Association of Oxidative Stress with Neurological Disorders

Background: Oxidative stress is one of the main contributing factors involved in cerebral biochemical impairment. The higher susceptibility of the central nervous system to reactive oxygen species mediated damage could be attributed to several factors. For example, neurons use a greater quantity of oxygen, many parts of the brain have higher concentraton of iron, and neuronal mitochondria produce huge content of hydrogen peroxide. In addition, neuronal membranes have polyunsaturated fatty acids, which are predominantly vulnerable to oxidative stress (OS). OS is the imbalance between reactive oxygen species generation and cellular antioxidant potential. This may lead to various pathological conditions and diseases, especially neurodegenerative diseases such as, Parkinson’s, Alzheimer’s, and Huntington’s diseases. Objectives: In this study, we explored the involvement of OS in neurodegenerative diseases. Methods: We used different search terms like “oxidative stress and neurological disorders” “free radicals and neurodegenerative disorders” “oxidative stress, free radicals, and neurological disorders” and “association of oxidative stress with the name of disorders taken from the list of neurological disorders. We tried to summarize the source, biological effects, and physiologic functions of ROS. Results: Finally, it was noted that more than 190 neurological disorders are associated with oxidative stress.

The protein-binding pocket of Botulinum neurotoxin B accommodates a preassembled synaptotagmin / ganglioside complex

Botulinum neurotoxin serotype B (BoNT/B) uses two separate protein and polysialoglycolipid-binding pockets to interact with synaptotagmin 1/2 and gangliosides. However, an integrated model of this therapeutic tool bound to its neuronal receptors in a native membrane topology is still lacking. Using a panel of in silico and experimental approaches, we present here a new model for BoNT/B binding to neuronal membranes, in which the toxin binds to a preassembled synaptotagmin-ganglioside GT1b complex and a free ganglioside. This interaction allows a lipid-binding loop of BoNT/B to engage in a series of concomitant interactions with the glycone part of GT1b and the transmembrane domain of synaptotagmin. Furthermore, our data provide molecular support for the decrease in BoNT/B sensitivity in Felidae that harbor the natural variant synaptotagmin2-N59Q. These results reveal multiple interactions of BoNT/B with gangliosides and support a novel paradigm in which a toxin recognizes a protein/ganglioside complex.

Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane

Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity of amyloid-β peptides in Alzheimer’s disease. To gain a detailed understanding of the mutual interference of amyloid-β oligomers and the neuronal membrane, we carried out microseconds of all-atom molecular dynamics (MD) simulations on the dimerization of amyloid-β (Aβ)42 in the aqueous phase and in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The dimerization in solution is characterized by a random coil to β-sheet transition that seems on pathway to amyloid aggregation, while the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. As the neurotoxic activity of amyloid oligomers increases with oligomer order, these results suggest that GM1 is neuroprotective against Aβ-mediated toxicity.

Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease

Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme.

Protective Role of a Donepezil-Huprine Hybrid against the β-Amyloid (1-42) Effect on Human Erythrocytes

Aβ(1-42) peptide is a neurotoxic agent strongly associated with the etiology of Alzheimer’s disease (AD). Current treatments are still of very low effectiveness, and deaths from AD are increasing worldwide. Huprine-derived molecules have a high affinity towards the enzyme acetylcholinesterase (AChE), act as potent Aβ(1-42) peptide aggregation inhibitors, and improve the behavior of experimental animals. AVCRI104P4 is a multitarget donepezil-huprine hybrid that improves short-term memory in a mouse model of AD and exerts protective effects in transgenic Caenorhabditis elegans that express Aβ(1-42) peptide. At present, there is no information about the effects of this compound on human erythrocytes. Thus, we considered it important to study its effects on the cell membrane and erythrocyte models, and to examine its protective effect against the toxic insult induced by Aβ(1-42) peptide in this cell and models. This research was developed using X-ray diffraction and differential scanning calorimetry (DSC) on molecular models of the human erythrocyte membrane constituted by lipid bilayers built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). They correspond to phospholipids representative of those present in the external and internal monolayers, respectively, of most plasma and neuronal membranes. The effect of AVCRI104P4 on human erythrocyte morphology was studied by scanning electron microscopy (SEM). The experimental results showed a protective effect of AVCRI104P4 against the toxicity induced by Aβ(1-42) peptide in human erythrocytes and molecular models.

Extracellular and intracellular components of the impedance of neural tissue

Electric phenomena in brain tissue can be measured using extracellular potentials, such as the local field potential, or the electro-encephalogram. The interpretation of these signals depend on the electric structure and properties of extracellular media, but the measurements of these electric properties are subject to controversy. Some measurements point to a model where the extracellular medium is purely resistive, and thus parameters such as electric conductivity and permittivity should be independent of frequency. Other measurements point to a pronounced frequency dependence of these parameters, with scaling laws that are consistent with capacitive or diffusive effects. However, these experiments correspond to different preparations, and it is unclear how to correctly compare them. Here, we provide for the first time, impedance measurements in various preparations, for acute brain slices and primary cell cultures, and we compare to measurements using the same setup in artificial cerebrospinal fluid with no biological material. The measurements show that when the current flows across a cell membrane, the frequency dependence of the macroscopic impedance between intracellular and extracellular electrodes is significant, and cannot be captured by a model with resistive media. Fitting a mean-field model to the data shows that this frequency dependence could be explained by the ionic diffusion mainly associated to Debye layers surrounding the membranes. We conclude that neuronal membranes and their ionic environment induce strong deviations to resistivity, that should be taken into account to correctly interpret extracellular potentials generated by neurons.

Biosensor concept and data input to biomedical infornation systems

Background. In present publication we generalized and analyzed deeply the experience of some biosensors studying in biophysical experiments with aim to incorporate them further to electronic information systems. Output biosensor electrical signals were input ones to electronic information system making their connection into joined bioinformation system. Materials and methods. Methods of comparative analysis of the characteristics of input and output electrical information signals of biosensor were applied; its physical and mathematical models were developed. For biosensor properties studies the methods of transmembrane electric currents recording in voltage-clamp mode as well as patch-clamp on hippocampal neuronal membranes were used. Results. Biosensor concept and their general characteristic were given, corresponding prototypes were observed. The physical model of biosensor was developed and some test results of this device were suggested. The biosensor was examined as abstraction in consistent unity of its functions: signal receiver — filter — analyzer — encoder/decoder. A brief mathematical description of biosensor functioning was given as well as corresponding algorithm. As a result of performed works the possibilities of this biosensor incorporation to bioinformation electronic systems were substantiated and the example of such system «EcoIS» was observed. Conclusion. In conclusion following results of the works were summarized. The detailed description of technical devices — biosensors as elements of biomedical information systems were done as well as analysis of electrical information signals at output of biosensor, its ability to encode information and detailed analysis of the possibility to incorporate this biotechnical device into electronic information systems due to biosensor output electricals signals.