Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats
Initially discovered for its role in blood coagulation, there is now convincing evidence that vitamin K (VK) has important actions in the nervous system. In brain, VK is present in the form of menaquinone-4 (MK-4), a byproduct of the main dietary source, phylloquinone. It contributes to the biologic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2018.00213/full |
| _version_ | 1819231165001760768 |
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| author | Sahar Tamadon-Nejad Bouchra Ouliass Joseph Rochford Joseph Rochford Guylaine Ferland Guylaine Ferland |
| author_facet | Sahar Tamadon-Nejad Bouchra Ouliass Joseph Rochford Joseph Rochford Guylaine Ferland Guylaine Ferland |
| author_sort | Sahar Tamadon-Nejad |
| collection | DOAJ |
| description | Initially discovered for its role in blood coagulation, there is now convincing evidence that vitamin K (VK) has important actions in the nervous system. In brain, VK is present in the form of menaquinone-4 (MK-4), a byproduct of the main dietary source, phylloquinone. It contributes to the biological activation of various proteins (i.e., Gas6), and participates in the synthesis of sphingolipids, a class of lipids widely present in brain cell membranes with important cell signaling functions. In a previous study, we reported that lifetime consumption of a low VK diet resulted in mild cognitive impairment in aged rats, a finding associated with an alteration of the sphingolipid profile. To confirm the role of VK as it relates to sphingolipids, cognition, and behavior outside the context of aging, we conducted a study of acute VK deficiency using a pharmacological model of VK deficiency in brain. In this procedure, rats (8 weeks) are maintained on a ratio of warfarin (a VK antagonist) to VK whereby coagulation is maintained while inducing VK deficiency in extrahepatic tissues. After 10 weeks of treatment, rats who were subjected to the warfarin plus phylloquinone protocol (WVK) exhibited longer latencies in the Morris water maze test as well as lower locomotor activity and exploratory behavior in the open field test, when compared to control rats. The WVK treatment resulted in a dramatic decrease in MK-4 level in all brain regions despite the presence of high local concentrations of phylloquinone, which suggests an inhibition of the biosynthetic MK-4 pathway in the presence of warfarin. Additionally, WVK treatment affected sphingolipid concentrations in key brain regions, notably those of the ganglioside family. Finally, brain MK-4 was correlated with performances in the open field test. This study confirms the modulatory role of VK in cognition and behavior and the implication of sphingolipids, notably those of the ganglioside family. |
| first_indexed | 2024-12-23T11:40:37Z |
| format | Article |
| id | doaj.art-eb12aba69a5443cdb7390450171fcd38 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-23T11:40:37Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-eb12aba69a5443cdb7390450171fcd382022-12-21T17:48:31ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652018-07-011010.3389/fnagi.2018.00213352624Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in RatsSahar Tamadon-Nejad0Bouchra Ouliass1Joseph Rochford2Joseph Rochford3Guylaine Ferland4Guylaine Ferland5Center for Addiction and Mental Health, Toronto, ON, CanadaMontreal Heart Institute Research Centre, Montreal, QC, CanadaDouglas Institute Research Center, Montreal, QC, CanadaDepartment of Psychiatry, McGill University, Montreal, QC, CanadaMontreal Heart Institute Research Centre, Montreal, QC, CanadaDépartement de Nutrition, Université de Montréal, Montreal, QC, CanadaInitially discovered for its role in blood coagulation, there is now convincing evidence that vitamin K (VK) has important actions in the nervous system. In brain, VK is present in the form of menaquinone-4 (MK-4), a byproduct of the main dietary source, phylloquinone. It contributes to the biological activation of various proteins (i.e., Gas6), and participates in the synthesis of sphingolipids, a class of lipids widely present in brain cell membranes with important cell signaling functions. In a previous study, we reported that lifetime consumption of a low VK diet resulted in mild cognitive impairment in aged rats, a finding associated with an alteration of the sphingolipid profile. To confirm the role of VK as it relates to sphingolipids, cognition, and behavior outside the context of aging, we conducted a study of acute VK deficiency using a pharmacological model of VK deficiency in brain. In this procedure, rats (8 weeks) are maintained on a ratio of warfarin (a VK antagonist) to VK whereby coagulation is maintained while inducing VK deficiency in extrahepatic tissues. After 10 weeks of treatment, rats who were subjected to the warfarin plus phylloquinone protocol (WVK) exhibited longer latencies in the Morris water maze test as well as lower locomotor activity and exploratory behavior in the open field test, when compared to control rats. The WVK treatment resulted in a dramatic decrease in MK-4 level in all brain regions despite the presence of high local concentrations of phylloquinone, which suggests an inhibition of the biosynthetic MK-4 pathway in the presence of warfarin. Additionally, WVK treatment affected sphingolipid concentrations in key brain regions, notably those of the ganglioside family. Finally, brain MK-4 was correlated with performances in the open field test. This study confirms the modulatory role of VK in cognition and behavior and the implication of sphingolipids, notably those of the ganglioside family.https://www.frontiersin.org/article/10.3389/fnagi.2018.00213/fullvitamin Kmenaquinone-4nutritional deficiencybraincognitionsphingolipids |
| spellingShingle | Sahar Tamadon-Nejad Bouchra Ouliass Joseph Rochford Joseph Rochford Guylaine Ferland Guylaine Ferland Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats Frontiers in Aging Neuroscience vitamin K menaquinone-4 nutritional deficiency brain cognition sphingolipids |
| title | Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats |
| title_full | Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats |
| title_fullStr | Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats |
| title_full_unstemmed | Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats |
| title_short | Vitamin K Deficiency Induced by Warfarin Is Associated With Cognitive and Behavioral Perturbations, and Alterations in Brain Sphingolipids in Rats |
| title_sort | vitamin k deficiency induced by warfarin is associated with cognitive and behavioral perturbations and alterations in brain sphingolipids in rats |
| topic | vitamin K menaquinone-4 nutritional deficiency brain cognition sphingolipids |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2018.00213/full |
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