Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity

Advances in Nutrition ◽

10.1093/advances/nmab033 ◽

2021 ◽

Author(s):

Felix Hadtstein ◽

Misha Vrolijk

Keyword(s):

Peripheral Neuropathy ◽

Sensory Neurons ◽

Sensory Neuropathy ◽

Vitamin B ◽

Hereditary Neuropathy ◽

Pyridoxal Kinase ◽

Peripheral Tissues ◽

Adverse Health Effects ◽

Gaba Signaling ◽

Gaba Neurotransmission

ABSTRACT Vitamin B-6 in the form of pyridoxine (PN) is commonly used by the general population. The use of PN-containing supplements has gained lots of attention over the past years as they have been related to the development of peripheral neuropathy. In light of this, the number of reported cases of adverse health effects due to the use of vitamin B-6 have increased. Despite a long history of study, the pathogenic mechanisms associated with PN toxicity remain elusive. Therefore, the present review is focused on investigating the mechanistic link between PN supplementation and sensory peripheral neuropathy. Excessive PN intake induces neuropathy through the preferential injury of sensory neurons. Recent reports on hereditary neuropathy due to pyridoxal kinase (PDXK) mutations may provide some insight into the mechanism, as genetic deficiencies in PDXK lead to the development of axonal sensory neuropathy. High circulating concentrations of PN may lead to a similar condition via the inhibition of PDXK. The mechanism behind PDXK-induced neuropathy is unknown; however, there is reason to believe that it may be related to γ-aminobutyric acid (GABA) neurotransmission. Compounds that inhibit PDXK lead to convulsions and reductions in GABA biosynthesis. The absence of central nervous system-related symptoms in PDXK deficiency could be due to differences in the regulation of PDXK, where PDXK activity is preserved in the brain but not in peripheral tissues. As PN is relatively impermeable to the blood–brain barrier, PDXK inhibition would similarly be confined to the peripheries and, as a result, GABA signaling may be perturbed within peripheral tissues, such as sensory neurons. Perturbed GABA signaling within sensory neurons may lead to excitotoxicity, neurodegeneration, and ultimately, the development of peripheral neuropathy. For several reasons, we conclude that PDXK inhibition and consequently disrupted GABA neurotransmission is the most plausible mechanism of toxicity.

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Cancer Exacerbates Chemotherapy Induced Sensory Neuropathy

10.1101/667105 ◽

2019 ◽

Author(s):

Stephen N. Housley ◽

Paul Nardelli ◽

Dario Carrasco ◽

Emily Pfahl ◽

Lilya Matyunina ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Ion Channel ◽

Neurological Disorders ◽

Neuronal Excitability ◽

Inflammatory Responses ◽

Transcriptional Profiling ◽

Sensory Neuropathy ◽

Potential Contributor ◽

Sensory Encoding ◽

Linear Interactions

AbstractFor the constellation of neurological disorders known as chemotherapy induced peripheral neuropathy, mechanistic understanding, and treatment remain deficient. Here we present the first evidence in preclinical investigation of rats that chronic sensory neuropathy depends on non-linear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as a potential contributor to sensory neuron dysfunction. These original findings identify novel contributors to peripheral neuropathy, and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer.

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Sensory Neurons, Ion Channels, Inflammation and the Onset of Neuropathic Pain

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100013937 ◽

2012 ◽

Vol 39 (4) ◽

pp. 416-435 ◽

Cited By ~ 46

Author(s):

Patrick L. Stemkowski ◽

Peter A. Smith

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Pain Management ◽

Sensory Neurons ◽

Inflammatory Mediators ◽

Primary Afferents ◽

Ectopic Activity ◽

Management Procedures

Neuropathic pain often fails to respond to conventional pain management procedures. here we review the aetiology of neuropathic pain as would result from peripheral neuropathy or injury. We show that inflammatory mediators released from damaged nerves and tissue are responsible for triggering ectopic activity in primary afferents and that this, in turn, provokes increased spinal cord activity and the development of ‘central sensitization’. Although evidence is mounting to support the role of interleukin-1β, prostaglandins and other cytokines in the onset of neuropathic pain, the clinical efficacy of drugs which antagonize or prevent the actions of these mediators is yet to be determined. basic science findings do, however, support the use of pre-emptive analgesia during procedures which involve nerve manipulation and the use of anti-inflammatory steroids as soon as possible following traumatic nerve injury.

