Deciphering the role of metal and non-metals in the treatment of epilepsy

Sande, Ruksar; Doshi, Gaurav Mahesh; Godad, Angel

doi:10.1016/j.neuint.2023.105536

Cited by 5 publications

(5 citation statements)

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“…Additionally, research has shown that children with epilepsy on long-term antiepileptic drug treatment have higher serum copper levels compared to healthy children [28]. This may be attributed to the impact of antiepileptic drugs on liver function and ceruloplasmin production, leading to increased serum copper levels [29]. However, some studies have indicated no signi cant differences in serum copper concentrations between epilepsy patients and healthy individuals [30].…”

Section: Discussionmentioning

confidence: 99%

Association of Serum Copper, Zinc, and Zinc/Copper Ratio with Epilepsy: A Cross-Sectional Study

Su,

Wang,

et al. 2024

Preprint

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Using data from the National Health and Nutrition Examination Survey (NHANES) in the United States, this study examines the association between serum copper, zinc, and zinc/copper ratio with epilepsy. This study utilized data from American adults obtained from the NHANES cycles of 2013–2014 and 2015–2016. To assess the relationship between serum copper, zinc, and zinc/copper ratio with epilepsy, a weighted logistic regression model was employed. Age and gender were analyzed as subgroups. Based on a logistic regression analysis, serum zinc, and zinc/copper ratio were found to be negatively correlated with epilepsy. In the fully adjusted model, the OR (95% CI) for intermediate levels of serum zinc was 0.37(0.17–0.80), and for high levels of zinc/copper ratio, the OR (95% CI) was 0.18(0.08–0.43). Serum copper was positively correlated with epilepsy in individuals over 40 years old. For the 40–59 age group, the OR (95% CI) for intermediate and high levels of serum copper were 4.22(1.16–15.36) and 3.85(1.21–12.27), respectively. The study concludes that serum zinc and zinc/copper ratio are inversely related to epilepsy among American adults, while serum copper exhibits a positive association with epilepsy in individuals aged over 40, particularly within the 40–59 age group.

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Section: Discussionmentioning

confidence: 99%

Association of Serum Copper, Zinc, and Zinc/Copper Ratio with Epilepsy: A Cross-Sectional Study

Su,

Wang,

et al. 2024

Preprint

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“…Our findings indicate an increased risk of focal epilepsy with HS, associated with zinc, paralleling mechanistic research where zinc ions enhance neuronal excitability and provoke seizures through the activity of the Na + –K + ATPase, altering GABA levels or carbonic anhydrase activity ( 43 ). Conversely, studies found that oral zinc supplementation served as an adjunct therapy in children with intractable epilepsy, suggesting a dose-dependent dichotomy where zinc can exhibit both neurotoxic and neuroprotective properties ( 5 , 44 ). The observed OR of 1.010 (95% CI, 1.000–1.020, p = 0.045) for zinc’s effect on focal epilepsy with HS from two-sample MR, and MVMR results were 1.010 (95% CI, 1.000–1.020, p = 0.057) with carotene, 1.008 (95% CI, 0.998–1.019, p = 0.114) with vitamin B6, and 0.998 (95% CI, 0.976–1.020, p = 0.837).…”

Section: Discussionmentioning

confidence: 99%

“…Recent investigations have shed light on the intricate link between epilepsy and the dysregulation of micronutrients, with elements such as copper, iron, manganese, zinc, selenium, phosphorus, magnesium, and vitamins D, vitamin B6, and folate being implicated in the modulation of the disease’s progression ( 5 – 8 ). However, the evidence has predominantly derived from animal studies, remains preliminary, and is often marred by the inherent limitations of observational research, such as residual confounding and reverse causality, thus calling for a more rigorous methodological approach to ascertain these relationships.…”

Section: Introductionmentioning

confidence: 99%

Causal links between serum micronutrients and epilepsy: a Mendelian randomization analysis

Chen,

Zheng,

Cai

et al. 2024

Front. Neurol.

