Metabolic and neurologic consequences of chronic lopinavir/ritonavir administration to C57BL/6 mice.

Abstract

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 (50/12.5-200/50 mg/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 motor 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.

• Authors: Paul J Pistell, Sunita Gupta, Alecia G Knight, Michelle Domingue, Romina M Uranga, Donald K Ingram, Indu Kheterpal, Carmen Ruiz, Jeffrey N Keller, Annadora J Bruce-Keller
• Journal: Antiviral research (Antiviral Res) Vol. 88 Issue 3 Pg. 334-42 (Dec 2010) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 20970459 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Drug Combinations
• HIV Protease Inhibitors
• Pyrimidinones
• Lopinavir
• Ritonavir

Topics

• Animals
• Cognition (drug effects)
• Drug Administration Schedule
• Drug Combinations
• HIV (drug effects)
• HIV Infections (drug therapy)
• HIV Protease Inhibitors (adverse effects, metabolism, therapeutic use)
• Lopinavir
• Male
• Metabolic Syndrome (chemically induced, metabolism)
• Mice
• Mice, Inbred C57BL
• Motor Activity (drug effects)
• Pyrimidinones (administration & dosage, adverse effects, metabolism)
• Ritonavir (administration & dosage, adverse effects, metabolism)
• Weight Loss (drug effects)