The potential therapeutic advantages of the encapsulation of idebenone within pegylated liposomes were investigated in vitro on primary cortical astrocytes of rats. In particular, both the concentration-dependent effects and the therapeutic effectiveness toward excitotoxic injury, elicited by chronic treatment with ethanol (100 muM) for 12 days, were evaluated. The following parameters were taken into consideration to assay free or liposom ally entrapped idebenone: lactic dehydrogenase release, respiratory capacity measured by tetrazolium salt conversion, glutamine synthetase, and the levels of constitutive and inducible 70-kD a heat shock proteins. To evaluate the effects on astrocytes, three different drug concentrations were used (0.5 muM, 5 muM,and 50 muM). At the highest concentration used (50 muM), a toxic effect of the free and liposomally entrapped drug was observed. Toxic effects seem to be due to a cellular membrane perturbation, as demonstrated by 45 Ca2+ permeation. The therapeutic effect of free or liposomally entrapped idebenone on ethanol-induced injury of primary cortical astrocytes was evaluated as a function of the drug concentration. The drug liposome formulation was much more effective than the free drug in counteracting the ethanol-induced damage in astrocytes, i.e., 10-times-lower doses of liposomally entrapped idebenone are able to provide a greater protective action than the free drug. The improved action. of idebenone-loaded liposomes is probably due to the greater drug bioavailability at the cellular level. (C) 2004 Wiley-Liss, Inc. and the American Pharmacists Association.
Tolerability and Improved Protective Action of Idebenone-Loaded Pegylated Liposomes on Ethanol-Induced Injury in Primary Cortical Astrocytes
Paolino D;FRESTA M
2004-01-01
Abstract
The potential therapeutic advantages of the encapsulation of idebenone within pegylated liposomes were investigated in vitro on primary cortical astrocytes of rats. In particular, both the concentration-dependent effects and the therapeutic effectiveness toward excitotoxic injury, elicited by chronic treatment with ethanol (100 muM) for 12 days, were evaluated. The following parameters were taken into consideration to assay free or liposom ally entrapped idebenone: lactic dehydrogenase release, respiratory capacity measured by tetrazolium salt conversion, glutamine synthetase, and the levels of constitutive and inducible 70-kD a heat shock proteins. To evaluate the effects on astrocytes, three different drug concentrations were used (0.5 muM, 5 muM,and 50 muM). At the highest concentration used (50 muM), a toxic effect of the free and liposomally entrapped drug was observed. Toxic effects seem to be due to a cellular membrane perturbation, as demonstrated by 45 Ca2+ permeation. The therapeutic effect of free or liposomally entrapped idebenone on ethanol-induced injury of primary cortical astrocytes was evaluated as a function of the drug concentration. The drug liposome formulation was much more effective than the free drug in counteracting the ethanol-induced damage in astrocytes, i.e., 10-times-lower doses of liposomally entrapped idebenone are able to provide a greater protective action than the free drug. The improved action. of idebenone-loaded liposomes is probably due to the greater drug bioavailability at the cellular level. (C) 2004 Wiley-Liss, Inc. and the American Pharmacists Association.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
