Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : July 31, 2018
Accepted : August 24, 2018
Published online : September 30, 2018
doi:10.24659/gsr.5.3_147

Review article

Glycative stress and anti-aging: 9. Glycative stress and schizophrenia.
Masayuki Yagi, Yoshikazu Yonei
Anti-Aging Medical Research Center and Glycative Stress Research Center, Faculty ofLife and Medical Sciences, Doshisha University, Kyoto, Japan

Abstract

Schizophrenia is a mental disease characterized by hallucination and delusion; its clinical conditions have many unclear
points. There are dopamine hypothesis, glutamate hypothesis and protein posttranslation modification for schizophrenia.
Protein posttranslation modification means that phosphorylation, ubiquitination, methylation and glycosylation after protein
synthesis are involved in clinical conditions of schizophrenia. In schizophrenia, there is a multiplex family with a frameshift
mutation of the glyoxalase 1 (GLO1) gene existing in the No. 6 chromosome. In the blood of the patient in this case, theconcentration of pentosidine, a kind of advanced glycation end products (AGEs), increased and vitamin B6 having carbonyl
scavenging activities decreased, compared with those of healthy people. Therefore, it is thought that schizophrenia is acondition where glycative stress has been enhanced. In patients with carbonyl stress-induced schizophrenia, a decrease ofvitamin B6 in their blood is observed; therefore, the effectiveness of vitamin B6 replacement therapy can be expected. Clinical
trials of the administration of pyridoxiamine to patients with schizophrenia suggest the possible effectiveness of this therapy.

KEY WORDS: glyoxalase 1, carbonylation, pyridoxiamine, pentosidine1. Introduction:
What is Schizophrenia?
Schizophrenia is a mood disorder similar to major
depressive disorder and bipolar disorder. It is characterized
by symptoms such as hallucination and delusion. In thiscase, functions of managing family and social lives while
communicating with other people are damaged, and thepatients become unable to reflect on themselves andunderstand that “their feeling, thinking and behavior aredistorted because of disease.” Progress of the disease is likely
to follow a chronic process, during that time, an acute stage
appears where hallucination and delusion become strong.
According to a 2014 survey of patients by the Ministry ofHealth and Welfare, the number of patients with mental
disease admitted in hospital was 266,000. Among those,
the number of patients with schizophrenia, schizophrenic
disorder and delusional disorder was 166,000 1). The reasons
why the general recognition of schizophrenia is low are thatits symptoms are difficult to be discerned, that it is subjected
to social prejudice and that its only treatment is conservative

Contact Address: Professor Masayuki Yagi, PhD
Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University
1- 3 Tatara Miyakodani, Kyotanabe, Kyoto, 610 - 0394 Japan
Phone/Fax: + 81-774 -65- 6394 Email: myagi@mail.doshisha.ac.jp
Co-author: Yonei Y, yyonei@mail.doshisha.ac.jp

pharmacotherapy.
Although there are many unclear points in clinicalconditions of schizophrenia, it is known that it has dopamine
hypothesis, glutamate hypothesis and protein posttranslation
modification 2. 3). Dopamine hypothesis is that the over activityof the subcortical dopamine nerve function accompanied by
the low activity of the dopamine nerve function in the frontal
cortex is involved in clinical conditions of schizophrenia.
Glutamate hypothesis is that the dysfunction of glutamatergic
neurotransmission is involved in clinical conditions ofschizophrenia. Protein posttranslation modification is that
phosphorylation, ubiquitination, methylation and glycosylation
after protein synthesis are involved in clinical conditionsof schizophrenia. It is already understood that irreversible
changes such as oxidation, carbonylation, glycation andnitration of in vivo protein are involved in the onset andprogressions of various disorders 4).

_ 147 _Glycative Stress Research 2018; 5 (3): 147-150(c) Society for Glycative Stress ResearchGlycative Stress and Schizophrenia

2. Schizophrenia and Glycative Stress

Many cases of the involvement of No. 6 chromosome
in schizophrenia have been reported 5). An enzyme gene
called glyoxalase 1 (GLO1) exists in this chromosome.
Glyoxalase decomposes carbonyl compounds resulting
from oxidant stress and glycative stress. Among in vivo
carbonyl compounds, there are methylglyoxsal, glyoxsal and3 -deoxyglucosone generated from glucose and lipids. They
are also glycation reaction intermediates. As they modifyprotein and generate advanced glycation end products(AGEs), they are the substances responsible for glycativestress. The condition where protein modifications such as
AGEs are progressed by carbonyl compounds is also calledcarbonyl stress.
The frameshift mutation is found in the GLO1 geneof patients with carbonyl stress-induced schizophrenia.
Therefore, it was found that the expression of GLO1, of thepatient in this case, fell to 50% of that of healthy people 5).

