Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications

Fuu Jen Tsai, Mao Wang Ho, Chih Ho Lai, Chen Hsing Chou, Ju Pi Li, Chi Fung Cheng, Yang Chang Wu, Xiang Liu, Hsinyi Tsang, Ting Hsu Lin, Chiu Chu Liao, Shao Mei Huang, Jung Chun Lin, Chih Chien Lin, Ching Liang Hsieh, Wen Miin Liang, Ying Ju Lin

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Abstract

Antiretroviral (ART) drugs has previously been associated with lipodystrophic syndrome, metabolic consequences, and neuropsychiatric complications. ART drugs include three main classes of protease inhibitors (PIs), nucleoside analog reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our previous work demonstrated that a high risk of hyperlipidemia was observed in HIV-1-infected patients who received ART drugs in Taiwan. Patients receiving ART drugs containing either Abacavir/Lamivudine (Aba/Lam; NRTI/NRTI), Lamivudine/Zidovudine (Lam/Zido; NRTI/NRTI), or Lopinavir/Ritonavir (Lop/Rit; PI) have the highest risk of hyperlipidemia. The aim of this study was to investigate the effects of Aba/Lam (NRTI/NRTI), Lam/Zido (NRTI/NRTI), and Lop/Rit (PI) on metabolic and neurologic functions in mice. Groups of C57BL/6 mice were administered Aba/Lam, Lam/Zido, or Lop/Rit, orally, once daily for a period of 4 weeks. The mice were then extensively tested for metabolic and neurologic parameters. In addition, the effect of Aba/Lam, Lam/Zido, and Lop/Rit on lipid metabolism was assessed in HepG2 hepatocytes and during the 3T3-L1 preadipocyte differentiation. Administration with Aba/Lam caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in leptin serum levels. Administration with Lop/Rit also caused cognitive and motor impairments in mice, as well as their metabolic imbalances, including alterations in serum levels of total cholesterol, and HDL-c. Treatment of mice with Aba/Lam and Lop/Rit enhanced the lipid accumulation in the liver, and the decrease in AMP-activated protein kinase (AMPK) phosphorylation and/or its downstream target acetyl-CoA carboxylase (ACC) protein expression. In HepG2 hepatocytes, Aba/Lam, Lam/Zido, and Lop/Rit also enhanced the lipid accumulation and decreased phosphorylated AMPK and ACC proteins. In 3T3-L1 pre-adipocyte differentiation, Aba/Lam and Lop/Rit reduced adipogenesis by decreasing expression of transcription factor CEBPb, implicating the lipodystrophic syndrome. Our results demonstrate that daily oral administration of Aba/Lam and Lop/Rit may produce cognitive, motor, and metabolic impairments in mice, regardless of HIV-1 infection.

Original languageEnglish
Article number1004
JournalFrontiers in Pharmacology
Volume9
Issue numberSEP
DOIs
Publication statusPublished - Sep 4 2018

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Keywords

  • Antiretroviral drug
  • HIV-1
  • Lipodystrophy
  • Metabolic syndrome
  • Neurologic function

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Tsai, F. J., Ho, M. W., Lai, C. H., Chou, C. H., Li, J. P., Cheng, C. F., Wu, Y. C., Liu, X., Tsang, H., Lin, T. H., Liao, C. C., Huang, S. M., Lin, J. C., Lin, C. C., Hsieh, C. L., Liang, W. M., & Lin, Y. J. (2018). Evaluation of oral antiretroviral drugs in mice with metabolic and neurologic complications. Frontiers in Pharmacology, 9(SEP), [1004]. https://doi.org/10.3389/fphar.2018.01004