Metabolic and Neurologic Consequences of Chronic Lopinavir/Ritonavir Administration to C57BL/6 mice

PISTELL, PAUL J.; GUPTA, SUNITA; KNIGHT, ALECIA G.; DOMINGUE, MICHELLE; URANGA, ROMINA M.; INGRAM, DONALD K.; KHETERPAL, INDU; RUIZ, CARMEN; KELLER, JEFFREY N.; BRUCE-KELLER, ANNADORA J.

ANTIVIRAL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Netherlands; Año: 2010

0166-3542

It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5 to 200/50mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motoric functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders.