Neurocognitive and Neuroarchitectural Changes in the Prefrontal Cortex of Wistar Rats Treated with Highly Active Antiretroviral Therapy

Abstract

The use of highly active antiretroviral therapy has proven to be highly effective in the treatment of human immunodeficiency virus 1 (HIV-1) infection. However, its impact on cognition has not been fully explored. This study was designed to assess the impacts of antiretroviral therapy on cognitive function and histoarchitecture of the prefrontal cortex of Wistar rats. Forty adult male Wistar rats weighing 180-200 g were randomly assigned to 4 groups: control, tenofovir, lamivudine and efavirenz (n=10), which received 1 ml distilled water and 6 mg/kg, 6 mg/kg and 12 mg/kg, respectively. Spatial memory scores were assessed using the Y-maze test. Following behavioural studies, the animals were euthanized, and their whole brains harvested. The prefrontal cortex was sectioned and processed for oxidative stress, histological and immunohistochemical analyses. There was a significant decrease in percentage alternation evaluated from the right/wrong decisions scored from the tenofovir and lamivudine groups, compared to the control group (p<0.05). malondialdehyde (MDA) and reduced glutathione (GSH) levels were elevated following lamivudine and tenofovir exposure in the rats’ prefrontal cortices, respectively, compared to control (p<0.05). There were also significant alterations of cortical pyramidal cells in the tenofovir and lamivudine groups. Additionally, marked astrogliosis with increased glial fibrillary acidic protein expression was observed, consistent with the structural alterations, especially in the lamivudine group. Our findings suggest that, of the three highly active antiretroviral therapy (HAART) drugs studied, lamivudine may be a major culprit in the progressive neurological damage and cognitive impairment in HIV-infected individuals on HAART.