Neurodevelopmental and behavioral consequences of perinatal exposure to the HIV drug efavirenz in a rodent model
Open accessAbstract
Efavirenz is recommended as a preferred first-line drug for women of childbearing potential living with human immunodeficiency virus. Efavirenz is known for its central nervous system side effects, which are partly mediated by serotonergic actions. The neurotransmitter serotonin exerts neurotrophic effects during neurodevelopment and antenatal exposure to serotonergic agents has been linked to developmental delay. Although the teratogenic risks of efavirenz appear to be minimal, data on long-term developmental effects remain scarce. Here, we aimed to investigate the short- and long-term behavioral and neurodevelopmental effects of perinatal efavirenz exposure. We treated pregnant rats from gestation day 1 until postnatal day 7 with efavirenz (100 mg/kg) or vehicle. We measured behavioral outcomes in male offspring during the first 3 postnatal weeks, adolescence and adulthood, and conducted brain immunohistochemistry analyses after sacrifice. Perinatal efavirenz exposure resulted in reduced body weight and delayed reflex and motor development. During adulthood, we observed a decrease in the total number of cells and mature neurons in the motor cortex, as well as an increase in the number of Caspase-3-positive cells and serotonergic fibers. Together, our data show a developmental delay and persistent changes in the brain motor cortex of rats exposed to efavirenz perinatally. Because over 1 million children born annually are exposed to antiretroviral therapy, our findings underline the need for clinical studies on long-term neurodevelopmental outcomes of perinatal exposure to efavirenz.
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Perinatal exposure to antiretroviral drugs such as Efavirenz (EFV) to treat HIV leads to an altered prefrontal cytoarchitecture.
“Perinatal HIV infections can alter the course of brain development (see below), on the other hand perinatal exposure to antiretroviral drugs such as Efavirenz (EFV) to treat HIV leads to an altered prefrontal cytoarchitecture [335, 336].”
From Development of prefrontal cortex (2022) · cites this paper as [335]
The Discussion reports persistent changes in M1 cytoarchitecture after perinatal efavirenz exposure in rats, supporting a cortical effect. It identifies M1 as the motor cortex, not the prefrontal cortex; the Introduction’s mention of prefrontal changes concerns other serotonergic manipulations, not efavirenz. The study also does not establish this effect in humans. (LLM, conf=0.88)
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Development of prefrontal cortex
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“Perinatal HIV infections can alter the course of brain development (see below), on the other hand perinatal exposure to antiretroviral drugs such as Efavirenz (EFV) to treat HIV leads to an altered prefrontal cytoarchitecture [335, 336].”
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- Authors
- van de Wijer, L., Garcia, L. P., Hanswijk, S. I., Rando, J., Middelman, A., ter Heine, R., Mast, Q. D., Martens, G. J. M., van der Ven, A. J. A. M., Kolk, S. M., Schellekens, A. F. A., & Homberg, J. R.
- Affiliations
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Corresponding author
- Kolk, Sharon M.
- Schellekens, Arnt F. A.
- Homberg, Judith R.
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2019-02-11
- Volume
- 9
- Issue
- 1
- Pages
- 84-84
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC6370772
- OpenAlex
- W2913511733
- Cited by
- 13
- References
- 54
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 2
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Radboud Universitair Medisch Centrum (RvB14.51623)
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (11914/13-0)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Keywords
- efavirenz, HIV, brain development, behavioral development, motor cortex, serotonergic neurons, caspase-3, neuronal apoptosis, developmental delay, teratogenicity, antiretroviral drugs
- MeSH terms
- Alkynes, Animals, Body Weight, Developmental Disabilities, Cyclopropanes, Female, Male, Motor Activity, Motor Cortex, Neurons, Pregnancy, Prenatal Exposure Delayed Effects, Serotonin, Reflex, Startle, HIV Infections, Rats, Wistar, Benzoxazines, Rats
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