Schematic representation of the mechanism of HIV viral proteins and methamphetamine-induced oxidative damage to the blood brain barrier, and the protective role of the thiol antioxidant N-acetylcysteineamide (NACA). HIV viral protein gp120 and Tat, along with methamphetamine, synergistically increases oxidative stress induced damage by lowering the level of antioxidant enzymes GSH and GPx and increasing oxidative modification of proteins and lipids in the brain. This leads to decrease in the expression of tight junction proteins in the blood brain barrier (BBB), as a result of which the BBB permeability increases. Further, oxidative modification of the tight junction proteins also aids in increase in permeability of the BBB, leading to increased passage of toxins and leukocytes in to the brain leading to severe dementia in HIV patients abusing methamphetamine. However, pretreatment with the novel antioxidant, NACA partially restores the oxidative balance in the brain and maintains the BBB permeability, thus protecting the brain from toxins and inflammation.