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Elevated melatonin levels in natalizumab-treated female patients with relapsing-remitting multiple sclerosis: Relationship to oxidative stress

European Journal of Pharmacology, pages 26 - 30

Abstract

Natalizumab is currently the most successful clinical treatment for multiple sclerosis. The use of this drug is associated with the reduction in the number of relapses and a slowing in disease progression, as well as an improvement in signs and symptoms displayed by the patients. To evaluate the effect of natalizumab on melatonin and its relationship with peripheral oxidative damage, we studied the serum melatonin levels in 18 patients with relapsing-remitting multiple sclerosis. Natalizumab caused significant increases in serum melatonin concentrations. This change was associated with a rise in increase of antioxidants and a reduction in oxidative stress biomarkers. In conclusion, these data may explain, at least in part, some of the beneficial effects exhibited by disease antibody such as its antioxidant capacity.

Keywords: Melatonin, Natalizumab, Oxidative stress, Relapsing-remitting multiple sclerosis, Tysabri®.

1. Introduction

The most common cause of non-traumatic neurological disorder in young adults is multiple sclerosis. Its pathogenesis involves inflammation, oxidative stress, demyelinization and neuronal loss (Compston and Coles, 2002, Compston and Coles, 2008, and Miller, 2012). There are four types of MS: (i) progressive relapsing, (ii) primary progressive, (iii) relapsing-remitting, and (iv) secondary progressive (Compston and Coles, 2002 and Compston and Coles, 2008).

Oxidative stress seems to play an important role in this neurodegenerative condition. Thus, reactive oxygen species have a relevant function in multiple sclerosis pathogenesis (Melamud et al, 2012, Miller et al, 2012, Tasset et al, 2012a, and Tasset et al, 2012b). Our recent studies found that multiple sclerosis patients have elevated levels of oxidative stress biomarkers, together with a global antioxidant deficiency. This supports the hypothesis that an imbalance between reactive oxygen species and antioxidant system precedes the inflammatory response, at least, in terms of a relapse (Tasset et al, 2012a and Tasset et al, 2012b).

Environmental factors have important role in multiple sclerosis pathogenesis (Ghorbani et al, 2013 and Hedstrom et al, 2011). Studies have shown a reduction in blood melatonin (N-acetyl-5-methoxy-tryptamine) levels and dysregulation of its synthesis, secretion and circadian rhythm associated with fatigue, depression and sleep disorder in multiple sclerosis patients (Akpinar et al, 2008, Compston and Coles, 2002, Ghorbani et al, 2013, Melamud et al, 2012, and Sandyk and Awerbuch, 1993). Melatonin produced by pineal gland and elsewhere is a potent free radical scavenger and antioxidant (Fischer et al, 2013, Galano et al, 2011, Galano et al, 2013, and Miller et al, 2012) and, as such, it may be protective against the neural damage associated with multiple sclerosis.

Natarajan et al. (2012) reported that the melatonin pathway genes are involved in progression of multiple sclerosis. In addition, a recent study found that its administration reduced oxidative status associated to multiple sclerosis. This was accompanied by a reported improvement in functional characteristics of patients, evaluated by the Expanded Disability Status Scale, though the difference could not be statistically verified ( Natarajan et al., 2012 ). These data are consistent with the idea that this, melatonin, may play an important role in the development and progression of multiple sclerosis.

To date, there is no cure for multiple sclerosis, so treatments are aimed at preventing relapses and mitigating the signs and symptoms associated with this disease. A variety of drugs are used in therapy; natalizumab (Tysabri®) is reported to be the most effective (Cadavid et al, 2013, Phillips et al, 2011, Stephenson et al, 2012, and Wickstrom et al, 2013), whereas the most common is interferon-beta.

With this background, we addressed the idea that the changes produced after treatment with natalizumab may be due, in part, to the stabilization of melatonin levels and its antioxidant effects.

2. Materials and methods

Eighteen patients (5 men and 13 women) with relapsing-remitting multiple sclerosis were recruited for the study from the Department of Neurology at Queen Sofia University Hospital in Cordoba. The revised McDonald ( Polman et al., 2005 ) criteria were used and the patients were treated with 300 mg natalizumab (anti-VLA-4; Tysabri, Biogen Idec, Cambridge, MA, USA) administered via intravenous infusion every 4 weeks (28 days) in concordance with current Spanish guidelines during 56 weeks (MS-56) ( Fig. 1 ). The infusions were given between 16:00 and 18:00 hours. Clinical examination was performed using the Expanded Disability Status Scale (EDSS) ( Kurtzke, 1983 ).

gr1

Fig. 1 Schematic of natalizumab administration.

