Region-specific interference of PrPSc accumulation in spleen and brain by poly-L-arginine (PLR)

Abstract

Background: In our previous study, PLR was shown to inhibit prion propagation in the cell culture model of prion diseases (1). In current study, we investigated the effect of PLR in vivo whether it inhibits prions.

Material and Methods: Firstly, mice inoculated intraperitoneally (IP) with prions were administered with PLR twice a week for 4 weeks 10–40 mg/kg by the IP route. Spleen were collected from infected mice at every 21-day until 84 days post-inoculation. In another approach, to observe the delay of disease onset, mice infected intracerebrally with prions, were administered with PLR twice a week for 4 weeks 10–25 mg/kg PLR by the IP route. As disease onsets, the brain and spleen were collected. The level of PrPSc in the brain and spleen were detected by Western blotting. The accumulation of the PrPSc and glial fibrillary acidic protein were monitored using immunohistochemistry. Vacuolation in the brain was investigated using H&E stained brain sections.

Result: PrPSc propagation was suppressed in the spleen of PLR-treated group during the asymptomatic stage. Administration with 10–25 mg/kg PLR prolonged the incubation time of prion diseases over seven days. At the disease onset, the level of PrPSc reduced in the spleen, but unchanged in the brain. However, immunohistochemistry analysis showed that the level of PrPSc in white pulp of the spleen and specific areas of the brain, such as hypothalamus, cortex, and hippocampus, but not mid-brain, thalamus, and straitum, was reduced by PLR. Moreover, glial fibrillary acidic protein staining indicated that PLR decreased astrogliosis in thalamus, cortex, and polymorph layer 3 of cerebral cortex of brain but not in other brain regions. In addition, H & E staining indicated that the decrease of vacuolation area and vacuole counts in mid-brain, hypothalamus, hippocampus, and straitum regions of the brains from the PLR-administered mice.

Conclusion: Considering suppression of prion propagation in spleen during asymptomatic stage, significant increase of survival time and brain region-specific inhibition of neuropathological onsets, we demonstrated PLR as a potential therapeutic candidate for prion diseases and the value of further studies.