http://informahealthcare.com/iht ISSN: 0895-8378 (print), 1091-7691 (electronic) Inhal Toxicol, 2014; 26(14): 885–890 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/08958378.2014.970786

RESEARCH ARTICLE

Proteins as biomarkers of carbon monoxide neurotoxicity Tomasz Gawlikowski1, Magdalena Golasik2, Ewa Gomo´łka3, and Wojciech Piekoszewski2 Department of Clinical Toxicology, Jagiellonian University School of Medicine, Krakow, Poland, 2Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University, Krakow, Poland, and 3Laboratory of Analytical Toxicology and Therapeutic Drug Monitoring, Jagiellonian University School of Medicine, Krakow, Poland

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1

Abstract

Keywords

Context: Carbon monoxide (CO) poisoning is the most common form of accidental lethal poisoning and is associated with a risk of brain damage in survivors. Objective: The goal of this study was to examine whether Tau protein or S100B protein may be used as a biomarker for acute brain dysfunction. Materials and methods: The determination of Tau and S100B proteins was performed in serum samples collected from 27 CO-poisoned patients and 12 healthy volunteers. Results: The level of Tau protein in the serum of patients (444 ± 227 ng L1) differed significantly compared with those in the healthy controls (240 ± 61 ng L1) and correlated with the level of carboxyhemoglobin. A higher concentration of Tau protein was found in patients who had lost consciousness during CO exposure. The concentration of S100B in the serum of CO-poisoned subjects (0.08 ± 0.03 mg L1) was not statistically different from values obtained for the controls (0.07 ± 0.02 mg L1). Conclusion: CO poisoning appears to be associated with an elevated level of Tau and S100B proteins in the serum of patients who had suffered a loss of consciousness. The study has shown that Tau protein is a more sensitive biomarker than S100B protein for the earlier stage of neurotoxic effects of CO intoxication.

CO poisoning, neurological biomarkers, serum, S100B protein, Tau protein

Introduction Accidental exposure to carbon monoxide (CO) occurs most frequently in a residential setting and is the leading cause of poisoning in the United States and Western European countries (Gawlikowski et al., 2013; Iqbal et al., 2012). The major pathophysiological mechanism of intoxication is the ability of CO to bind to hemoglobin molecules with high affinity (250 times higher than to oxygen), which reduces the oxygen carrying capacity of the blood and could lead to tissue hypoxia (Omaye, 2002). The target organs for CO toxicity are the brain and heart. The cardiotoxicity of CO, besides hypoxic damage, is related to direct lesions at the cellular or subcellular level. Their mechanism includes the inhibition of the mitochondrial transport system and increased production of free-radicals, which can cause lipid peroxidation (Lippi et al., 2012). Myocardial injury occurs frequently in hospitalized patients and it is a significant predictor of mortality (Henry et al., 2006).

Address for correspondence: Prof. Wojciech Piekoszewski, PhD, DSc, Department of Analytical Chemistry, Faculty of Chemistry, Jagiellonian University of Krakow, Ingardena 3, 30-060 Krakow, Poland. Tel: (+48 12) 663 56 00. E-mail: [email protected]

History Received 3 July 2014 Revised 19 August 2014 Accepted 14 September 2014 Published online 30 October 2014

In addition to myocardial damage after CO poisoning, neurological aftereffects are the most frequent form of CO-induced morbidity (Gorman et al., 2003; Omaye, 2002). It is assumed that brain damage caused by CO is secondary to hypoxia. However, other mechanisms, such as inflammation (Thom et al., 2006b) and oxidative process (Cronje et al., 2004), may also contribute to neuronal injuries. According to recent studies, acute brain injury in CO-poisoned patients appears to arise largely from hypoxia in the globus pallidus region (Chu et al., 2004), although the demyelination of white matter is probably responsible for delayed neuropsychiatric effects (Kim et al., 2003; Thom et al., 2006a). Several symptoms have been suspected of being associated with the neurotoxic effects of CO, such as unconsciousness and coma after poisoning, and early changes in the globus pallidus or white matter (Annane et al., 2001; Hu et al., 2011; Moon et al., 2011; Parkinson et al., 2002). Although carboxyhemoglobin (COHb) is widely used as a biomarker of CO poisoning, there is currently no universally accepted biomarker of heart and brain injury resulting from CO intoxication. Some proteins in serum, such as myelin basic protein, neuron-specific enolase and protein S100B, have been examined as possible biomarkers of these effects of CO. S100B is an acidic, dimeric protein that plays an important role in calcium homeostasis. It is synthesized in the glial cells in the brain. The cells of astroglia are as sensitive to hypoxia and stress oxidation as neurons, so the concentration

