ABSTRACT
OBJECTIVES: Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aß) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aß peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aß generation and consequently impair cognitive function in mice. METHODS: TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid ß 1-42 (Aß1-42) and Aß deposits were measured in the hippocampal tissue upon completion of treatment. RESULTS: Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aß1-42 concentration. Nevirapine further upregulated BACE1 expression and Aß deposits. CONCLUSION: Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aß accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aß accumulation and the persistence of HANDs.
Subject(s)
AIDS Dementia Complex/chemically induced , Amyloid beta-Peptides/drug effects , Anti-HIV Agents/pharmacology , HIV Infections/drug therapy , Learning Disabilities/chemically induced , Memory/drug effects , Administration, Oral , Amyloid Precursor Protein Secretases/drug effects , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/drug effects , Amyloid beta-Protein Precursor/metabolism , Animals , Anti-HIV Agents/adverse effects , Anti-HIV Agents/toxicity , Aspartic Acid Endopeptidases/drug effects , Aspartic Acid Endopeptidases/metabolism , Brain/drug effects , Brain/metabolism , Brain/virology , Cognitive Dysfunction/chemically induced , Disease Models, Animal , Female , HIV Infections/complications , HIV Infections/virology , HIV-1/isolation & purification , Hippocampus/metabolism , Lipid Peroxidation/drug effects , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Nevirapine/adverse effects , Nevirapine/pharmacology , Nevirapine/toxicity , Tenofovir/adverse effects , Tenofovir/pharmacology , Tenofovir/toxicityABSTRACT
BACKGROUND: Current malaria treatment is either "anti-parasitic", "anti-infectivity" or both without addressing the pathophysiological derangement (anti-disease aspect) associated with the disease. Asiatic acid is a natural phytochemical with oxidant, antioxidant and anti-inflammatory properties whose effect on malarial and accompanying pathophysiology are yet to be investigated. Asiatic acid influence in P. berghei-infected Sprague Dawley rats on %parasitaemia and malarial anaemia were investigated. METHODS: Plasmodium berghei-infected rats (90-120 g) were orally administered with Asiatic acid (5, 10, 20 mg/kg) and 30 mg/kg chloroquine as a positive control. Changes in %parasitaemia and haematological parameters in Asiatic acid administered rats were monitored in a 21 day study and compared to controls. RESULTS: All animals developed stable parasitaemia (15-20 %) by day 7. Asiatic acid doses suppressed parasitaemia, normalised haematological measurements and influenced biophysical characteristics changes. Most positive changes were associated with intragastric administration of 10 mg/kg Asiatic acid dose. Peak %parasitaemia in Asiatic acid administration occurred at days 12 with a shorter time course compared to day 9 for chloroquine (30 mg/kg) treatment with a longer time course. CONCLUSIONS: Oral Asiatic acid administration influenced %parasitaemia suppression, ameliorated malarial anaemia and increased biophysical properties on infected animals. Asiatic acid may be a replacement alternative for chloroquine treatment with concomitant amelioration of malaria pathophysiology. Due to different action time courses, Asiatic acid and chloroquine may be possible candidates in combination therapy.