New CO2-philic hydrocarbon molecules were synthesized by reversible addition fragmentation chain-transfer polymerization. These poly(vinyl alkylates) show the highest solubility in supercritical CO2 of any hydrocarbon reported to date. By utilizing the anchoring ability of the thiocarbonylthio end group, the dispersion polymerization of N-vinyl pyrrolidone was successfully achieved in scCO2 leading to high yields of well-defined spherical polymer particles.
The ability of highly active antiretroviral therapy (HAART) to prevent the onset of HIV-associated dementia and to prevent or reduce the neuropathological features of HIV encephalitis (HIVE) remains unclear. Using a severe combined immunodeficient (SCID) mouse model of HIVE, we determined the effects of regular HAART treatment on HIVE. Before studying HAART in infected SCID mice, nonmanipulated SCID mice were treated with a single injection of the HAART cocktail (consisting of zidovudine, lamivudine, and indinavir) to determine optimum dosage and sampling time and to measure antiretroviral levels in the brain. After these preliminary studies, SCID mice that were inoculated with either HIV-infected or uninfected human monocytes were given intraperitoneal (IP) injections of HAART three times daily over a 1- and 2-week period. All three drugs were detected in the brain using a novel drug extraction technique and a modified high-performance liquid chromatography method. HAART significantly decreased the amount of astrogliosis and viral load in treated mice compared with mice that received vehicle injections. These studies offer insight into the ability of HAART to treat HIV infection of the brain.
Multicatalytic proteinase complex (MPC) was isolated from bovine brain and the susceptibility of myelin basic protein (MBP) and P2 protein of bovine central and peripheral nervous system was examined. SDS-polyacrylamide electrophoretic analysis of purified MPC revealed protein bands of molecular weight ranging from 22-35 kDa. The enzyme is activated by SDS at a concentration less than 0.01%. Upon incubation with MPC, purified MBP and P2 proteins were degraded into smaller fragments. There was a 57% and 100% loss of MBP at 2 and 6 hours of incubation. The P2 protein which is not susceptible to any endogenous non-lysosomal enzyme thus far studied was digested into small peptide fragments only in the presence of SDS (0.01%) and not in its absence. These results indicate that MPC which is active at physiological conditions may have a role in the turnover of myelin proteins and in demyelinating diseases.
The effect of indomethacin, a non-steroidal anti-inflammatory drug upon purified calpain has been studied. Also, its effects upon Ca2+-mediated degradation of cytoskeletal proteins (neurofilament) in spinal cord homogenate has been investigated. A dose-dependent inhibition of purified calpain activity was observed. A 50% inhibition of 14C-caseinolytic activity was obtained with less than 1.1 mM of indomethacin while the activity was completely inhibited at 3.3 mM concentration. The inhibitory effect of ketorlac, another non-steroidal anti-inflammatory drug, upon calpain was weaker than that of indomethacin. The degradation of myelin basic protein (MBP) by cathepsin B, a lysosomal cysteine protease, was significantly inhibited by indomethacin. It also inhibited the Ca2+-mediated degradation of neurofilament protein (NFP) in spinal cord homogenate. The extent of NFP degradation was analyzed by SDS-PAGE and the inhibition shown by indomethacin was weaker than that observed with leupeptin and the calpain inhibitor E64-d. The inhibitory effect of indomethacin on the activity of multicatalytic proteinase complex was negligible. These results suggest that indomethacin, a non-steroidal anti-inflammatory drug and cyclooxygenase inhibitor also inhibits proteinases, including cathepsin B and calpain.
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