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of S100B (the structural protein of the astroglia) can indirectly reflect neuronal damage (Gonc¸alves et al., 2008; Sakatani et al., 2008). Recent studies have shown a clear association between the increase in the level of S100B protein in serum and both the damage of brain cells and enhancement of the blood–brain barrier permeability. Therefore, S100B protein is now increasingly recognized as a marker for assessing the degree of damage to brain tissue resulting from cardiac arrest, stroke, subarachnoid hemorrhage and traumatic head injury (Yardan et al., 2009). Some authors reported that the increase in the level of S100B could be a useful marker in the assessment of the clinical status of CO-poisoned patients (Cakir et al., 2010; Yardan et al., 2009). Another protein, also considered a biomarker of the neurotoxic effects of CO, is Tau protein. The proteolytically cleaved Tau protein can diffuse into the cerebrospinal fluid and serum as an effect of hypoxic or traumatic axonal injuries (Zemlan et al., 1999). The Tau protein is a family of proteins that are a part of the neuronal cytoskeleton and are localized mostly in axons, where they bind to microtubules (MAP-Tau) (Li et al., 2011; Mandelkow & Mandelkow, 2012). The most relevant biological functions of Tau protein are as follows: the construction and stabilization of microtubules that are involved in cell division, the polarization of neurites and the maintenance of the stability of microtubules (Drubin & Kirschner, 1986). Tau protein was proposed in some studies as a marker for the axonal loss of grey matter axons (Bitsch et al., 2002), in an acute ischemic stroke (Wunderlich et al., 2006), closed head injury and mild traumatic brain injury (Shaw et al., 2002), plus in some neurodegrative diseases, e.g. Alzheimer disease (Zetterberg et al., 2013). Although the use of protein markers of neurotoxic effects of CO can be of great value in the diagnosis of poisoning, only limited research has been conducted so far. To the best of our knowledge, there is only one report concerning a correlation between the level of Tau protein in serum and CO poisoning (Kilicaslan et al., 2012). The aim of this study was to examine the changes in the serum level of two proteins, S100B and Tau, in CO-poisoned patients and to evaluate whether there is any correlation between the level of COHb – the common marker of CO poisoning – and the level of proteins examined as markers of neurotoxicity caused by CO exposure.

evaluated, and the information about the duration of exposure and time between the end of exposure and blood sampling were recorded during a physical examination and medical interview. This study was approved by the Bioethical Committee of the Jagiellonian University in Krakow.

Methods

Statistical analyses were performed with Statistica 10 software (StatSoft Poland, Krakow, Poland). The values are given as mean ± SD. The Kolmogorov–Smirnov test (with Lilliefors significance correction) and the Shapiro– Wilk test were used to test the normality of the distribution of the variables. The serum S100B protein level was normally distributed, while the level of COHb and Tau protein in serum were not. The means were compared by a two-tailed unpaired t-test, or Mann–Whitney U test as appropriate, to investigate the differences between the groups. The correlations between individual parameters were assessed by Spearman’s rank correlation coefficients. All p values were two-tailed, and the value of p50.05 was accepted as statistically significant.

