Metabolic and neurologic consequences of chronic lopinavir/ritonavir administration to C57BL/6 mice.
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.
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, 70808, United States.
Paul J
PJ
Pistell
Sunita
S
Gupta
Alecia G
AG
Knight
Michelle
M
Domingue
Romina M
RM
Uranga
Donald K
DK
Ingram
Indu
I
Kheterpal
Carmen
C
Ruiz
Jeffrey N
JN
Keller
Annadora J
AJ
Bruce-Keller
D000818:Animals; D003071:Cognition / Q000187:drug effects; D004334:Drug Administration Schedule; D004338:Drug Combinations; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D061466:Lopinavir; D008297:Male; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D019438:Ritonavir