Medical Sciences Group/Inter-Institute Cooperative LaboratoriesItokawa Laboratory
(Biomedical Sciences Group, TMiMS)

Why is homo sapience suffered from mental illnesses? Numerous numbers of people in field of religion or philosophy had ever investigated the maze far past. Only three hundred years have passed since medical sciences involved in this theme. We are challenging to resolve the twister interwoven with brain and mind by using methods and tools of biology. Functional psychiatric disease is the brain disorder causing emotional and thinking difficulty without any abnormal sings in electric encephalography or brain imaging. Schizophrenia is the major one of those as well as mood disorder We perform genomic and metabolome analysis using blood samples from patients with schizophrenia in order to reveal pathophysiology of the disease. We create animal and culture cell-based model utilizing genetic polymorphisms and aberrant metabolism seen in the patients. Human iPS cells induced from a schizophrenic patient carrying the rare genetic variation were differentiated to neural cells to be analyzed for investigation of pathophysiology of the disease. Schizophrenia is a common disease that the prevalence is around 1% of population at any region of the world. Why has schizophrenia survived natural selection during human evolution? We are also seeking answer of the question by using our models of animals and culture cells. Ego-function such as self-identity is also disturbed in patients with schizophrenia. We challenge to reveal ego and self-consciousness, the fields that had ever been investigated by religion or philosophy far past,by using tools and methods of molecular biology. Oxidative stress is a central mediator of advanced glycation end product (AGE) formation, and pyridoxamine[vitamin (vit)B6]] (biosynthesized from pyridoxal in vivo) is known to detoxify reactive carbonyl compounds (RCOs) via carbonyl-amine chemistry.Cellular removal of AGEs hinges largely upon the activity of the zinc metalloenzyme glyoxalase I (GLO1). We detected idiopathic carbonyl stress in a subpopulation of schizophrenia. We first found an interesting case carrying genetic defect of glyoxalase 1 (GLO1)that increased AGEs and decreased vitamin B6 since GLO1 detoxifies AGEs and vitamin B6 is carbonyl scavenger. We obtained 20% of patients showing carbonyl stress by the manner expanding concept of the case over the general schizophrenic patients. This manner can resolve the problem of research on schizophrenia derived from the heterogeneity of the disease. Genetic defect of GLO1 contributes to the stress by 5 time’s higher risk compared to that of intact gene. AGEs level was significantly correlated with negative symptoms of the patients. Pyridoxamine, active vitamin B6, could be the first medicine for negative symptoms of schizophrenia as most of the antipsychotic medicines are not effective for negative symptoms. We here present unique report of resolution of research difficulty due to heterogeneity of schizophrenia and possible discovery of the drug for negative symptoms of the disease.

mental illness, mind, brain, molecular biology, genome
  • Figure 1 . Plasma pentos idine accumulation and serum pyridoxal(vitamin B6) depletion.Levels of plasma pentos idine (A) and serum pyridoxal (B ) were analyzed us ing hig h-performance liquid chromatog raphy techniques .Values were compared using the Mann-Whitney U tes t (2 -tailed). Error bars indicate s tandard devi

  • Nishizawa D. et al. Mol Psychiatry 19(1):55-62, 2014
  • Ichikawa T. et al. Mol Genet Metab 105(1):103-109, 2012
  • Arai M. et al. Arch Gene Psychiatry 67:589-597, 2010
  • Doi N. et al. PLoS One 4(11):e7799, 2009
  • Hiroi N. et al. Proc Natl Acad Sci U S A.102:19132-19137,
  • 2005
  • Sora Natl Acad Sci U S A.98:5300-5305,2001
  • Lin Z. et al. FASEB J. 14(5):715-528, 2000
Page Top