Combination of Styrylbenzoazole Compound and Hydroxypropyl Methylcellulose Enhances Therapeutic Effect in Prion-Infected Mice.

Prion diseases are fatal transmissible neurodegenerative disorders. Tremendous efforts have been made for prion diseases; however, no effective treatment is available. Several anti-prion compounds have a preference for which prion strains or prion-infected animal models to target.

Anti-prion activity of cellulose ether is impaired in mice lacking pre T-cell antigen receptor α, T-cell receptor δ, or lytic granule function.

The anti-prion activity of cellulose ether (CE) has been reported in rodents, but the mechanism of action is not well understood. As defects in early T-cell development have been reported in Tga20 mice which show only a slight effect of CE administration, we investigated the involvement of immune functions in the CE action. We confirmed an insertion of the prion protein transgene into the pre T-cell antigen receptor α gene of Tga20 mice, and its impaired expression in the thymus and other tissues.

Polymorphisms in glia maturation factor β gene are markers of cellulose ether effectiveness in prion-infected mice.

Anti-prion effects of cellulose ether (CE) are reported in rodents, but the molecular mechanism is fully unknown. Here, we investigated the genetic background of CE effectiveness by proteomic and genetic analysis in mice. Proteomic analysis in the two mouse lines showing a dramatic difference in CE effectiveness revealed a distinct polymorphism in the glia maturation factor β gene.

Intermolecular crosslinking of abnormal prion protein is efficiently induced by a primuline-sensitized photoreaction.

In prion diseases, infectious pathogenic particles that are composed of abnormal prion proteins (PrP) accumulate in the brain. PrP is biochemically characterized by its protease-resistance core (PrP), but its structural features have not been fully elucidated. Here, we report that primuline, a fluorescent dye with photosensitization activity, dramatically enhances UV-irradiation-induced SDS-resistant PrP oligomer formation that can be detected by immunoblot analysis of prion-infected materials.

Pyrene conjugation and spectroscopic analysis of hydroxypropyl methylcellulose compounds successfully demonstrated a local dielectric difference associated with in vivo anti-prion activity.

Our previous study on prion-infected rodents revealed that hydroxypropyl methylcellulose compounds (HPMCs) with different molecular weights but similar composition and degree of substitution have different levels of long-lasting anti-prion activity. In this study, we searched these HPMCs for a parameter specifically associated with in vivo anti-prion activity by analyzing in vitro chemical properties and in vivo tissue distributions. Infrared spectroscopic and thermal analyses revealed no differences among HPMCs, whereas pyrene conjugation and spectroscopic analysis revealed that the fluorescence intensity ratio of peak III/peak I correlated with anti-prion activity.

Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels.

A Single Subcutaneous Injection of Cellulose Ethers Administered Long before Infection Confers Sustained Protection against Prion Diseases in Rodents.

Prion diseases are fatal, progressive, neurodegenerative diseases caused by prion accumulation in the brain and lymphoreticular system. Here we report that a single subcutaneous injection of cellulose ethers (CEs), which are commonly used as inactive ingredients in foods and pharmaceuticals, markedly prolonged the lives of mice and hamsters intracerebrally or intraperitoneally infected with the 263K hamster prion. CEs provided sustained protection even when a single injection was given as long as one year before infection.

Secretin receptor involvement in prion-infected cells and animals.

The cellular mechanisms behind prion biosynthesis and metabolism remain unclear. Here we show that secretin signaling via the secretin receptor regulates abnormal prion protein formation in prion-infected cells. Animal studies demonstrate that secretin receptor deficiency slightly, but significantly, prolongs incubation time in female but not male mice.

Efficacy and mechanism of a glycoside compound inhibiting abnormal prion protein formation in prion-infected cells: implications of interferon and phosphodiesterase 4D-interacting protein.

Unlabelled: A new type of antiprion compound, Gly-9, was found to inhibit abnormal prion protein formation in prion-infected neuroblastoma cells, in a prion strain-independent manner, when the cells were treated for more than 1 day. It reduced the intracellular prion protein level and significantly modified mRNA expression levels of genes of two types: interferon-stimulated genes were downregulated after more than 2 days of treatment, and the phosphodiesterase 4D-interacting protein gene, a gene involved in microtubule growth, was upregulated after more than 1 day of treatment. A supplement of interferon given to the cells partly restored the abnormal prion protein level but did not alter the normal prion protein level.