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Involvement of PGD2 in pathological condition

We are pursuing the involvement of PGD₂ in the progress and repair of damaged tissue such as in necrotic muscle in Duchenne muscular dystrophy, multiple sclerosis, and traumatic brain injury. It is our intention to find drugs selective to H-PGDS expressed in damaged tissues and to develop a novel method that could delay the progression of such diseases and generate therapies against them.

A few years ago we reported that H-PGDS was expressed in necrotic muscle fibers of patients with Duchenne muscular dystrophy or multiple myositis (Okinaga, T., et al. Acta. Neuropath., 2002). We found that H-PGDS was expressed in the necrotic muscle fibers in a bupivacaine-injected mouse model and mdx dystrophic mice, a model for gene mutation-driven dystrophy. We confirmed that the necrotic area was magnified in H-PGDS TG mice

A few years ago we reported that H-PGDS was expressed in necrotic muscle fibers of patients with Duchenne muscular dystrophy or multiple myositis (Okinaga, T., et al. Acta. Neuropath., 2002). We found that H-PGDS was expressed in the necrotic muscle fibers in a bupivacaine-injected mouse model and mdx dystrophic mice, a model for gene mutation-driven dystrophy. We confirmed that the necrotic area was magnified in H-PGDS TG mice and shrank upon treatment with HQL-79. In addition, we found that HQL-79 treatment diminished the area of necrosis in the muscle of the Duchenne muscular dystrophy model mouse, mdx (Mohri, I., et al. Am. J. Pathol., 2009).

We are designing and synthesizing several alternative inhibitors of H-PGDS based on the X-ray crystallographic structure of the enzyme. Through pilot studies on the effect of the synthesized inhibitors on purified H-PGDS, human cell lines expressing H-PGDS, and transgenic mice over-expressing H-PGDS, we found a highly potent selective inhibitor for H-PGDS. In vivo experiments using mdx muscular dystrophy model mice will be carried out to confirm that these candidate inhibitors impede the expansion of the necrotic area of the muscles.

Concomitantly, we established a quantification method for the aid of an X-ray CT device capable of determining the extent of a lesion in an individual animal non-invasively. In addition, we are also engaged in the development of a method of quantifying PGD2 and its metabolites produced in damaged areas for a proof-of-concept experiment. The urinary level of PGD2 metabolite (tetranor-PGDM) was about 3 times higher in the mdx mice than in the wild-type mice. Administration of H-PGDS inhibitor (HQL-79) to mdx mice for 5 days significantly decreased the level of urinary tetranor-PGDM and showed significant improvement in muscle strength. We showed a good correlation between the pathologic variation and the urinary PGD2 metabolite level, suggesting that urinary tetranor-PGDM is useful as a clinical indicator for DMD pathology.

Moreover, we found that H-PGDS inhibitor treatment to experimental autoimmune encephalomyelitis (EAE) mice, an animal model for multiple sclerosis, suppressed the disease progression of EAE.

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Small Animal X-ray CT imaging device

In lieu of the existing assessment methods such as histochemistry of necrotic tissues or quantification of dye-leakage into necrotic tissues, we established a non-invasive method for the continuous tracking of myonecrotic areas in the whole boy of the experimental animal by using X-ray CT imaging that we developed jointly with ALOKA Corporation.

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