Participants A total of 27 consecutive adult patients (19 women and 8 men) suffering from CO poisoning after exposure at home were enrolled in this study. No patient died during hospitalization. The samples were collected from them just after admission to the Toxicology Clinic of the Jagiellonian University in Krakow (Poland), between December 2012 and April 2013. The control group comprised of 12 healthy individuals (seven women and five men). The signs of CO poisoning, such as headache, dizziness, nausea, cardiac dysrhythmia, myocardial ischemia, weakness, vomiting, confusion, loss of consciousness and seizures, were

Samples and measurements Two blood samples were collected from each subject. The first sample was collected in a heparinized tube (whole blood) for the determination of COHb, while the second one for the determination of Tau and S100B proteins was drawn to the tubes without anticoagulant. The serum (second tube) was separated by centrifugation at 3000 rpm for 10 min at room temperature and was stored at 30  C before the analysis of selected proteins, but not for longer than two weeks. The level of COHb in whole blood on admission to hospital was measured by the spectrophotometric method at different wavelengths, ranging between 500 and 700 nm, using the CO-Oximeter AVL 912 analyzer (Roche, Basel, Switzerland). Sensitivity of the method was 0.1%, lower limit of quantification (LOQ) was 0.1% and the coefficients of variation were 1.96% and 0.40% for the COHb concentration of 3.4% and 24.4%, respectively. The level of Tau protein in serum was measured by a commercially available enzyme-linked immunosorbent assay (Human total Tau Proteins (t) Elisa Kit, Hangzhou Easbiopharm Co. Ltd., Hangzhou, China). Absorbance measurements at 450 nm were made using an ELx800 spectrophotometer (Green Mountains, VT). The assay range was from 20 to 1800 ng L1, and LOQ was 12 ng L1. The intra-assay precision for the laboratory samples (the concentration of Tau protein: 322 ng L1) was 1.99%, and the inter-assay precision was 2.44%. The serum S100B protein level was measured with a Cobas e411 S100 electrochemiluminescence assay (Roche Diagnostics, Mannheim, Germany). The assay range was from 0.005 to 39 mg L1, and LOQ was 0.02 mg L1. The inter-assay precision for the following concentration of S100B protein: 0.26 and 3.33 mg L1 was 1.8% and 1.4%, respectively, while the intra-assay precision was 2.3% and 1.7%, respectively. Statistical analysis

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Table 1. Clinical characteristics of the study groups. CO-poisoned patients

Controls (n ¼ 12)

p

Whole group (n ¼ 27) Conscious (n ¼ 16) Unconscious (n ¼ 11)

36.7 ± 18.9 444 ± 227 374 ± 153 544 ± 283

29.1 ± 11.3 240 ± 61

0.15 50.0001 0.0002 50.0001

S100B protein (mg L1)

Whole group (n ¼ 27) Conscious (n ¼ 16) Unconscious (n ¼ 11)

0.08 ± 0.03 0.08 ± 0.03 0.08 ± 0.03

0.07 ± 0.02

0.29 0.32 0.41

COHb (%)

Whole group (n ¼ 27) Conscious (n ¼ 16) Unconscious (n ¼ 11)

19.3 ± 8.8 13.83 ± 3.8 27.33 ± 7.8 2.1 ± 0.3 117.6 ± 142.8 74.4 ± 83.8 5 6

Parameter

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Age (year) Tau protein (ng L1)

Group

Lactate (mmol L1) Time of CO exposure (min) Time between CO exposure and collection of samples (min) Loss of consciousness 55 min (n) Loss of consciousness 45 min (n)

55 NA NA NA NA NA

NA NA NA NA NA NA NA NA

NA, data not available.

