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

doi:10.3389/fphar.2018.01004

Evaluation of Oral Antiretroviral Drugs in Mice With Metabolic and Neurologic Complications

Front Pharmacol. 2018 Sep 4:9:1004. doi: 10.3389/fphar.2018.01004. eCollection 2018.

Authors

Fuu-Jen Tsai^{1

2

3}, Mao-Wang Ho⁴, Chih-Ho Lai^{5

6}, Chen-Hsing Chou^{1

7}, Ju-Pi Li^{1

8}, Chi-Fung Cheng^{2

7}, Yang-Chang Wu⁹, Xiang Liu¹⁰, Hsinyi Tsang¹⁰, Ting-Hsu Lin², Chiu-Chu Liao², Shao-Mei Huang², Jung-Chun Lin¹¹, Chih-Chien Lin¹², Ching-Liang Hsieh¹³, Wen-Miin Liang⁷, Ying-Ju Lin^{1

2}

Affiliations

¹ School of Chinese Medicine, China Medical University, Taichung, Taiwan.
² Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
³ Department of Biotechnology, Asia University, Taichung, Taiwan.
⁴ Section of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁵ Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan.
⁶ Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan.
⁷ Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan.
⁸ Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan.
⁹ Graduate Institute of Natural Products and Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁰ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.
¹¹ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹² Department of Cosmetic Science, Providence University, Taichung, Taiwan.
¹³ Graduate Institute of Integrated Medicine, School of Chinese Medicine, China Medical University, Taichung, Taiwan.

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.

Keywords: HIV-1; antiretroviral drug; lipodystrophy; metabolic syndrome; neurologic function.