Finally, 1-flouro-2,4-dinitrobenzene was added to the mixture for the detection at 365 nm. Tetracyclines bind not only to PrP aggregates but also to Dimesna neurotoxic peptides, antagonizing their toxic effect on nerve and glial cells, and inhibiting astroglial proliferation. Intracerebroventricular administration of quinacrine, amphotericin B, pentosan polysulfate and quinoline derivatives in transgenic mice inoculated ic with 263K, RML and Fukuoka 1 strains was carried out by Doh-ura et al. and MurakamiKubo et al. in an experimental model of prolonged infusion lasting four weeks. The treatment with amphotericin B or pentosan polysulfate was effective when started in early stages of the disease and quinine had efficacy when given in a relatively late stage of the disease. We investigated the effectiveness of doxycycline and minocycline at an advanced stage of infection, i.e. 60 days after inoculation of 263 K scrapie strain 4-Demethylepipodophyllotoxin homogenate, when 50% of animals showed the first neurological symptoms. A single infusion of 25 mg/20 ml icv of tetracyclines entrapped in liposomes was used since infusion of tetracycline solutions can induce overt acute toxicity. This enabled us to reach doxycycline and minocycline levels of 50 mg/g in brain, well above the Cmax that can be measured in rats after 25 mg/kg of minocycline iv. The concentration of tetracycline in liposomes infused icv was the highest possible based upon the entrapment recovery of the drugs. A single icv infusion of the onset of the first neurological symptoms increased survival, reaching statistical significance for doxycycline and close to significance for minocycline. In our opinion this difference, however, reflects the small number of animals in each experimental group, which reduced the statistical power of the analysis, and the lower effectiveness of minocycline in sensitizing PrP peptides to protease hydrolysis, as shown in cell-free tests. Moreover, the comparable efficacy of icv indicates that the BBB is crucial in the survival of animals treated ip. Minocycline, which is known to cross the BBB to a greater extent than tetracycline and doxycycline, was the most effective molecule.