Enhanced carbonyl stress linked to schizophrenia
MedWire News: Carbonyl stress may play a pivotal role in schizophrenia in some patients, research suggests.
Carbonyl stress results from an accumulation of reactive carbonyl compounds, which results in the modification of proteins and the eventual formation of advanced glycation end (AGE) products.
Masanari Itokawa, from the Tokyo Institute of Psychiatry in Japan, and colleagues found that levels of one of these AGE products, pentosidine, were on average 1.73-fold higher in a subpopulation of schizophrenia patients compared with mentally healthy individuals.
Also, this was concomitant with reduced levels of pyridoxal (vitamin B6), which is known to detoxify reactive carbonyl compounds (RCOs) including AGEs.
The researchers studied a total of 45 patients with schizophrenia and 61 mentally healthy individuals and found that 21 of the patients had plasma pentosidine levels above 55.2 ng/ml, compared with just two of the mentally healthy individuals, while three had very high levels above 130 ng/ml.
A concomitant marked decrease in pyridoxal levels of below 3 ng/ml, was found in 11 of the schizophrenia patients but none of the controls.
The researchers report in the Archives of General Psychiatry that “agents able to inhibit AGE formation or entrap carbonyl compounds may... prove to be of therapeutic value, if carbonyl stress is directly linked to schizophrenic signs and symptoms.”
One mechanism possibly underlying the alterations in the pentosidine/pyridoxal levels in schizophrenia patients appeared to be deficits in the glyoxyalase 1 (GLO1) gene, which encodes for an enzyme that is required for the cellular detoxification of RCOs.
Resequencing analysis involving 1761 patients with schizophrenia and 1921 control individuals, including those already studied, identified two different heterozygous frameshift mutations and a functional Glu111Ala polymorphism.
Biochemical analyses revealed that these genetic variations resulted in a 10–50% reduction in GLO1 activity in red blood cells in schizophrenia patients and were linked to increased plasma pentosidine and decreased pyridoxal.
The GLO1 genetic defects were also identified in a fraction of controls, but in contrast to schizophrenia patients, these controls exhibited normal pentosidine and pyridoxal levels.
“Our findings suggest a cross-sectional link, albeit incomplete, between GLO1 defect-elicited carbonyl stress and a subgroup of patients with schizophrenia,” the researchers write.
They conclude that elucidation of the mechanisms by which healthy individuals with GLO1 defects escape carbonyl stress may provide clues to “novel therapeutic approaches” in patients with carbonyl stress.
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By Lucy Piper