Our data confirm that liposomes containing tetracyclines can be safely administered icv and suggest that continuous infusions could improve their therapeutic index. The development of pharmaceutical formulations employing liposomes or nanoparticles to facilitate the BBB passage of these drugs might offer alternative ways of administration such as continuous iv or ip infusions to attain high steady-state drugs levels in the brain. The broad efficacy of tetracyclines has to be confirmed in different animal models and with different prion strains. In fact, the onset and progression of the disease is variable and highly dependent on the prion strain and host animal species considered. The host/prion strain interaction is regulated by multiple factors, such as accumulation and distribution of PrPSc, incubation time and length of the disease as well as protein sensitivity to proteinase K degradation. The last factor is likely to be crucial in dictating sensitivity to tetracyclines, induction of proteinase Kdependent degradation of PrPSc is purported to be the major mechanism underlying the anti-prion activity of these drugs. In this context, it is worth mentioning that the antibiotic Amphotericin B, which is known to decrease resistance to proteinase K digestion, prolongs the lifespan of hamsters infected with the 263K strain of PrPSc. However, its therapeutic activity is limited to this prion strain and is not observed after infection of the animals with other strains. Ongoing studies are aimed at Tenacissoside-I verifying the effectiveness of tetracycline treatment in hamsters and mice using PrPSc Presapogenin-CP4 strains with different propagation properties and sensitivity to proteinase K action. A further point worth exploring is the dissociation between the anti-microbial and anti-fibrillogenic activity of tetracyclines. Formally we have not excluded the possibility that the beneficial effect of tetracyclines may results from other as yet unresolved mechanisms. Though unlikely, it is possible that the increased survival of the animals is related to antibiotic activity of tetracyclines. As the chemical functionalities responsible of the antibiotic activity of these drugs are known we are in the process of testing the anti-prion properties of tetracyclines devoid of anti-microbial activity.