Upstream eventOxidative Stress in Brain
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Lipid peroxidation is a following event after oxidative stress. During oxidative stress the level of ROS is rising, which increases the concentration of free radical species. These highly unstable free radicals can easily react with macromolecules such as lipids. The brain has a high level of PUFAs and neuronal cells are known to be relatively unable to neutralize free radicals. Together with the knowledge that free radicals mainly attack PUFAs make neuron cells vulnerable for lipid peroxidation. The reaction between free radicals and PUFAs leads to the formation of highly reactive electrophilic aldehydes, such as MDA and HNE. Lipid peroxidation can be described by 5 steps. The initiation of the free radical, production of peroxyl radical, self-perpetuating chain reaction (leading to several by-products), termination by which radicals form stable products and finally termination, where reaction between radicals and antioxidants (vitamin C and E) give rise to non-radical products and unreactive radicals.
Evidence Supporting this KER
Many recent reviews describes how ROS can react with PUFAs in cell membranes, also schematic representations of moleculaire reactions are known. Examples of earlier research done showed that inducement of antioxidants decreases the level of lipid peroxidation. Devasagayam et al. showed that increased concentration of caffeine, glutathione and ascorbic acid ihibited lipid peroxidation by reducing ROS formation. Measurements were performed in rat microsomes where TBARS (known as MDA equivalent) and LOOH (product of lipid peroxidation) were used as markers. Leuter et al. showed that there was a correleation between an increased concentration of ROS and lipid peroxidation. Leuter et al. performed the study in the brain of rats which where aging overtime. Finally, in a more recent study, resveratrol was used to measure the TBARS level at various concentration. Resveratrol is known to act as an antioxidant in vitro. Nosál et al. showed that a higher concentration of resveratrol leads to a lower level of TBARS, which indirectly showes that a lower concentration of ROS leads to less lipid peroxidation
The link between ROS and lipid peroxidation is biological plausible.
Uncertainties and Inconsistencies
Lipid peroxidation is a general description, the link with ROS is well known but literature also describes the possibility that lipid peroxidation can cause oxidative stress. The product HNE of lipid peroxidation can form protein adducts which can lead to cell damage.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Reed, T. T. Lipid peroxidation and neurodegenerative disease. Free Radical Biology and Medicine 51, 1302–1319 (2011).
Sultana, R., Perluigi, M. & Butterfield, D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 62, 157–169 (2013).
Hernández, J. A., López-Sánchez, R. C. & Rendón-Ramírez, A. Lipids and Oxidative Stress Associated with Ethanol-Induced Neurological Damage. Oxidative Medicine and Cellular Longevity 2016, (2016).
Devasagayam, T. P. A., Kamat, J. P., Mohan, H. & Kesavan, P. C. Caffeine as an antioxidant: Inhibition of lipid peroxidation induced by reactive oxygen species. Biochim. Biophys. Acta - Biomembr. 1282, 63–70 (1996).
Leutner, S., Eckert, A. & Müller, W. E. ROS generation, lipid peroxidation and antioxidant enzyme activities in the aging brain. J. Neural Transm. 108, 955–967 (2001).
Nosáľ, R. et al. On the molecular pharmacology of Resveratrol on oxidative burst inhibition in professional phagocytes. Oxid. Med. Cell. Longev. 2014, (2014).
Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity 2014, (2014).
Reed, T. T. Lipid peroxidation and neurodegenerative disease. Free Radical Biology and Medicine 51, 1302–1319 (2011)