A

This was derived via the analysis of DNA of an individualof a multiplex family with schizophrenia. It is reported thatthe concentration of pentosidine, one of AGEs, in the bloodof the patient of this case increased up to 3.7 times of thecomparison subject. The concentration of vitamin B6 withcarbonyl scavenging activities in vivo, similar to glyoxalase,decreased to 20% lower than in a healthy person 3, 6).
Furthermore, on the survey of patients with schizophrenia
without diabetes, a kidney problem or an inflammatory
disorder, it was confirmed that the concentration ofpentosidine in blood significantly rose and that of vitamin
B6 significantly fell ( Fig. 1 ) 6).
Furthermore, the increase of an accumulation of skinAGEs 7) and the increase of argpyrimidine, an AGE derived
from methylglyoxal, in 56-KDa protein in red cells 8) werereported for patients with schizophrenia. Therefore, it can besaid that schizophrenia is the result of progressed symptomsof glycative stress.

Bp < .001

45300

Patient 1

40240

35210

30180
150120Pyridoxal, ng/mL

Pentosidine, ng/mL270

p < .001

Patient 2
Patient 3

2520
1590

1060

53000

Schizophrenic
IndividualControl

Schizophrenic
IndividualFig. 1. Plasma pentosidine accumulation and serum pyridoxal (vitamin B6) depletion.

ControlLevels of plasma pentosidine (A) and serum pyridoxal (B) were analyzed using high-performance liquid chromatography techniques.
Values were compared using the Mann-Whitney U test (2-tailed). Error bars indicate standard deviations. The figure is adapted fromReference 6.

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3. Possibility of Schizophrenia Treatment
by Inhibiting Glycative StressA decrease of vitamin B6 in blood is recognized inpatients with carbonyl stress-induced schizophrenia, sothe effectiveness of vitamin B6 replacement therapy canbe expected. There are three substances of pyridoxine,pyridoxal and pyridoxiamine in vitamin B6 and they are inparallel relationship in solution. Pyridoxiamine among themhas carbonyl scavenging activities 9). Pyridoxiamine inhibits
the formation of carbonyl compounds caused by glycationand oxidization in vivo, therefore, the improvement ofschizophrenia can be expected ( Fig. 2) 10). There is a report ofclinical testing of pyridoxiamine administration for patientswith schizophrenia. As the result of the administration ofpyridoxiamine 1,200 -2,400 mg per day for 24 weeks tothe patients with schizophrenia with a high concentration
value of pentosidine in their blood, the concentration of thepentosidine in their blood decreased by 26.8 %. In the caseof patients presenting typical carbonyl stress with frameshift
mutation in the GLO1 enzyme, pentosidine decreased andtheir psychological symptoms improved 11). Therefore, it ispresumed that therapy by administration of pyridoxiamine
to the patients with schizophrenia accompanied by carbonyl
stress is very effective.

Acknowledgement
This work was partially supported by the JapaneseCouncil for Science, Technology and Innovation, SIP (ProjectID 14533567 ), “Technologies for creating next-generation
agriculture, forestry and fisheries” (funding agency: Biooriented Technology Research Advancement Institution,NARO).

Conflict of Interest Statement

Fig. 2. Glyoxalase detoxification system and glycative stress.

The authors claim no conflict of interest in this study.

Accumulation of reactive carbonyl compounds results in modification of proteins and the eventual formation of advanced glycation end
products (AGEs) and methylglyoxal-adducts. Glyoxalase proteins are ubiquitously expressed in various tissues, including the brain, andprovide an effective defense against the accumulation of reactive dicarbonyl compounds. Vitamin B6 also detoxifies reactive carbonylcompounds by trapping these products and/or by inhibiting the formation of AGEs. GLO1, glyoxalase 1; GLO2, glyoxalase 2; GSH,glutathione. The figure is adapted and modified from Reference 10.

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