Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice

Jeanclos, Elisabeth; Albersen, Monique; Ramos, Rúben J.; Raab, Annette; Wilhelm, Christian; Hommers, Leif; Lesch, Klaus‐Peter; Verhoeven‐Duif, Nanda M.; Gohla, Antje

doi:10.1016/j.bbadis.2018.08.018

Cited by 22 publications

(16 citation statements)

References 78 publications

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“…In line with these reports, pyridoxine improves novel object recognition memory in healthy mice [10] and spatial memory in isocarbophos-induced vascular dementia rats tested on the Morris water maze [43]. In addition, PLP phosphatase knockout mice exhibit improved spatial learning and memory compared to controls [22]. Although a previous study showed that maternal pyridoxine deficiency affects hippocampal electrical activity in offspring [24], our study provides new insight into memory impairment induced by pyridoxine deficiency in juvenile and young-adult mice.…”

Section: Discussionsupporting

confidence: 63%

“…In addition, pyridoxine protects neurons from Parkinson's disease by facilitating the dimerization of PKM2 to promote glutathione biosynthesis [21]. The knockout of PLP phosphatase, a degradation enzyme of PLP, improves the cognitive function of mice [22]. In addition, previous studies demonstrate that pyridoxine treatment significantly increases hippocampal neurogenesis in mice [10,12], while pyridoxine deficiency causes growth retardation [13,23] and abnormalities in structures and electrical activity in the hippocampus [24].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Pyridoxine Deficiency on Hippocampal Function and Its Possible Association with V-Type Proton ATPase Subunit B2 and Heat Shock Cognate Protein 70

Jung

Kim

Hahn

et al. 2020

Cells

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Pyridoxine, one of the vitamin B6 vitamers, plays a crucial role in amino acid metabolism and synthesis of monoamines as a cofactor. In the present study, we observed the effects of pyridoxine deficiency on novel object recognition memory. In addition, we examined the levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenethylamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid and the number of proliferating cells and neuroblasts in the hippocampus. We also examined the effects of pyridoxine deficiency on protein profiles applying a proteomic study. Five-week-old mice fed pyridoxine-deficient diets for 8 weeks and showed a significant decrease in the serum and brain (cerebral cortex, hippocampus, and thalamus) levels of pyridoxal 5′-phosphate, a catalytically active form of vitamin-B6, and decline in 5-HT and DA levels in the hippocampus compared to controls fed a normal chow. In addition, pyridoxine deficiency significantly decreased Ki67-positive proliferating cells and differentiated neuroblasts in the dentate gyrus compared to controls. A proteomic study demonstrated that a total of 41 spots were increased or decreased more than two-fold. Among the detected proteins, V-type proton ATPase subunit B2 (ATP6V1B2) and heat shock cognate protein 70 (HSC70) showed coverage and matching peptide scores. Validation by Western blot analysis showed that ATP6V1B2 and HSC70 levels were significantly decreased and increased, respectively, in pyridoxine-deficient mice compared to controls. These results suggest that pyridoxine is an important element of novel object recognition memory, monoamine levels, and hippocampal neurogenesis. Pyridoxine deficiency causes cognitive impairments and reduction in 5-HT and DA levels, which may be associated with a reduction of ATP6V1B2 and elevation of HSC70 levels in the hippocampus.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Effects of Pyridoxine Deficiency on Hippocampal Function and Its Possible Association with V-Type Proton ATPase Subunit B2 and Heat Shock Cognate Protein 70

Jung

Kim

Hahn

et al. 2020

Cells

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“…As initially demonstrated, the expression of PLP-dependent enzymes and the positive regulator, PDXK, but not the negative regulator PDXP, occurs early following activation and this expression profile may be both necessary and sufficient to support later proliferation. In line with this, previous studies using whole body knockout of Pdxp in mice, have achieved a 3-fold elevation of PLP levels in a variety of tissues, including brain, skeletal muscle and red blood cells (29). To extend our investigation of the role of vitamin B6 kinase/ phosphatase regulators in immune cell activity, we intend to generate T cell-specific double-floxed PDXP and PDXK dLck Cre knockout mouse models.…”

Section: Discussionmentioning

confidence: 86%

Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses

et al. 2022

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Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5’-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.

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“…organs (brain, muscle, red blood cells) and γ-aminobutyric acid in the brain, leading to phenotypical changes in behavior and cognition as well as decreased performance in motor tests (Jeanclos et al, 2019). This suggests that as-of-yet unidentified variants of PDXP could result in neurological disorders.…”

Section: Geneticsmentioning

confidence: 99%

Preparatory work for the update of the tolerable upper intake levels for vitamin B6

Tetens

Petersen

Christensen

et al. 2023

EFSA Supporting Publications

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To support EFSA in the preparatory work for the assessment of Tolerable Upper Intake Levels (UL) for vitamin B6, a tailored ‘high level’ protocol was developed, based on a template protocol and taking into account the specificities of vitamin B6. This protocol outlined the methods, the relevant endpoints and priority adverse health effects in relation to high intakes of vitamin B6. Systematic reviews (SR) were conducted following a tailored literature search, data extraction, evidence appraisal (i.e. risk of bias (RoB) assessment) and evidence synthesis. Narrative reviews (NR) were conducted to gather contextual evidence relevant to the interpretation of the main body of evidence. In the SR on the dose‐response relationship between vitamin B6 and peripheral neuropathy, 3793 records were identified and reduced to 32 individual records after screening for eligibility. The evidence appraisal revealed an overall moderate to high RoB of the individual studies and an overall rating of the total body of evidence as very low due mainly due to the type of data from case studies/case reports and limited number of other data. The available evidence confirmed a high degree of inter‐individual variability to sensitivity to a high exposure of vitamin B6 in relation to development of peripheral neuropathic outcomes but did not allow to determine a No Observed Adverse Effect Level or Lowest Observed Adverse Effect Level. In the SR on developmental toxicity, 4941 records were identified and reduced to 23 individual records including human and animal studies after screening for eligibility. The available data demonstrated a high degree of heterogeneity with respect to exposure and adverse health outcomes and overall, showed no positive or causal relationship between vitamin B6 intake and adverse developmental effects, including congenital defects. The NRs showed a paucity of data on high intake of vitamin B6 vitamers and their metabolism.

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Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice

Cited by 22 publications

References 78 publications

Effects of Pyridoxine Deficiency on Hippocampal Function and Its Possible Association with V-Type Proton ATPase Subunit B2 and Heat Shock Cognate Protein 70

Effects of Pyridoxine Deficiency on Hippocampal Function and Its Possible Association with V-Type Proton ATPase Subunit B2 and Heat Shock Cognate Protein 70

Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses

Preparatory work for the update of the tolerable upper intake levels for vitamin B6

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