Washington: Antiretroviral drugs -life-changing therapies for HIV patients - may take a toll on the patient's brain, according to scientists who found that the medicines lead to forgetfulness, confusion and behavioural changes.Mounting evidence has implicated these drugs in contributing to HIV-associated neurocognitive disorders (HAND). Researchers from the University of Pennsylvania in the US have now pinpointed some of the key players in causing neuronal damage. The research suggests that certain protease inhibitors, among the most effective HIV drugs, lead to the production of the peptide beta amyloid, often linked to Alzheimer's disease.The drugs prompt an increase in levels of the enzyme that cleaves the amyloid precursor protein, APP, to produce beta amyloid, which is responsible for the damage to neurons. Notably, inhibiting that enzyme, called BACE1, protected human and rodent brain cells from harm, suggesting that targeting this pathway with a new drug could minimise damage to neurons in patients on antiretroviral therapies."Protease inhibitors are very effective antiviral therapies, but they do have inherent toxicities," said Kelly Jordan-Sciutto, professor at University of Pennsylvania. "Our findings may cause us to rethink how we're using these drugs and even consider developing an adjunctive therapy to reduce some of these negative effects," said Jordan-Sciutto.Protease inhibitors such as ritonavir and saquinavir are a key part of the drug cocktail that has reduced mortality in HIV-infected people by 50 per cent. These protease inhibitors are widely used in Africa and other developing areas hit hard by HIV/AIDS. They work by blocking viral enzymes necessary for creating infectious particles that allow the virus to spread through the body.Previous research have shown that protease inhibitors can have toxic effects on the central nervous system. One study, demonstrated that they triggered the activation of stress-response pathways, including oxidative stress and a process called the unfolded-protein response, or UPR. The study appears in the American Journal of Pathology.