Results The study comprised 27 CO-exposed patients and 12 healthy volunteers (control group). Eleven patients were unconscious when emergency personnel arrived, and six of them were unconscious for more than five minutes. The rest of the patients (16) did not lose consciousness at any stage of poisoning. They were treated with normobaric oxygen. The time between CO exposure and collection of samples ranged between 30 min and 420 min (median: 60 min). The mean COHb level in the whole blood of CO-poisoned patients was 19.3 ± 8.8% and ranged from 7.0% to 43.7%. It was higher in the patients with a loss of consciousness (27.3 ± 7.8%) than in conscious patients (13.8 ± 3.8%) (p50.05) (Table 1). In the control group, the level of COHb in whole blood was below 5%. The normal level of Tau protein in the serum of the healthy volunteers was established at 240 ± 61 ng L1. The mean concentration of Tau protein in the serum of the intoxicated patients was 444 ± 227 ng L1 and was statistically higher than in the control group (p50.0001). The concentration of Tau protein in serum was found to be statistically different (p50.05) in the poisoned patients with an episode of unconsciousness (544 ± 283 ng L1) than in the patients who had no loss of consciousness during CO poisoning (374 ± 153 ng L1) (Figure 1). No difference was found between the patients with a loss of consciousness that lasted for less than five minutes or longer. The level of Tau protein in serum was positively correlated with the concentration of COHb in whole blood (r ¼ 0.41, p50.05; Figure 2), while there was no correlation between the level of Tau protein and the duration of exposure to CO, or the period of time from poisoning to blood sampling. The mean concentration of S100B was 0.07 ± 0.02 mg L1 and 0.08 ± 0.03 mg L1 in the control and patients’ groups, respectively. The differences between the two groups were not statistically significant, and also no difference was observed between the group of unconscious patients and the control group (Table 1). The level of S100B was not correlated with the concentration of COHb, time of exposure to CO or the amount of

Figure 1. The concentration of Tau protein in all study subjects: controls (n ¼ 12), patients who lost consciousness after exposure to CO (n ¼ 11) and patients who stayed conscious (n ¼ 16). All patients showed a statistically significant difference in the mean level of Tau protein with respect to controls (p50.0001). Patients with an episode of unconsciousness had significantly increased Tau protein (p50.05) compared with those who did not lose consciousness. The serum concentration of Tau protein was determined by ELISA.

time that passed between intoxication and the collection of blood samples.

Discussion Until now, there has been little previous research on the application of protein biomarkers to assess the neurotoxicity of CO poisoning. Most of the reports concern the use of neuron-specific enolase, S-100B and Tau proteins in the diagnosis of chronic diseases such as Alzheimer’s and Parkinson’s diseases (Avila et al., 2004). However, several studies demonstrating the diagnostic and even prognostic value of these proteins in acute neuronal injury: traumatic

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Figure 2. Association between the serum levels of COHb and Tau protein in CO-poisoned patients (n ¼ 27). A significant positive correlation was found between these two biochemical parameters (p50.05). COHb in whole blood was determined spectrophotometrically, and Tau protein in serum was measured with ELISA.

brain injury (Shakeri et al., 2013; Yokobori et al., 2013) and acute ischemic stroke (Wunderlich et al., 2006). Information on the changes in the level of Tau protein in serum, which can be used to evaluate the neurotoxic effects of CO, is scarce. In our study, the CO-poisoned patients had an elevated level of Tau protein, and it was greater in those who had lost consciousness. Similar observations were made by Kilicaslan et al. (2012), although the concentrations of the protein biomarker were 10 times lower than those obtained in our study for both the patients’ and control groups. Nevertheless, in both studies, the increase of Tau protein level in unconscious patients compared to conscious patients was in the same range. On the other hand, the serum level of Tau protein obtained in our study was in the same range as those reported by other authors (Hu et al., 2012; Sparks et al., 2012). The study of Liliang et al. (2010) using animal model of traumatic brain injury had shown that the rise of Tau protein level was dependent on time and severity of damage. Examination of Tau protein primarily concerned neurons. This protein is present mainly in the neurons of the central and peripheral nervous system, and astrocytes and oligodendrocytes in CNS (Trojanowski & Lee, 2002). Its occurrence has also been reported within other tissues, for example, as a component of the cytoskeleton of podocytes (Shankland, 2006). The increased level of Tau protein is typical for neurodegenerative disorders from the group of so-called tauopathies. Such neuroselectivity of Tau protein makes it a promising marker in acute central nervous system injuries. In recent years, the expression of Tau protein in various cancers of non-neuronal tissues (prostate, breast and stomach) has been examined (Souter & Lee, 2009; Wang et al., 2013a,b) what seems to be helpful in the selection of optimal treatment. Our study revealed a correlation between the level of Tau protein in serum and the concentration of COHb in whole blood (p50.05), but it did not correlate with the length of

