TY - JOUR A1 - Baum, Petra A1 - Toyka, Klaus V. A1 - Blüher, Matthias A1 - Kosacka, Joanna A1 - Nowicki, Marcin T1 - Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects JF - International Journal of Molecular Sciences N2 - The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy. KW - diabetic neuropathy KW - pathogenesis KW - inflammation KW - iron KW - treatment-induced neuropathy in diabetes (TIND) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284556 SN - 1422-0067 VL - 22 IS - 19 ER - TY - JOUR A1 - Sian-Hulsmann, Jeswinder A1 - Riederer, Peter T1 - The nigral coup in Parkinson's Disease by α-synuclein and its associated rebels JF - Cells N2 - The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder. KW - Parkinson's disease KW - substantia nigra KW - alpha-synuclein KW - genetics KW - iron KW - neuroinflammation KW - viruses KW - immunology KW - aging and cell death Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234073 SN - 2073-4409 VL - 10 IS - 3 ER - TY - JOUR A1 - Macdougall, Iain C. A1 - Bircher, Andreas J. A1 - Eckhardt, Kai-Uwe A1 - Obrador, Gregorio T. A1 - Pollock, Carol A. A1 - Stenvinkel, Peter A1 - Swinkels, Dorine W. A1 - Wanner, Christoph A1 - Weiss, Günter A1 - Chertow, Glenn M. T1 - Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference JF - Kidney International N2 - Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects. KW - chronic kidney disease KW - hypersensitivity KW - infections KW - iron KW - overload KW - oxidative stress Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191467 VL - 89 IS - 1 ER - TY - JOUR A1 - Hausoel, A. A1 - Karolak, M. A1 - Şaşιoğlu, E. A1 - Lichtenstein, A. A1 - Held, K. A1 - Katanin, A. A1 - Toschi, A. A1 - Sangiovanni, G. T1 - Local magnetic moments in iron and nickel at ambient and Earth's core conditions JF - Nature Communications N2 - Some Bravais lattices have a particular geometry that can slow down the motion of Bloch electrons by pre-localization due to the band-structure properties. Another known source of electronic localization in solids is the Coulomb repulsion in partially filled d or f orbitals, which leads to the formation of local magnetic moments. The combination of these two effects is usually considered of little relevance to strongly correlated materials. Here we show that it represents, instead, the underlying physical mechanism in two of the most important ferromagnets: nickel and iron. In nickel, the van Hove singularity has an unexpected impact on the magnetism. As a result, the electron–electron scattering rate is linear in temperature, in violation of the conventional Landau theory of metals. This is true even at Earth’s core pressures, at which iron is instead a good Fermi liquid. The importance of nickel in models of geomagnetism may have therefore to be reconsidered. KW - ferromagnetism KW - electronic properties and materials KW - magnetic properties and materials KW - nickel KW - iron Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170681 VL - 8 IS - 16062 ER - TY - JOUR A1 - Riederer, Peter A1 - Laux, Gerd T1 - MAO-inhibitors in Parkinson's Disease JF - Experimental Neurobiology N2 - Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD. KW - selegiline KW - rasagiline KW - moclobemide KW - phenelzine KW - tranylcypromine KW - acetylcholine KW - Alzheimer disease KW - antidepressive agents KW - depression KW - freezing KW - head KW - indans KW - iron KW - levodopa KW - monoamine oxidase KW - monoamine oxidase inhibitors KW - Parkinson disease Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140930 VL - 20 IS - 1 ER -