Evidence of Oxidative Stress in the Neocortex in Incidental Lewy Body Disease

Abstract

Oxidative stress has been well documented in the substantia nigra in Parkinson disease (PD), but little is known about oxidative damage, particularly lipoxidation, advanced glycation (AGE), and AGE receptors (RAGE) in other structures, including the cerebral cortex, in early stages of diseases with Lewy bodies. The present study was undertaken to analyze these parameters in the frontal cortex (area 8), amygdala, and substantia nigra in selected cases with no neurologic symptoms and with neuropathologically verified incidental Lewy body disease-related changes, comparing them with healthy age-matched individuals. Results of the present study have shown mass spectrometric and immunologic evidences of increased lipoxidative damage by the markers malondialdehyde-lysine (MDAL) and 4-hydroxynonenal-lysine (HNE), increased expression of AGE in the substantia nigra, amygdala, and frontal cortex, and increased and heterogeneous RAGE cellular expression in the substantia nigra and frontal cortex in cases with early stages of parkinsonian neuropathology. In addition, increased content of the highly peroxidizable docosahexaenoic acid in the amygdala and frontal cortex. These changes were not associated to alpha-synuclein aggregation in cortex, contrasting with aggregates found in SDS-soluble fractions of frontal cortex in dementia with Lewy bodies (DLB) cases. The pattern of lipidic abnormalities differed in DLB and incidental Lewy body disease. Furthermore, although AGE and RAGE expression were raised in DLB, no increase in the total amount of HNE and MDAL adducts was found in the cerebral cortex in DLB. Preliminary analyses have identified 2 proteins with lipoxidative damage, alpha-synuclein and manganese superoxide dismutase (SOD2), in incidentally Lewy body disease cortex. This study demonstrates abnormal fatty acid profiles, increased and selective lipoxidative damage, and increased AGE and RAGE expression in the frontal cortex in cases with early stages of parkinsonian neuropathology without treatment. These findings further support antioxidant therapy in the treatment of PD to reduce cortical damage associated with oxidative stress.

Effect of 4-Hydroxy-2-nonenal Modification on α-Synuclein Aggregation

“…This oxidative stress could in turn lead to lipid peroxidation and ultimately to HNE formation. There are several reports suggesting increased HNE modification in Parkinson disease (42,43,53). Because ␣-synuclein in its normal physiological situation is bound to membranes containing substantial unsaturated fatty acyl chains, it will inevitably be exposed to significant amounts of HNE, so these observations are consistent with a potentially toxic effect of HNE modification of ␣-synuclein.…”

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

“…Studies in the substantia nigra and midbrain have shown increased levels of lipid hydroperoxides (47) and 4-hydroxy-2-nonenal (an end product of lipid peroxidation) (48), as well as changes in PUFAs susceptible for lipid peroxidation, leading to increased generation of malondialdehyde and hydroperoxides (20,49). Interestingly, oxidative damage in the substantia nigra is present in iPD (20). Only recently, evidence for lipid peroxidation and oxidative damage in cortical structures was demonstrated in PD and iPD (20,50).…”

“…Thus, the highly peroxidizable docosahexaenoic acid (DHA) appears to be significantly increased in the frontal cortex in iPD and PD (20). Whether altered lipid composition affects highly specialized structures such as lipid rafts in PD and iPD is not known.…”

“…Molecular neuropathology has elucidated a series of modifications that may result in impaired function of selected metabolic pathways, these including altered mitochondrial function, glycolysis and protein degradation pathways in the frontal cortex in PD and iPD (17,18). There is some agreement that molecular damage in PD is due to oxidative stress, which enhances oxidative DNA damage and increases the expression levels of lipoxidation, nitration and glycoxidation markers and lipid peroxides and increases the expression of RAGE (advanced glycation end products receptor) in the frontal cortex of PD and iPD (19)(20)(21).…”

Magnesium in the Central Nervous System

“…Possible pathomechanisms in Parkinson's disease Mitochondrial damage and oxidative stress Increased expression of 4--hydroxy--2--nonenal (HNE) (Yoritaka et al, 1996), decreased activity of mitochondrial complex I and a decreased amount of alpha--ketoglutarate dehydrogenase complex (KGDHC) in the pigmented neurons of the substantia nigra (Hattori et al, 1991;Mizuno et al, 1994) have been reported in affected patients. In the substantia nigra, decreased activity of catalase and peroxidase (Ambani et al, 1975) and increased amounts of protein carbonyls, 8--hydroxy--2'--deoxyguanosine (8--OHdG)/8--hydroxy--guanine (8--OHG), 4--hydroxynonenal--lysine and malondialdehyde--lysine (MDAL) (Alam et al, 1997a,b;Zhang et al, 1999;Dalfo et al, 2005) have been reported. 1--Methyl--4--phenyl--1,2,3,6--tetrahydropyridine (MPTP) was the first human parkinsonian agent to be characterized.…”