Iron and Oxidative Stress in Parkinson's Disease: An Observational Study of Injury Biomarkers.

Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD

N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups.

BACKGROUND AND AIMS:Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers. METHODS:Rat pups were injected with GA (5 umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). LPS (2 mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed. RESULTS:GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-α and IL-1β levels. The co-administration of these compounds potentiated the increase of IL-1β levels but not TNF-α levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers. CONCLUSIONS:These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I

Comparison of oxidative stress and antioxidant peripheral biomarkers between patients with Parkinson’s disease and control.

<p>Comparison of oxidative stress and antioxidant peripheral biomarkers between patients with Parkinson’s disease and control.</p

Sociodemographic information of patients with Parkinson’s disease and controls.

<p>Sociodemographic information of patients with Parkinson’s disease and controls.</p

Comparison of iron, ferritin, and transferrin peripheral blood levels between patients with Parkinson’s disease and controls.

<p>Comparison of iron, ferritin, and transferrin peripheral blood levels between patients with Parkinson’s disease and controls.</p

Effect of early postnatal chronic GA, NAC and LPS administration on TBARS content.

<p>NAC prevented the increase of TBARS content induced by GA and LPS. *P < 0.01 compared with saline treated group and ^#P< 0.05 compared with respective control group (Duncan’s multiple comparisons test). Data are presented as means ± S.E.M. for n = 7 in each group.</p

Effect of early postnatal chronic GA, NAC and LPS administration on cytokine levels on the second day of Barnes maze.

<p>NAC prevented the increase in TNF-α (A) and IL-1β (B) levels. *P < 0.001 compared with saline treated group, ^#P< 0.001 compared with the respective control group and ^δP < 0.05 compared with GA-treated group (Duncan’s multiple comparisons test). Data are presented as means ± S.E.M. for n = 6-7 in each group.</p

NAC prevented the decrease of α1 subunit activity of Na⁺,K⁺-ATPase enzyme.

<p>Effect of early postnatal chronic GA, NAC and LPS administration on Na⁺,K⁺-ATPase total activity (A); on α1 subunit activity of Na⁺,K⁺-ATPase enzyme (B); and on α2/3 subunit activity of Na⁺,K⁺-ATPase enzyme (C), on the second day of Barnes maze.*P < 0.001 compared with saline traded group and ^#P< 0.001 compared with respective control group (Student–Newman–Keuls test). Data are presented as means ± S.E.M. for n = 7-9 in each group.</p

NAC prevents the memory deficit induced by GA and LPS measured as escape latency of rat pups in the Barnes maze.

<p>*P < 0.05 compared with saline treated group, ^#P< 0.05 compared with respective control group and ^δP < 0.001 compared with GA-treated group (Duncan’s multiple comparisons test). Data are presented as means ± S.E.M. for n = 7-9 in each group. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078332#pone-0078332-g003" target="_blank">Figures 3B and 3C</a> show an amplification of the second day of test.</p

Effect of early postnatal chronic GA, NAC and LPS administration on NPSH content, GSH level, CAT and SOD activities.

<p>NAC prevented the decrease of antioxidant defenses induced by GA and LPS.*P < 0.001 compared with saline treated group and ^#P< 0.001 compared with respective control group (Duncan’s multiple comparisons test). Data are presented as means ± S.E.M. for n = 7 in each group.</p