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exposure to CO or with the time between intoxication and the blood sampling. There are no the data about these kind of correlations reported by other authors. S100B protein is not a selective biomarker because many extracerebral sources contribute to the concentration of this protein in serum. Some reports have examined the serum levels of S100B in multiple trauma patients without any kind of head injury, but with acute stroke, bone damage and cardiac arrest, and have shown that these clinical conditions resulted in elevated serum concentration of S100B (Foerch et al., 2005; Sen & Belli, 2007; Wojtczak-Soska & Lelonek, 2010). Nonetheless, several studies have demonstrated the usefulness of S100B protein in the diagnosis of acute and delayed brain injury resulting from CO poisoning on the basis of the concentration of this protein in cerebral spinal fluid and also in serum (Cakir et al., 2010; Ide et al., 2012; Park et al., 2012; Yardan et al., 2009). The study conducted by Brvar et al. (2004) demonstrated that people who had lost consciousness because of CO intoxication (especially at the place of exposure) had an elevated level of S100B. However, the concentration of this protein in CO-poisoned patients without loss of consciousness was at a normal level. We did not observe this phenomenon – the concentration of S100B protein was similar in both patients’ group (conscious and unconscious) and in healthy volunteers. Rasmussen et al. (2004) also reported such findings. The weak point of their study is the lack of any details about the time of exposure to CO and the time that elapsed between the end of exposure and the blood sampling. On the other hand, Park et al. (2012) have found that the serum level of the S100B protein can be useful in the diagnosis of the delayed neurotoxicity of CO. Authors observed very high increase in the level of S100B protein (for median value, it was 10 time increase, and for individual patients, it was even 50 times increase). On the basis of our study, we can conclude that the measurement of Tau protein, but not S100B, in serum just after admission to the hospital can be used to assess the acute neurotoxic effects of CO. CO poisoning causes the elevation of the concentration of Tau protein. It is correlated with the level of COHb and is higher in patients who lost consciousness after the exposure to CO. Coma on arrival at the hospital is still the only generally accepted and undisputed indication for hyperbaric-oxygen therapy. However, sometimes disturbed consciousness is triggered by a few concomitant factors, e.g. CO, alcohol or drugs, what can have an impact on the choice of treatment. Tau protein could be an additional criterion for hyperbaric oxygen therapy, especially when concomitant factor does not influence its level (Brvar et al., 2004). It seems that Tau protein is a more sensitive marker than S100B during the early stage of neurotoxic effects of CO intoxication. On the other hand, the concentration of S100B can reflect the delayed onset of neurological symptoms (Park et al., 2012; Thelin et al., 2014).

Conclusions A biomarker of neurotoxicity resulting from acute CO poisoning that can be determined in blood (a quick and easily accessible biological material) will be invaluable in everyday medical practice. Our research shows that Tau

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DOI: 10.3109/08958378.2014.970786

protein can be regarded as an indicator of an acute neurotoxicity. It seems that it may be an important, additional parameter that would allow for making decisions as to the suitability of patients for treatment with hyperbaric oxygen therapy. Our study was limited by a small sample size and the short time from CO exposure to blood sampling. However, it was dedicated to diagnose an immediate neurotoxic effect of CO poisoning. Our study provides promising preliminary results and suggests that this issue deserves further investigations, involving larger numbers of CO-poisoned patients and the blood samples collected after different times following exposure to CO. Further studies are necessary in order to find out the relationship between the concentration of Tau protein and long-term functional disorders of the central nervous system. Probably Tau protein, apart from being an early parameter of acute neurotoxicity of CO and thus qualifying marker useful in the treatment of patients with hyperbaric oxygen therapy, will be also an early biomarker of late neuropsychiatric effect. This would allow immediately after poisoning the selection of those from CO-poisoned patients, who are at risk of distant CNS dysfunction. Such knowledge will give the opportunity to better planning of care, selection of health check and the use of long-term follow-up among these patients.

Acknowledgements The authors gratefully thank Miss Mariola Gruszka, chemistry student, for her technical assistance.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Proteins as biomarkers of carbon monoxide neurotoxicity.

Carbon monoxide (CO) poisoning is the most common form of accidental lethal poisoning and is associated with a risk of brain damage in survivors...
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