Mini-Review: Is iron-mediated cell death (ferroptosis) an identical factor contributing to the pathogenesis of some neurodegenerative diseases?

The review article briefly discusses a hypothesis based on the potential participation of iron dyshomeostasis and iron-mediated cell death (ferroptosis) in the pathogenesis of some neurodegenerative diseases. Iron dyshomeostasis (especially cellular iron overload) is considered to be a critical condition of neurodegeneration. The etiopathogenesis of many neurodegenerative diseases including Alzheimer's and Parkinson's diseases, Multiple sclerosis, and others, is different. However, there are several identical cellular processes, such as iron dyshomeostasis (an excessive iron deposition), iron-induced oxidative stress, the accumulation of lipid-generated reactive oxygen species, and ferroptosis that accompany these diseases. Based on the existing theoretical and experimental evidence, the article provides current insight into iron dyshomeostasis and ferroptosis as a contributing factor to the pathogenesis of neurodegeneration. In addition, special attention is addressed to the possible relationship between cellular iron overload and key pathological features of selected neurodegenerative diseases, such as ß-amyloid and tau proteins, α-synuclein, and demyelination. The mechanism by which ferroptosis may be involved in the pathogenesis of various neurodegenerative diseases is not fully elucidated. Further experimental and clinical studies are needed to clarify the hypothesis on the potential role of ferroptosis in the pathogenesis of neurodegenerative diseases.

Methionine metabolism and multiple sclerosis.

CONTEXT: Methylation reactions are particularly important in the brain and their inhibition can lead to a number of serious pathologies. Multiple sclerosis is one of the most common neurological disorders caused by interaction of genetic and environmental factors, but little is known about its cause or factors that contribute to the disorder. Although multiple sclerosis is primarily regarded as demyelinating disorder, there are no many articles focusing on methionine determination. OBJECTIVE: The aim of this work was to investigate whether serum methionine and its related compounds like homocysteine, cysteine, glutathione and asymmetric dimethylarginine were changed in multiple sclerosis patients. MATERIALS AND METHODS: Sulphur-containing compounds were determined by using high-performance liquid chromatography with electrochemical detection in a single run for providing more complex view on methionine metabolism and asymmetric dimetylarginine was measured by a commercial enzyme-linked immunosorbent assay kit. RESULTS: Methionine and glutathione were decreased, but homocysteine, asymmetric dimethylarginine and cysteine were unchanged in patients with multiple sclerosis compared with controls. CONCLUSIONS: Methionine and glutathione seem to be potential biomarkers for prognosis of the disease.

Changes in levels of oxidative stress markers and some neuronal enzyme activities in cerebrospinal fluid of multiple sclerosis patients.

OBJECTIVES: The aim of the present study was to assess cerebrospinal fluid (CSF) levels of malondialdehyde (MDA), F2 isoprostanes (8-iso-PGF2α) and total antioxidant status (TAS) in relapsing-remitting (RR) and secondary progressive (SP) course of MS and neurological controls. These parameters were correlated with brain tissue damage parameters - neuron-specific enolase and 3´,5´-cAMP-phosphodiesterase (PDE) in CSF. METHODS: CSF samples were obtained from MS patients divided into two groups according to the disease severity (EDSS) - RR and SP course of MS. Control group composed of neurological diagnoses without demyelination and neurodegeneration. 8-iso-PGF2α and NSE levels in the CSF samples were determined using specific immunochemistry assays. MDA levels in the CSF were measured by HPLC method after reaction with thiobarbituric acid in acidic conditions. TAS and total PDE activity of CSF was determined spectrophotometrically. RESULTS: There were significant differences in CSF MDA levels between MS group and controls and also between RR and SP disease course. By contrast, CSF levels of 8-iso-PGF2α in MS group and both forms of MS were comparable to control values. In addition, the results show increased CSF levels of PDE in MS group and no changes of NSE in CSF between MS and control group. CONCLUSION: These findings point to a possibility of using the parameters of different specificity to lipid peroxidation for monitoring different stages (acute/progressive) of MS. This study support the idea, that combination of CSF markers is important for monitoring overall brain tissue pathology in MS.

Role of astrocytes in pathogenesis of multiple sclerosis and their participation in regulation of cerebral circulation.

There is about 30% higher risk of the myocardial infarction in patients diagnosed with multiple sclerosis (MS) than in people without MS. Increased risk of cardiovascular disease development positively correlates with levels of serum markers of an endothelial dysfunction, and may give rise to a global cerebral hypoperfusion. It appears that these complications precede progressive loss of axons, which mechanisms are complex and should be linked to a loss of ß2 adrenergic receptors on astrocytes of demyelinating lesions. Consequence of this deficiency, the cause of which is not known yet, is a decline in energy metabolism of axons. Moreover, the loss of these receptors is linked to a reduced redistribution of potassium ions by astrocytes, glutamate excitotoxicity and increase of calcium ion concentration in the axon with subsequent activation of necrotic processes. In addition to immunological aspects we should take into account also parameters of the functional state of endothelium when appropriate targeted therapy for patient is considered.