Co-exposure of antiretroviral therapy and nicotine induces brain metabolic impairments in a mouse model

Gabriel C Gauthier; Emma G Foster; Mariano G Uberti; Balasrinivasa R Sajja; Aditya N Bade; Yutong Liu

doi:10.1515/nipt-2025-0006

Co-exposure of antiretroviral therapy and nicotine induces brain metabolic impairments in a mouse model

NeuroImmune Pharm Ther. 2025 May 22;4(2):265-271. doi: 10.1515/nipt-2025-0006. eCollection 2025 Jun.

Authors

Gabriel C Gauthier¹, Emma G Foster², Mariano G Uberti¹, Balasrinivasa R Sajja¹, Aditya N Bade², Yutong Liu^{1

2}

Affiliations

¹ Department of Radiology, University of Nebraska Medical Center, Omaha, NE, USA.
² Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.

Abstract

Objectives: Anti-retroviral therapy (ART) drastically improves human immunodeficiency virus type 1 (HIV-1) outcomes, but may induce adverse neurochemical changes. Interactive effects of ART with recreational drugs are unknown. Notably, people living with HIV-1 (PLWH) smoke at twice the rate of the general population and are more prone to tobacco-linked illness. Thus, chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) was employed to investigate potential ART-nicotine co-morbid neuro-metabolomic influence.

Methods: 16 healthy, male, C57BL/6 mice were divided into four groups: vehicle-treatment, ART-treatment, nicotine-treatment, and ART-nicotine co-treatment. CEST-MRI was performed at day 12 following daily treatments to determine effects on neurometabolic profiles. Magnetic resonance spectroscopy (MRS) was used to contextualize metabolic outcomes.

Results: CEST-MRI detected significantly lower 3 ppm contrast in ART, nicotine, and co-treatment groups, suggesting ART- and nicotine-linked glutamate alteration. Co-treatment induced significantly higher hippocampal nuclear Overhauser effects (NOE) compared to ART-treatment, whereas individual treatments lacked effect on NOE, indicating adverse effect on membrane lipids. MRS confirmed CEST findings of membrane turnover, detecting significantly lower hippocampal total choline across all groups compared to controls.

Conclusions: CEST-MRI detects adverse neuro-metabolomic alterations induced by ART- and nicotine-exposure. This warrants investigation with HIV-1-infection to assess potential influences of co-exposure on PLWH cognition.

Keywords: antiretroviral therapy; chemical exchange saturation transfer; human immunodeficient virus; magnetic resonance imaging; magnetic resonance spectroscopy; nicotine.