013;12:7.

  • 35. Yates KF, Sweat V, Yau PL, et al. Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler Thromb Vasc Biol. 2012;32(9):2060-7.

  • 36. Freeman LR, Haley-Zitlin V, Rosenberger DS, et al. Damaging effects of a high-fat diet to the brain and cognition: A review of proposed mechanisms. Nutr Neurosci 2014;17(6):241-51.

  • 37. Kosari S, Badoer E, Nguyen JCD, et al. Effect of western and high fat diets on memory and cholinergic measures in the rat. Behav Brain Res 2012;235:98-103.

  • 38. Kanoski SE, Davidson TL. Different patterns of memory impairments accompany short- and longer-term maintenance on a high-energy diet. J Exp Psychol Anim Behav Process 2010;36(2):313-9.

  • 39. Jurdak N, Kanarek RB. Sucrose-induced obesity impairs novel object recognition learning in young rats. Physiol Behav 2009;96:1-5.

  • 40. Ramos JMJ. Long-term spatial memory in rats with hippocampal lesions. Eur J Neurosci 2000;12(9):3375-84.

  • 41. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 2012;13(2):93-110.

  • 42. Chouet J, Ferland G, Féart C, et al. Dietary vitamin K intake is associated with cognition and behavior among geriatric patients: The CLIP ctudy. Nutrients 2015;7:6739-50.

  • 43. Broadbent NJ, Squire LR, Clark RE. Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci USA. 2004;101(40):14515-20.

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