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Abstract

As a main aim we want to point out the sources of oxidants as key factors in understanding the role oxidants play in the pathogenesis of brain vascular endothelial dysfunction. The question remains whether iron inversion and subsequent radical formation is a primary or secondary event in neurodegenerative disease.

Recent research suggest that iron inversion is an initial cause of neuronal cell death and axonal degeneration. Methemoglobin and their catabolic products, provoke adverse effects on vascular endothelium dysfunction, reduced regenerative capacity and increased rate of endothelial cell apoptosis.

The main diference  between the hemoglobin and methemoglobin heme oxygenation is that the hemoglobin last degradation products are bilirubin-biliverdin, CO and Ferrous (Fe++) iron , but in the methemoglobin catabolism last products are bilirubin-biliverdin, CO and Ferric (Fe+++) iron, which in methemoglobinemia pathological condition have an important role having a redox-active and cytotoxic property, and as valuable biomarker.     

Key words

biomarkers metheoglobin catabolism, brain blood barrier, brain ferric iron accumulation, neurodegenerative diseases

Introduction

The objective is to direct attention about methemoglobin as a biomarker which has an important role in the detection of adverse effects of the oxidative stress, misbalanced production of ROS (Reactive Oxygen Species), RNS (Reactive Nitrogen Species) and RSS (Reactive Sulfur Species). According to our hypothesis, the people continuously inhaling environmental toxics as fuel burning products, methemoglobin as product of hemoglobin oxidation, takes on an important role, causing increased systemic oxidative stress of vital organs.

Strong exogenous oxidants such as NOx (Nitrogen Oxides: NO and NO₂) reversibly oxidize oxyhemoglobin (Fe²⁺) to methemoglobin (Fe³⁺), and irreversible methemoglobinemia can arise because of the disruption of the oxidant/antioxidant balance, supported by the synergic SO₂ metabolites degradation of antioxidant thiols. The formation of methemoglobin-ferric iron (Fe³⁺) from hemoglobin-ferrous iron (Fe²⁺) leads to the destruction of erythrocytes, so that free hemoglobin from hemolysis can be directly cytotoxic and can alter the state of endothelial cells and endothelial dysfunction. From the methemoglobin and heme catabolism there is released into the blood-stream the cytotoxic redox-active ferric iron, which contributes to endothelial injury and the development of neurovascular diseases.

Results

Our results, obtainded in a large number of cases [1-3,6-8,16-20]  point out the consequence of mother-fetal methemoglobinemia caused by environmental oxidants, causing oxyhemoglobin and methemoglobin hemolysis, hyperbilirubinemia and toxic brain damage with the view to the role of methemoglobin catabolism as the source of ferric(Fe(III)) form concentrated in various brain regions.

The role of methemoglobin on the structural and functional changes in the vascular endothelium

Methemoglobin and hemolysis both occur as a result of oxidative stress, but the prevalent difference between them is that methemoglobin is a reversible phenomenon (oxidant–antioxidant balance) whereas hemolysis, which occurs as a result of oxidative stress on the erythrocyte membrane, is an irreversible event. Methemoglobinemia can additionally exacerbate an existing anemia, stimulating hypoxia that may be additional dangerous. Own prospective study of methemoglobin in pregnancy, revealed a significant rise in the level of methemoglobin >1.5 g/L (r = 0.72, p < 0.01) in the air-polluted exposure period, which can be explained on the basis of an oxidant–antioxidant imbalance, resulting in methemoglobinemia [1]. Methemoglobinemia and stillbirth recorded throughout exposure period are significantly higher than those recorded in the control period (p = 0.0205) and the frequencies of reproductive loss were significantly lower in the control than in the exposure period (p < 0.05) [2]. In healthy women the methemoglobin participates with less than 1% of the haemoglobin level but its level rises in pathophysiological conditions when red blood cells are affected by genetic, xenobiotic, pharmaceutical, idiopathic or toxic agents from food and chemical compounds from the environment [3,4].

As I have found no evidence of the consequences of mother methemoglobinemia on the fetus, the second objective is to direct attention to methemoglobin as an early biomarker of the environmental toxic of oxidative stress effects, which puts pregnancy at risk and may later impair the health of newborns, children and adolescents. High concentrations of methemoglobin and its catabolites affect the function of the kidney, brain, and other vital organs, and are manifested as mother's preeclampsia and/or “fetal preeclampsia” [5]. The increase of maternal methemoglobin could be a useful biomarker to determine when the health of pregnant women is threatened by toxic substances in the environment. The conversion of haemoglobin to methemoglobin (ferrous to ferric state) leads to haemolysis [6], and the consequences thereof.

Discussion

In methemoglobinemia pathological conditions, methemoglobin catabolises into heme, and the activity of heme-oxygenase leads to products such as bilirubin-biliverdin, carbon monoxide, and Fe (III) with paramagnetic and toxic properties. Acting as oxidants, methemoglobin and heme affect the function of the capillary endothelium of blood-brain barrier, facilitating the passage on brain parenchyma the harmful substances as the methemoglobin, heme and/or the deposition of containing toxic Ferric (III) iron in the brain.

It is well known that ferrimethemoglobin (III) releases heme in the endothelial cells, inducing increased hem-oxygenase activity and Ferritin production. In fetal blood, Nitric oxide and Superoxide form Peroxinitrites (ONOO^-) which converts oxyhaemoglobin into methemoglobin, and the methemoglobin-released hem induces endothelial cytolysis [7-11].

Iron is essential for the normal cell function, but it also generates toxic ROS that adversely affects vascular endothelium and the blood-brain barrier [12]. Astrocytes distribute iron in the brain and possess transporters for transferrin-bound, haemin-bound, and non-transferrin-bound iron [13]. In the brain, non-heme-bound iron is mostly found in ferritin. Nowadays, non-heme-bound Fe (III) is quantified using Magnetic Resonance Imaging (MRI), thanks to its paramagnetic properties [14]. It is believed that most non-heme-bound iron is deposited in the form of ferritin, haemosiderin, or methemoglobin catabolic products [15], whereas transferrin-bound iron concentration is always low and cannot be detected by MRI.

Conclusion

Vascular endothelial cells are direct targets for free hemoglobin and for its oxidative derivative methemoglobin which readily release heme, an abundant source of redox-active Ferric iron which  impact on brain vascular endothelial dysfunction and apoptosis performing Ferric- iron  brain accumulation on the endothelium and cause  brain capillary defects, and gradually manifest brain harmful effects from the mother-fetal pregnancy complication, manifest in new-born hyperbilirubinemia, children and adults mild disorders as dyslexia or learn and memory deficiency to the age process, and to the hard neurodegenerative disorders  as Alzheimer, Parkinson and Multiple Sclerosis diseases.

Reference

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