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BackgroundMicronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR).MethodsA two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes. The analysis included calcium, iron, zinc, selenium, copper, magnesium, potassium, folate, vitamins B6, B12, C, D, E, retinol, and carotene against all epilepsy, generalized epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized tonic–clonic seizures alone and with spike–wave electroencephalography (GTCS), and various focal epilepsy phenotypes [with hippocampal sclerosis (HS), lesions other than HS, lesion-negative]. The random-effects inverse-variance weighted (IVW) model was the primary method used, supported by heterogeneity and pleiotropy assessments. Multivariable Mendelian randomization analyses (MVMR) were used to identify micronutrients that are significantly causally associated with different epilepsy subtypes and to confirm the most potential causal risk factors for these subtypes.ResultsZinc conferred an increased risk of focal epilepsy with HS (OR = 1.01; p = 0.045). Carotene was similarly linked to higher risks of lesion-negative cases (OR = 1.129; p = 0.037). Conversely, vitamin B6 was associated with reduced risks of focal epilepsy with HS (OR = 0.949; p = 0.020), and vitamin D was linked to decreased risks of both CAE (OR = 0.976, 95% CI: 0.959–0.993, p = 0.006) and JAE (OR = 0.986, 95% CI: 0.973–0.999, p = 0.032). These associations were robust, showing minimal heterogeneity and no evidence of pleiotropy across various sensitivity analyses. After adjustment using MVMR, significant causal relationships between vitamin D and both CAE and JAE remained. Furthermore, the causal relationship between zinc and vitamin B6 on focal epilepsy with HS became non-significant, while carotene shifted from a risk factor to a protective factor for focal epilepsy lesion-negative after adjusting for vitamin D.ConclusionMR estimates provide robust evidence for the causal effects of vitamin D on reducing the risk of CAE, and JAE, which might provide alternative treatment strategies.

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“…At the molecular level, zinc controls the activity of numerous important enzymes involved in brain metabolism, as well as gene expression via transcription factor activity. Depending on the concentration levels in the CNS, zinc exhibits a biphasic response that can be both neurotoxic and neuroprotective ( 4 ). Research has emphasized zinc’s dual action in studying its impact on seizure latency and severity in rats modeling temporal lobe epilepsy.…”

Section: Introductionmentioning

confidence: 99%

“…Zinc homeostasis can be altered by an excessive or insufficient zinc intake, leading to malfunctioning cellular systems. Therefore, moderate zinc intake through diet can work in conjunction with conventional antiseizure medication ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Association between dietary zinc intake and epilepsy: findings from NHANES 2013–2018 and a Mendelian randomization study

Huang,

Gao,

Chen

et al. 2024

Front. Nutr.

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BackgroundThe association between dietary zinc intake and epilepsy remains unclear. This study aimed to investigate the relationship between zinc intake from the diet and epilepsy, employing Mendelian randomization (MR) to explore potential causal links between zinc and epilepsy.MethodsThe cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2018. Among the 4,434 participants included, 1.5% (67/4,434) reported having epilepsy. Restricted cubic spline models and logistic regression models were employed to examine the relationships between dietary zinc intakes and epilepsy. Subsequently, a 2-sample Mendelian randomization (MR) analysis was conducted using the inverse variance weighted (IVW) approach as the primary analysis.ResultsIn the restricted cubic spline (RCS) analysis, the relationship between dietary zinc consumption and epilepsy displayed an L-shaped curve (nonlinear, p = 0.049). After multivariate adjustments, the adjusted odds ratios for epilepsy in T2 (5.0–11.0 mg/day) and T3 (≥11.0 mg/day) were 0.49 (95% confidence interval [CI]: 0.26–0.92, p = 0.026) and 0.60 (95% CI: 0.31–1.17, p = 0.132), respectively, compared to the lowest dietary zinc consumption tertile (T1, ≤5.0 mg/day). The IVW method indicated that genetically predicted zinc intake per standard-deviation increase was inversely associated with three types of epilepsy, including all types of epilepsy (OR = 1.06, 95% CI: 1.02–1.11, p = 0.008), generalized epilepsy (OR = 1.13, 95% CI: 1.01–1.25, p = 0.030), and focal epilepsy (documented hippocampal sclerosis) (OR = 1.01, 95% CI: 1.00–1.02, p = 0.025).ConclusionOur findings suggest that a daily zinc intake ranging from 5.0 to 11.0 mg is associated with the lowest risk of epilepsy. Furthermore, Mendelian randomization (MR) studies provide additional support for the existence of a causal relationship between zinc and epilepsy.

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Deciphering the role of metal and non-metals in the treatment of epilepsy

Cited by 5 publications

References 131 publications

Association of Serum Copper, Zinc, and Zinc/Copper Ratio with Epilepsy: A Cross-Sectional Study

Association of Serum Copper, Zinc, and Zinc/Copper Ratio with Epilepsy: A Cross-Sectional Study

Causal links between serum micronutrients and epilepsy: a Mendelian randomization analysis

Association between dietary zinc intake and epilepsy: findings from NHANES 2013–2018 and a Mendelian randomization study

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