ABSTRACT
Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of ß-amyloid (Aß) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer's disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aß, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aß as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aß and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aß and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57-1293, which acts by a different mechanism from ACV. We found that BAY 57-1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aß and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57-1293 than by ACV. These data suggest that BAY 57-1293 would be a more effective agent than ACV for treating AD.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Antiviral Agents/pharmacology , DNA Helicases/antagonists & inhibitors , DNA Primase/antagonists & inhibitors , Herpes Simplex/metabolism , Herpesvirus 1, Human/drug effects , Pyridines/pharmacology , Thiazoles/pharmacology , Viral Proteins/antagonists & inhibitors , tau Proteins/metabolism , Acyclovir/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/virology , Amyloid beta-Peptides/genetics , Down-Regulation/drug effects , Enzyme Inhibitors/pharmacology , Herpes Simplex/drug therapy , Herpes Simplex/virology , Herpesvirus 1, Human/enzymology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/metabolism , Humans , Sulfonamides , Virus Replication/drug effects , tau Proteins/geneticsABSTRACT
The chemical components of the four silicone rubber polymers were reviewed. Methods of controlling the porosity and density of both the one-component semisolid prepolymer and the two-component fluid prepolymer systems were evaluated. The variables examined were deairing of the fluid systems; trial packing, pressure sealing, and processing of the semisolid materials; injection versus hand packing of the mold; the effects of moist-heat versus dry-heat application during processing; and the need for investment of the mold within the confines of a closed flask. It can be concluded that porosity of medical-grade silicone rubber polymers may be totally prevented, or accurately controlled, by proper handling techniques.
