Treatment of Transmissible Spongiform Encephalopathy by Intraventricular Drug Infusion in Animal Models

Journal of Virology - Tập 78 Số 10 - Trang 4999-5006 - 2004
Katsumi Doh‐ura1,2, Kazuo Ishikawa1,2, Ikuko Murakami-Kubo1,2, Kensuke Sasaki1,2, Satoshi Mohri3,4, Richard Race5,6, Toru Iwaki1,2
1Department of Neuropathology 1 and Center of Biomedical Research,
2Department of Prion Research, Tohoku Univer-sity Graduate School of Medicine, Sendai 980-8575, Japan.
3Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, and Laboratory of Persistent Viral Diseases,
4Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840
5Department of Prion Re-search, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.
6Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840

Tóm tắt

ABSTRACT The therapeutic efficacy of direct drug infusion into the brain, the target organ of transmissible spongiform encephalopathies, was assessed in transgenic mice intracerebrally infected with 263K scrapie agent. Pentosan polysulfate (PPS) gave the most dramatic prolongation of the incubation period, and amphotericin B had intermediate effects, but antimalarial drugs such as quinacrine gave no significant prolongation. Treatment with the highest dose of PPS at an early or late stage of the infection prolonged the incubation time by 2.4 or 1.7 times that of the control mice, respectively. PPS infusion decreased not only abnormal prion protein deposition but also neurodegenerative changes and infectivity. These alterations were observed within the brain hemisphere fitted with an intraventricular infusion cannula but not within the contralateral hemisphere, even at the terminal disease stage long after the infusion had ended. Therapeutic effects of PPS were also demonstrated in mice infected with either RML agent or Fukuoka-1 agent. However, at doses higher than that providing the maximal effects, intraventricular PPS infusion caused adverse effects such as hematoma formation in the experimental animals. These findings indicate that intraventricular PPS infusion might be useful for the treatment of transmissible spongiform encephalopathies in humans, providing that the therapeutic dosage is carefully evaluated.

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Journal of Virology

Tập 78 Số 10

4999-5006

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