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

Abstract

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. These effects were linked with persistent residues of CEs in various tissues. More effective CEs had less macrophage uptake ratios and hydrophobic modification of CEs abolished the effectiveness. CEs were significantly effective in other prion disease animal models; however, the effects were less remarkable than those observed in the 263K prion-infected animals. The genetic background of the animal model was suggested to influence the effects of CEs. CEs did not modify prion protein expression but inhibited abnormal prion protein formation in vitro and in prion-infected cells. Although the mechanism of CEs in vivo remains to be solved, these findings suggest that they aid in elucidating disease susceptibility and preventing prion diseases.

Cellulose ether treatment in vivo generates chronic wasting disease prions with reduced protease resistance and delayed disease progression

“…Cellulose ethers CE compounds TC-5RW and 60SH-50 were dissolved at a concentration of 5% in water. Compound properties and details are as described previously (Teruya et al 2016).…”

“…Because it is a safe gas to use for both animals and users, isoflurane is the preferred and commonly gas anesthetic agent in many animal facilities including ours (Taylor and Mook 2009). Six to eight weeks old female TgElk mice were anaesthetized and as previously described (Teruya et al 2016) injected subcutaneously with a single dose of 4 g/kg body weight of CE for treated groups or vehicle (dH2O) for group control (see Figure S1 for the time line of the bioassay). The CE injections were administered to the different groups of mice in a manner that all prion infections were performed on mice with same age.…”

“…However, the prolongation of incubation time was less pronounced than for 263K prions, leading to the question of the influence of prion strain and/or mouse genetic background on treatment outcomes. Mechanistically, CEs most likely inhibit prion formation (Teruya et al 2016). Similarly, inhibition of a-synuclein amyloid formation (Breydo et al 2014) in vitro was demonstrated, suggesting that CEs have a general inhibitory effect on amyloid formation.…”

“…Mechanistically, CEs most likely inhibit prion formation (Teruya et al . ). Similarly, inhibition of α‐synuclein amyloid formation (Breydo et al .…”

“…CEs are hydrophilic macromolecules, which can be distributed throughout the whole body within days after a single subcutaneous injection. Teruya et al described the crucial role of macrophages in the efficacies of CEs through phagocytosis, which facilitates the decomposition or excretion of CEs (Teruya et al 2016). CE treatment significantly increased the survival of transgenic mice and hamsters, respectively, infected intracerebrally (i.c.)…”