CEST MRI detects antiretroviral drug toxicities in the developing mouse brain

Area of Science:

• Neuroscience
• Biomedical Imaging
• Pharmacology

Background:

• Antiretroviral drugs (ARVs) prevent mother-to-child HIV-1 transmission, increasing HIV-1-exposed uninfected (HEU) children.
• HEU children face increased neurodevelopmental risks due to *in utero* exposure to HIV-1 and ARVs.

Purpose of the Study:

• To investigate chemical exchange saturation transfer (CEST) MRI for monitoring *in utero* ARV exposure-associated neurodevelopmental dysregulations in a mouse model.
• To assess dolutegravir (DTG)-induced metabolic and macromolecular changes in embryo brains using CEST MRI.
• To evaluate the therapeutic potential of long-acting nanoformulation DTG delivery.

Main Methods:

• Utilized a mouse model to study *in utero* exposure to dolutegravir (DTG).
• Employed chemical exchange saturation transfer (CEST) MRI to measure brain metabolomic and macromolecular alterations at -3.5 ppm and 3.5 ppm.
• Performed non-targeted metabolomics to confirm CEST findings and analyze differential metabolite expression.

Main Results:

• CEST MRI detected hyperintensities in mouse embryo brains exposed to DTG, indicating altered lipids, proteins, and glutamate levels.
• Metabolomic analysis confirmed DTG-induced deficits in energy production, cell metabolism, and protein modification.
• CEST MRI demonstrated that nanoformulated DTG mitigated ARV-associated neurodevelopmental impairments.

Conclusions:

• CEST MRI serves as a non-invasive imaging biomarker for detecting ARV-induced neurodevelopmental deficits in embryos.
• DTG exposure *in utero* causes specific metabolomic and macromolecular changes in the developing brain.
• Long-acting nanoformulation of DTG shows promise in preventing ARV-related neurodevelopmental issues.