Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Abstract

Context: The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. Objective: We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Methods: Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. Results: The acute maximum (C max ) LT concentrations were higher than concentrations in survivors: C max for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Conclusions: Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.ARTICLE HISTORY

Progressive Chronic Retinal Axonal Loss Following Acute Methanol-induced Optic Neuropathy: Four-Year Prospective Cohort Study

“…The follow-up clinical examination protocol has been described in detail in our previously published studies. 10,21,22 The study protocol included complete ophthalmologic evaluation and standard ophthalmic tests, including VA measurement, slit-lamp examination, intraocular pressure measurement, fundus examination, color vision, visual fields, spectral-domain OCT (SD-OCT) with RNFL, VEP, MR of the brain, neurologic and neuropsychological examinations, biochemical tests (electrolytes, glucose, glycohemoglobin, albumin, pre-albumin, renal and hepatic tests, cholesterol, lipids, thyroid-stimulating hormone [TSH], vitamins B 12 and B 1 , carbohydrate-deficient transferrin, ethyl glucuronide in urine), and standardized questionnaire forms. The examiners were masked to the results of measurements, severity of poisoning, clinical course, treatment measures, and clinical outcomes.…”

Role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning

“…In experimental animal studies, it was demonstrated that the biomarkers of brain injury and the mediators of neuroinflammation reach the peripheral circulation either through blood brain barrier disruption or via the glymphatic system in the brain with an intact blood brain barrier and can be measured in the blood serum [22]. In our previous study, we demonstrated that the patients with acute methanol poisoning had elevated serum concentrations of leukotrienes LTB4, LTC4, LTD4, and LTE4, suggesting activation of the mechanisms of leukotriene-mediated neuroinflammation [1].…”

“…We measured the acute concentrations and the dynamics of HHE, HNE, and MDA in peripheral blood serum of patients with acute methanol poisoning, and the follow-up concentrations of survivors. We investigated if the process of lipid peroxidation was related to the activation of leukotrienemediated neuroinflammation and the concentrations of measured biomarkers of peroxidation were associated with acute serum concentrations of leukotrienes (LTB4, LTC4, LTD4 and LTE4) measured in our previous study and with the outcome [1]. Within the follow-up study of long-term health sequelae of poisoning, we measured the concentrations of the same markers in the survivors, 2 years after discharge, to test their associations with long-term outcomes of poisoning.…”

“…Methanol is one of the most widely used toxic alcohols worldwide, and it is often misused to produce adulterated alcoholic drinks. Poisonings can occur as isolated events, due to unintentional or intentional ingestion, or as cluster events, due to mass outbreaks or "epidemics" [1,2]. During the recent Czech Republic mass methanol poisoning outbreak in 2012, there were 121 affected persons; 41 affected individuals died, while the remaining survived with either short-or long-term sequelae [3,4].…”

“…Mitochondrial dysfunction leads to production of reactive oxygen species and toxic aldehydes, with oxidative damage of cellular structures; this is one of the key pathogenetic elements in the processes of acute and chronic neurodegeneration [14]. Leukotriene-mediated neuroinflammation, as a response to acute neuronal cell injury, may have both negative and protective roles in methanolinduced toxic brain damage [1].…”