Isofurans, but not F₂‐isoprostanes, are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

Abstract

F 2 -isoprostanes (F 2 -IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F 2 -IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F 2 -IsoPs and IsoFs. In this study, we attempted to compare the levels of F 2 -IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F 2 -IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F 2 -IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.

An Orally Active Catalytic Metalloporphyrin Protects against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine NeurotoxicityIn Vivo

“…Demonstration of neuroprotection by oral administration of a metal-based catalytic antioxidant is consistent with a large body of literature that suggests oxidative stress as a major therapeutic target for PD. Direct oxidative damage to proteins, lipids, and DNA has been detected in the substantia nigra from human and experimental PD (Dexter et al, , 1994aAlam et al, 1997a,b;Good et al, 1998;Giasson et al, 2000;Przedborski et al, 2001b;Fessel et al, 2003). Indirect evidence for oxidative stress in PD comes from studies showing decreased glutathione, increased iron levels and antioxidant imbalance (Perry et al, 1982;Dexter et al, 1987;Sian et al, 1994;Ara et al, 1998;Jha et al, 2000).…”

“…Lipid peroxidation is a well-known mechanism of cellular injury initiated by ROS (Sayre et al, 2001) and numerous studies have demonstrated its role in the pathogenesis of PD (Dexter et al, , 1994aFessel et al, 2003). The hydroaldehydes, MDA and particularly 4-HNE, are the most cytotoxic aldehydes produced in the process of lipid peroxidation (Esterbauer et al, 1991;Beal, 2002).…”

Neurofurans, Novel Indices of Oxidant Stress Derived from Docosahexaenoic Acid

“…They are even more abundant than iPs in tissues as diverse as kidney and hippocampus in the rat and may offer an adjunctive approach to the assessment of oxidant stress in vivo (6,7). They are formed preferentially under conditions of elevated oxygen tension (6).…”

Beyond Prostaglandins—Chemistry and Biology of Cyclic Oxygenated Metabolites Formed by Free‐Radical Pathways from Polyunsaturated Fatty Acids

“…Indeed, IsoF levels are significantly higher in substantia nigra in brains from patients with Parkinsons disease compared to age-matched controls. [177] This finding led to the hypothesis that analysis of both F 2 -IsoPs and IsoFs might provide a more complete and reliable index of oxidative stress. Such a determination is easy to achieve since F 2 -IsoPs and IsoFs can be purified on the same TLC plate and simultaneously quantified in a single GC/MS assay by including an additional ion channel for IsoFs, which is 16 Da higher than that for F 2 -IsoPs.…”