Abstract
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.
Highlights
The preservation of cognitive abilities and mobility is of primary importance to older people as cognitive decline and physical frailty result in loss of independence and decreased quality of life
We reported that lifetime consumption of a low vitamin K (VK) diet resulted in mild cognitive impairment in aged rats, a finding associated with an alteration of the sphingolipid profile
We provide new evidence of the detrimental effect of low VK status in brain on spatial learning ability, locomotor activity, and exploratory behavior, a phenotype associated with decreased cerebral MK-4 concentrations and altered sphingolipid pattern in key brain regions, notably of the ganglioside subtypes
Summary
The preservation of cognitive abilities and mobility is of primary importance to older people as cognitive decline and physical frailty result in loss of independence and decreased quality of life. Notably nutrition, are increasingly being confirmed as powerful modulators of cognition and physical functions in older age (Landi et al, 2015; Tucker, 2016; Vauzour et al, 2017). Discovered for its role in blood coagulation, vitamin K (VK) has recently emerged as an important nutrient for brain function. Vitamin K occurs naturally in two forms, phylloquinone which originates from plants, is the main dietary source, while the menaquinones, which are of bacterial origin, constitute a family of compounds with unsaturated isoprenyl side chains of various lengths (Ferland, 2012a; Shearer and Newman, 2014). VK in brain is overwhelmingly in the form of MK-4 (Thijssen and Drittij-Reijnders, 1994) where it has been shown to represent more than 98% of total VK in brains of Sprague-Dawley rats (Carrié et al, 2004, 2011)
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