N-acetylcysteine amide (NACA) is the amide derivative of N-acetylcysteine (NAC) that is rapidly converted to NAC after systemic administration. N-acetylcysteine amide has emerged as a promising thiol antioxidant for multiple indications. NACA could cross the blood-brain barrier. It also chelate Cu2+ (which catalyzes free radical formation), scavenge free-radicals, protect red blood cells from oxidative stress. Moreover, it prevents reactive oxygen species (ROS)-induced activation of JNK, mitogen-activated protein kinase MAPK (p38), and matrix metalloproteinases. Doxorubicin (DOX) is a potent and broad-spectrum antineoplastic agent used in the treatment of a variety of cancers, including leukemias, lymphomas, and breast, lung, and ovarian cancers. N-acetylcysteine amide decreases oxidative stress but not cell death induced by DOX in H9c2 cardiomyocytes.
In H9c2 cells, both N-acetylcysteine amide and NAC induced significant cytotoxicity at concentrations ≥ 10 mM and 2.0 mM, respectively. N-acetylcysteine amide or NAC further reduces cell viability by 80% at 20 mM. N-acetylcysteine amide is capable of restoring GSH, CYS, and GSH/GSSG ratio that DOX reduces. It also prevents the DOX-induced decrease of GR activity. Though N-acetylcysteine amide is able to provide oxidative relief, it only has a minimal protective effect on DOX-induced cytotoxicity. N-acetylcysteine amide prevents oxidative stress by elevation of GSH and CYS, reduction of ROS and lipid peroxidation, and restoration of antioxidant enzyme activities. In addition, N-acetylcysteine amide partially protected cells from IH-induced death by reverting the expression of Bcl-2, Mc1-1, and Bax expression through inhibition of p38 MAPK and iNOS pathway. N-acetylcysteine amide also inhibits cataract formation by limiting protein carbonylation, lipid peroxidation, and redox system components, as well as replenishing antioxidant enzymes.
N-Acetylcysteine amide is a cell membranes and blood-brain barrier permeant thiol antioxidant and neuroprotective agent.
Shi R, et al. BMC Pharmacol. 2009;9:7. Published 2009 Apr 15.