Peripheral blood samples were taken immediately prior to the first infusion (baseline) and before the fourteenth infusion. Blood was collected between 15:30 and 17:30 hours in chilled BD Vacutainer®tubes (Becton-Dickinson and Company, BD, Franklin Lakes, NJ, USA) without anticoagulant (for serum) or with anticoagulant, EDTA-K2 (for plasma and erythrocytes). Thereafter serum or plasma samples were immediately separated by centrifugation at 1500 g at 4 °C for 15 min and the fraction was frozen in aliquots and stored at −85 °C.

2.1. Biochemical parameters

Serum samples were tested for melatonin using enzyme immunoassay (Melatonin ELISA) kits according to the manufacturer׳s instructions (GenWay Biotech Inc., San Diego, CA, USA).

The quantity of the oxidative DNA adduct 8-hydroxy-2׳deoxyguanosine (8-OHdG) was evaluated using the assay kit (8-OHdG Check-437-0122) purchased from JaICA (Japan Institute for the Control of Aging, Fukuroi city Shizuoka, Japan). Reduced glutathione (GSH) levels were evaluated using the Bioxytech GSH-400 kit (Oxis International, Portland, OR, USA). The GSH concentration is based on a reaction which leads to the formation of a chromophore with absorbance at 400 nm. The total antioxidant capacity (PAO, KPA-050) was evaluated using a kit purchased from JaICA (Japan Institute for the Control of Aging, Fukuroi City Shizuoka, Japan); this assay is based on the reduction of Cu2+to Cu+by the combined action of all of the antioxidants present in the sample. Thus, the chromogenic reagent forms a complex with Cu+which has an absorbance at 490 nm.

For quantitative detection of the soluble vascular cell adhesion molecule-1 (sVCAM-1) an assay kit (Milliplex®MAP Kit, Human CVVD Panel 1 96-Well Plate Assay, Cat. # HCVD1-67AK) purchased from Millipore™ (Millipore Corporation, Concord Road, Billerica, MA, USA) was used.

2.2. Statistical analysis

Statistical evaluation was performed using SPSS 17.0®software (SPSS Iberica, Madrid, Spain) for Windows. Intergroup significance was determined by Wilconxon-matched pairs test to analyze nonparametric data.P<0.05 was considered significant.

3. Results

The demographic features of the study groups are presented in Table 1 . Our data did not find significant change between EDSS score before and after treatment. However, the EDSS increase suffered by patients after treatment presented a correlation with melatonin levels after treatment (Spearmen Rho,r: 0.777;P=0.04).

Table 1 Characteristics of patients with relapsing-remitting multiple sclerosis (RRMS). Values are expressed as mean±S.D. Baseline: patients with multiple sclerosis previous treatment (baseline) and after 56 weeks of treatment with natalizumab (MS-56).

  RRMS (18)
Gender (men/women) 5/13
Age (years) 40.5±7.8 (28–57)
Mean EDSS
 Baseline 4.2±1.5
 MS-56 4.4±1.4
 Δ (MS-56 – Baseline) 0.2±0.8
Disease duration (years) 7.6±3.9 (3–13)
No. of relapses before treatment 4.6±1.4
No. of relapses during treatment 0.6±0.8

Melatonin by age (pg/ml)
Baseline
 ≤40 years 4.4±1.8
 >40 years 7.1±2.2
MS-56
 ≤40 years 8.1±3.7
 >40 years 17.3±2.2 a

a P<0.05 vs baseline group.

Mean serum melatonin pre-treatment levels in the patient group were significantly lower than after the 56 weeks of treatment: 5.0 pg/ml in baseline vs 10.1 pg/ml after 56 weeks of treatment ( Fig. 2 ).

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Fig. 2 Serum levels of melatonin in patient with relapsing-remitting multiple sclerosis (RRMS). Values are expressed as mean±S.D. Baseline: Patients with RRMS previous treatment, and MS-56: after 56 weeks of treatment with natalizumab.lowastlowastP<0.01 vs baseline group;P<0.05 vs Men MS-56 group.

During treatment with natalizumab, women׳s levels of melatonin in serum increased significantly, 4.3 pg/ml (baseline) vs 10.8 pg/ml (after 56 weeks of treatment). Our data revealed that levels of melatonin increased by 21% in men after natalizumab treatment ( Fig. 1 ). However, the increase caused by nataluzimab was much more intense in women, establishing much higher levels in women than in men ( Fig. 2 ).

When the patients were separated by age into two groups, we only detected significant differences between baseline and after 56 weeks of treatment situation in patients over 40 years ( Table 1 ).