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Relationship Between Vitamin B-6 Status and Elevated Pyridoxal Kinase Levels Induced by Theophylline Therapy in Humans

Journal of Nutrition ◽

10.1093/jn/120.11.1352 ◽

1990 ◽

Vol 120 (11) ◽

pp. 1352-1359 ◽

Cited By ~ 10

Author(s):

Johan B. Ubbink ◽

Rhena Delport ◽

Siegbert Bissbort ◽

W. J. Hayward Vermaak ◽

Piet J. Becker

Keyword(s):

Vitamin B ◽

Pyridoxal Kinase

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Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Neurology ◽

10.1212/wnl.0000000000007743 ◽

2019 ◽

Vol 93 (2) ◽

pp. e143-e148 ◽

Cited By ~ 2

Author(s):

Bhaskar Roy ◽

Avash Das ◽

Kumar Ashish ◽

Dhrubajyoti Bandyopadhyay ◽

Abhishek Maiti ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Receptor Tyrosine Kinase ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Sensory Neuropathy ◽

Vascular Endothelial ◽

High Grade ◽

Patients With Cancer ◽

Endothelial Growth Factor ◽

Receptor Tyrosine Kinase Inhibitors

ObjectiveTo explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer.MethodsPublished data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment.ResultsThirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13–2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09–2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01–1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06–1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09–1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control.ConclusionsVEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

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Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup

BMJ Open ◽

10.1136/bmjopen-2018-027770 ◽

2019 ◽

Vol 9 (6) ◽

pp. e027770 ◽

Cited By ~ 5

Author(s):

Nicolas Kerckhove ◽

Jérome Busserolles ◽

Trevor Stanbury ◽

Bruno Pereira ◽

Valérie Plence ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Disease Free Survival ◽

Sensory Neuropathy ◽

Repeated Administration ◽

Public Health Issue ◽

Double Blind Study ◽

Double Blind ◽

Related Quality ◽

Registration Number ◽

Randomised Controlled

IntroductionMost patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%–50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects.Methods and analysisRILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety.Ethics and dessiminationThe study was approved by a French ethics committee (ref:39/18_1, ‘Comité de Protection des Personnes’ Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov.Trial registration numberN°2017-002320-25;NCT03722680

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Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

Clinical Chemistry ◽

10.1093/clinchem/39.9.1845 ◽

1993 ◽

Vol 39 (9) ◽

pp. 1845-1849 ◽

Cited By ~ 11

Author(s):

G W Hensels ◽

E A Janssen ◽

J E Hoogendijk ◽

L J Valentijn ◽

F Baas ◽

...

Keyword(s):

Preliminary Investigation ◽

Sensory Neuropathy ◽

Disease Type ◽

Chromosome 17 ◽

Hereditary Neuropathy ◽

Chromosomal Dna ◽

Gene Encoding ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

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Pmp22 super-enhancer deletion causes tomacula formation and conduction block in peripheral nerves

Human Molecular Genetics ◽

10.1093/hmg/ddaa082 ◽

2020 ◽

Vol 29 (10) ◽

pp. 1689-1699

Author(s):

Harrison Pantera ◽

Bo Hu ◽

Daniel Moiseev ◽

Chris Dunham ◽

Jibraan Rashid ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Schwann Cell ◽

Copy Number ◽

Regulatory Elements ◽

Copy Number Variations ◽

Hereditary Neuropathy ◽

Peripheral Myelin Protein 22 ◽

Super Enhancer

Abstract Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. The duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease type 1A, whereas the reciprocal deletion of this gene causes a separate neuropathy termed hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is robustly induced in Schwann cells in early postnatal development, and several transcription factors and their cognate regulatory elements have been implicated in coordinating the gene’s proper expression. We previously found that a distal super-enhancer domain was important for Pmp22 expression in vitro, with particular impact on a Schwann cell-specific alternative promoter. Here, we investigate the consequences of deleting this super-enhancer in vivo. We find that loss of the super-enhancer in mice reduces Pmp22 expression throughout development and into adulthood, with greater impact on the Schwann cell-specific promoter. Additionally, these mice display tomacula formed by excessive myelin folding, a pathological hallmark of HNPP, as have been previously observed in heterozygous Pmp22 mice as well as sural biopsies from patients with HNPP. Our findings demonstrate a mechanism by which smaller copy number variations, not including the Pmp22 gene, are sufficient to reduce gene expression and phenocopy a peripheral neuropathy caused by the HNPP-associated deletion encompassing PMP22.

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Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

International Journal of Molecular Sciences ◽

10.3390/ijms20061451 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1451 ◽

Cited By ~ 66

Author(s):

Renata Zajączkowska ◽

Magdalena Kocot-Kępska ◽

Wojciech Leppert ◽

Anna Wrzosek ◽

Joanna Mika ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Cancer Patients ◽

Health Care Providers ◽

Antineoplastic Agents ◽

Proteasome Inhibitors ◽

Sensory Neuropathy ◽

Vinca Alkaloids ◽

Care Providers ◽

Underlying Mechanisms ◽

The Moment

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonlyused drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

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Genetic variation in Charcot–Marie–Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy

Pharmacogenomics ◽

10.2217/pgs-2020-0053 ◽

2020 ◽

Vol 21 (12) ◽

pp. 841-851

Author(s):

Yongzhen Chen ◽

Fang Fang ◽

Kelley M Kidwell ◽

Kiran Vangipuram ◽

Lauren A Marcath ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Additive Model ◽

Systemic Exposure ◽

The Other ◽

Hereditary Neuropathy ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Genetic Predictors ◽

Paclitaxel Treatment ◽

Tooth Disease

Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot–Marie–Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes ( ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results: FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

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