Current studies 3

It is said that the lifetime prevalence of schizophrenia is 0.85% and the patients who have received treatment are more than 700,000 people in Japan. Unfortunately, the cause of the disease is still unknown and the medication is only symptomatic therapy.

Prof. Miyata discovered some families of severe schizophrenia patients who lost glyoxalase I (Glo1) in collaboration with Dr. Itokawa. The Glo1 is the enzyme which metabolizes the reactive carbonyl compounds generated from monosaccharides. In the Glo1-deficient patients, the carbonyl compounds and the advanced glycation end products (AGEs) which generated from protein modification of the carbonyl compounds were accumulated (carbonyl stress). In subsequent analysis, the polymorphism of Glo1 was found out and there was schizophrenia in the Ala/Ala homozygote that showed low Glo1 activity.

Miyata et al shows that pyridoxamine traps and removes both carbonyl compounds and AGEs in vivo. The accumulation of the carbonyl compounds and AGEs is known to be one of the causes of the diabetic nephropathy, and the clinical trial (Phase II).has been performing from.1999 in the United States. It was shown that pyridoxamine controlled the progress of the diabetic nephropathy in concurrence with decreasing the AGEs accumulation in the plasma. Therefore, the effect of pyridoxamine on the carbonyl stress-induced schizophrenia patient who has accumulated AGEs would be expected.

We proposed the concept of pyridoxamine treatment for carbonyl stress-induced schizophrenia and the preparation for clinical development (Phase II) is underway. We are also working for the making of Glo1 knockout mice to use the basic research for the concept certification.

1) Miyata T, Ueda Y, Yamada Y, Izuhara Y, Wada T, Jadoul M, Saito A, Kurokawa K, van Ypersele de Strihou C.　Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress in uremia.　J Am Soc Nephrol. 1998 Dec;9(12):2349-56