In addition, our results show that serum melatonin elevation is associated with a reduction in oxidative stress markers characterized by an increase in GSH levels and a reduction in 8OHdG levels, whereas PAO did not change ( Table 2 ).

Table 2 Effect of natalizumab on oxidative stress biomarkers (8-hydroxy-2'deoxyguanosine, 8-OHdG; reduced glutathione, GSH; total antioxidant capacity, PAO; soluble vascular cell adhesion molecule-1, sVCAM-1). Values are expressed as mean±S.D. Baseline: patients with MS previous treatment, and MS-56: after 56 weeks of treatment with natalizumab.

  8OHdG (ng/ml) GSH (μM/g Hb) PAO (mM) sVCAM-1 (ng/ml)
Baseline 80.8±35.7 68.9±24.9 0.22±0.1 586.0±188.1
MS-56 58.5±27.7 b 86.4±25.1 c 0.25±0.1 86.3±27.0 a

a P<0.001 vs baseline.

b P<0.01 vs baseline.

c P<0.05 vs baseline.

Finally, our analysis found that natalizumab induced a significant reduction in sVCAM ( Table 2 ), as well as these data present a significant correlation between melatonin and sVCAM levels after treatment (Spearman Rho:r−0.479,P<0.05).

4. Dicussion

So far as we can determine, this is the first evidence which shows that natalizumab affects circulating melatonin levels. Our findings reveal that natalizumab caused an increase in melatonin concentration, which was associated with an oxidative stress and adhesion molecule reduction. In addition, we observed the maintenance of EDSS during treatment with natalizumab, a situation that can be interpreted with a blockade, or at least slowing, in the progression of the disease.

Inadequate nocturnal levels of melatonin are associated with altered sleep–wake rhythm, aging and oxidative damage ( Cardinali et al., 2012 ). A reduction in melatonin levels has been reported with the development of RRMS. Thus, administration may cause an improvement in disease course and associated disorders as fatigue or sleep cycle disturbances. Moreover, due to its antioxidant capacity and different physiological actions, drop in melatonin levels maybe involved with aging and neurodegenerative disease, and thus its reduction may be a biomarker of some conditions (Lin et al, 2013, Melamud et al, 2012, Miller et al, 2013, Reiter et al, 2000, Wang, 2009, and Wang et al, 2013). Additionally, melatonin is characterized by presented a neuroprotective effect by mean different routes such as antioxidant, anti-inflammatory, antiapoptotic and anti-excitotoxicity activities (Esposito and Cuzzocrea, 2010, Luchetti et al, 2010, Reiter et al, 2000, Reiter et al, 1999, Rosales-Corral et al, 2012, Sewerynek et al, 1995, and Wang et al, 2013).

In our work, natalizumab caused a reduction in the oxidative stress biomarkers and number of relapses suffered by patients. This is consistent with other studies in which this drug prevents new outbreaks, and more recent findings show that natalizumab administration is associated with disease improvement (Cadavid et al, 2013, Stephenson et al, 2012, and Wickstrom et al, 2013). Additionally, data previously reported by our group showed that this agent induces a reduction in oxidative damage and an increase in translocation of nuclear factor (erythroid-derived 2)-like 2 factor (Nrf2) into the cell nucleus ( Tasset et al., 2013 ). Nrf2 is responsible for regulating the expression of genes encoding antioxidant protein system phase II such as heme-oxygenase 1 (HO-1), glutathione S-transferase (GST), NAD(P)H quinine oxidoreductase (NQO1) and other. The effect of natalizumab on Nrf2 has not been explained. However, the increase in circulating levels of melatonin may explain this change, considering that the pineal indole prompts Nrf2 translocation into de nucleus. Obviously, increasing melatonin levels induced by natalizumab justify and support a phenomenon previously observed by our group: natalizumab induces Nrf2 and acts as antioxidant (Tasset et al, 2012b and Tasset et al, 2013). Melatonin has the capacity to cause translocation of this factor. In addition, these results are indirectly agreement with studies of Miller et al. (Miller, 2012, Miller et al, 2013, and Miller et al, 2012) who found that melatonin administration reduced oxidative stress in the erythrocytes of patients with multiple sclerosis, increasing superoxide dismutasa (SOD) and glutathione peroxidasa (GPx) levels and decreasing of malonyldialdehyde (MDA) levels (Miller, 2012, Miller et al, 2013, and Miller et al, 2012).

Undoubtedly, the discovery of the effect of natalizumab on melatonin may give a better understanding of natalizumab action mechanism ( Fig. 3 ) and is indicative that at least part of its benefits maybe partly due to its ability to act on melatonin levels ( Fig. 3 ). While it is important to clarify the pathways and mechanisms by which natalizumab prompts changes in serum melatonin level.

