Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture

L.P Garcia,L Van De Wijer,S.I Hanswijk,J Rando,J.S Witteveen,A Middelman,R Ter Heine,Q De Mast,G.J.M Martens,A.J.A.M Van Der Ven,A.F.A Schellekens,J.R Homberg,S.M Kolk

doi:10.1016/j.bcp.2020.114050

L.P Garcia, L Van De Wijer + Show 11 more

Open Access

https://doi.org/10.1016/j.bcp.2020.114050

Copy DOI

Abstract

Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior.

Highlights

For the treatment of HIV infection, antiretroviral therapy (ART) is used, reducing morbidity and mortality significantly by decreasing retroviral replication [1]
We studied the effect of perinatal EFV exposure on prefrontal development, the cytoarchitecture of various subdomains of the medial (m)PFC of adult (PND75) offspring
The data suggest that animals perinatally exposed to EFV show changes in serotonergic and catecholaminergic innervation of the subdomains of the medial prefrontal cortex (mPFC) and that these changes persist into adulthood

Summary

Introduction

For the treatment of HIV infection, antiretroviral therapy (ART) is used, reducing morbidity and mortality significantly by decreasing retroviral replication [1]. EFV effectively reduces viral replication, displays a low degree of interaction with the other antiretroviral drugs, is low in costs, enables single daily dosing and has moderate side-effects which facilitates adherence to the treatment. Because of these characteristics, EFV is advised to be used by pregnant women to prevent the transfer of HIV from mother to child, decreasing the chance of infection to 5% [1,4,5,6,7]. EFV crosses the placenta freely [8] reaching the fetal blood. EFV is able to cross the blood-brain barrier [9]

Objectives

Methods

Results

Conclusion