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. 2012 Jul 10;2(7):e134.
doi: 10.1038/tp.2012.61.

Evidence of Oxidative Damage and Inflammation Associated With Low Glutathione Redox Status in the Autism Brain

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Free PMC article

Evidence of Oxidative Damage and Inflammation Associated With Low Glutathione Redox Status in the Autism Brain

S Rose et al. Transl Psychiatry. .
Free PMC article

Abstract

Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls (n=15 and n=12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum (P<0.01) and BA22 (P<0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 (P<0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 (P<0.01 and P=0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum (P<0.01). There was a significant increase in 3-CT levels in both brain regions (P<0.01), whereas aconitase activity was significantly decreased in autism cerebellum (P<0.01), and was negatively correlated with GSH/GSSG (P=0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.

Figures

Figure 1
Figure 1
Glutathione redox imbalance and increased biomarkers of oxidative stress in autism cerebellum (CB) and Brodmann area 22 (BA22). High-performance liquid chromatography (HPLC) and HPLC/mass spectrometry were used to measure biomarkers in autism and control tissue samples from CB and BA22 (n=15 and 12 cases and controls/group, respectively), and normalized for protein content. The concentrations of reduced glutathione (GSH; a), oxidized glutathione (GSSG; b), glutathione redox/antioxidant capacity (GSH/GSSG; c), 3-nitrotyrosine (3-NT; d), 3-chlorotyrosine (3-CT; e), 8-oxo-deoxyguanosine (8-oxo-dG; f) are presented as mean±s.d. *P<0.01; **P=0.01; #P=0.02.
Figure 2
Figure 2
Aconitase activity is decreased in autism cerebellum (CB) and associated with glutathione redox/antioxidant capacity (GSH/GSSG) in control and autism CB, and Brodmann area 22 (BA22). (a) Aconitase activity was measured in frozen post-mortem autism and control tissue samples from CB and BA22 (n=15 and 12 cases and controls/group, respectively), and normalized for protein content. Data are presented as mean±s.d. Aconitase activity was significantly decreased in autism CB (3.99±2.34) compared with control CB (7.29±1.85). The difference in aconitase activity between autism BA22 (3.30±1.88) and control BA22 (5.47±3.78) did not reach significance. (b) In the combined case and control cohort of samples from the CB, aconitase activity was significantly associated with GSH/GSSG (P=0.01). (c) Within BA22 in the combined case and control samples, aconitase activity was similarly significantly associated with GSH/GSSG (P=0.03). Although the significance of the correlations does not hold within the autism samples, the sample-specific clustering of case values (in open circles) in the bottom left quadrant of each graph is apparent. *P<0.01.
Figure 3
Figure 3
The 8-oxo-deoxyguanosine (8-oxo-dG) is associated with glutathione redox/antioxidant capacity (GSH/GGSG) in the cerebellum. In the combined case and control cohort of samples from the cerebellum, 8-oxo-dG was significantly associated with GSH/GSSG (P<.0001). Although the significance of the correlations does not hold within the autism samples, the sample-specific clustering of case values (in open circles) in the bottom left quadrant of each graph is apparent.
Figure 4
Figure 4
Mechanism of mitochondrial aconitase inactivation. Mitochondrial aconitase is a tricarboxylic acid (TCA) cycle enzyme that catalyzes the conversion of citrate to isocitrate. It contains an iron-sulfur cluster ([4Fe-4S]) in its active site that is inactivated by superoxide (O) produced in close proximity as a byproduct of the electron transport chain. This results in the release of a Fe+2 and a molecule of hydrogen peroxide (H2O2), which, through the Fenton reaction, can react to produce a hydroxyl radical (OH). The glutathione redox capacity (GSH/GSSG) will decrease as a result of the elevated free-radical production and will allow more superoxide inactivation of aconitase, creating a self-amplifying cycle if left unresolved.
Figure 5
Figure 5
Proposed interactions between measured biomarkers and oxidative stress. Elevated superoxide generated from dysfunctional mitochondria promotes the formation of excess H2O2, the substrate for myeloperoxidase (MPO)-mediated hypochlorous acid (HOCl) synthesis and the generation of the inflammatory biomarker, 3-chlorotyrosine (3-CT). An elevation in nitric oxide (NO) combined with elevated superoxide levels results in the formation of the peroxynitrite radical and the protein oxidative damage biomarker, 3-nitrotyrosine (3-NT). The hydroxyl radical is generated by both aconitase inactivation and MPO, and promotes the formation of 8-oxo-deoxyguanosine (8-oxo-dG). Chronic elevation of these free radicals will deplete the glutathione redox/antioxidant capacity (GSH/GSSG), allowing unopposed free-radical generation and a self-perpetuating cycle, leading to chronic oxidative stress.

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