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Fig. 3 This figure shows the possible biochemical and molecular mechanisms involved in multiple sclerosis and its relationship with melatonin level (A), presenting the blocking effect of natalizumab between VLA-4 and VCAM with preventing cell transmigration and exerts its protective effect. Thus, inhibition of leukocyte transmigration causes a neuroinflammation and, possibly assists and facilitates the recovery of the synthesis and release of melatonin, phenomenon which could help the patient׳s recuperation. This implicates that the effect of natalizumab on peripheral levels of melatonin, at least in part, might be finally causing beneficial effects observed after treatment with natalizumab, bearing in mind the different mechanisms of action of pineal indole (B). Although, the mechanisms by which this antibody would trigger this effect are not clearly known. Finally, we propose the activation of leukocytes, for subsequent migration to the central nervous system (CNS), requires a state of awareness and readiness prior derived from redox imbalance, especially glutathione, and an over production of reactive oxygen species (C). Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; ICAM: intercellular adhesion molecule; GPx: glutathione peroxidasa; GRd: glutathione reductase; GST: glutathione S-tranferase; HO-1: heme-oxygenase 1; NFκB: nuclear factor kappa-light-cjain-enhancer of activated B cells; NO: nitric oxide; NQO1: NAD(P)H quinine oxidoreductase; Nrf2-ARE: nuclear factor (erythroid-derived 2)-like 2 factor-antioxidant response element; O2: anion superoxide; TNFα: tumor necrosis factor alpha; VCAM: vascular cell adhesion molecule.

Both melatonin and natalizumab have been associated to an effect on adhesion factors such VCAM and intercellular adhesion molecule 1 (ICAM-1) (Constantinescu et al, 1997, Kang et al, 2001, Lin et al, 2013, and Wang, 2009). Thus, administration of melatonin in animal models showed a reduction in the levels of ICAM in experimental autoimmune encephalomyelitis (Constantinescu et al, 1997 and Kang et al, 2001). While most recent data show that melatonin triggers a reduction in the levels of ICAM-1and VCAM-1 in cultured endothelial aorta, a melatonin deficit due to pinealectomized is associated with increases of levels of VCAM-1, ICAM-1, matrix metallopoteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1) and oxidative stress biomarkers (Lin et al, 2013 and Wang, 2009). Again, the data indicate that some of the effects may be triggered by natalizumab are mediated by changes in melatonin levels. All these findings are line with the results reported by us where melatonin levels after treatment correlate inversely with sVCAM levels.

These data suggest two interesting and unique facts including as the increase of melatonin after treatment with natalizumab, and therefore from this perspective the action of natalizumab is greater in patients aged over 40 years and female.

This work has limitations since a time course study with melatonin was not performed and night-time melatonin levels were not measured. However, we should mention that the blood samples were taken over a period of hours when melatonin levels are lower, so we can deduce and understand that the increase is more relevant. In addition, another potential limitation of the small number is patients recruited. This is because treatment with natalizumab is very restrictive, which caused a reduction in the number of patients included in the study. Finally, another possible limitation is failing to evaluate the association between melatonin and its effect on the quality of sleep. Taken together, the findings indicate of the need for further studies for the purpose of improving an understanding of the mechanisms involved in the protective effects triggered by natalizumab.

In brief, natalizumab-treated patients had improvement on their general condition characterized by a reduction in the number of relapses and recovery associated with major levels of melatonin in peripheral blood. These events were related to reduce oxidative damage and a reduction in adhesion factors such as VCAM.

Acknowledgment

We are grateful to Prof. Russel J. Reiter for all support and assistance in both drafting and critical revision of the manuscript.

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Footnotes

a Department of Neurology, Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/Reina Sofia University Hospital/University of Cordoba, Spain

b Department of Sociosanitary, Radiology and Physical Medicine, Psychiatry Section, Faculty of Medicine, University of Cordoba, Spain

c Department of Morphological Sciences, Histology Section, Faculty of Medicine/ IMIBIC/Reina Sofia University Hospital/University of Cordoba, Spain

d Department of Clinical Analysis, IMIBIC/Regional Hospital of Pedroches Valley/University of Cordoba, Spain

e Department of Biochemistry and Molecular Biology, Faculty of Medicine/IMIBIC/Reina Sofia University Hospital/University of Cordoba, Spain

lowast Correspondence to: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. Tel.: +34 957 21 82 68; fax: +34 957 21 82 29.

1 Equal contributor.