Neurodevelopmental and behavioral consequences of perinatal exposure to the HIV drug efavirenz in a rodent model

Abstract

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.

Development of prefrontal cortex

“…Another field of recent study is the perinatal exposure to pharmaceuticals given to treat the pregnant mother. 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 ]. Although maternal stress itself can be detrimental to brain development in general and the developing PFC in particular (for review see [ 125 ]), treatments against maternal depression such as SSRIs can cause substantial structural damage to prefrontal subdomains [ 125 , 128 ].…”

Comparison of Efavirenz and Doravirine Developmental Toxicity in an Embryo Animal Model

“…Neuropsychological adverse effects have been explained through the direct interference of EFV with neurotransmitters. EFV acts as a serotonin (5-HT)-6 receptor inverse agonist, as a 5-HT2A, 5-HT2C, and 5-HT3A receptor antagonist, and a blocker of the 5-HT transporter (5-HTT) [20,40,41]. The 5-HT2, 5-HT3, and 5-HT6 receptors are involved in cell division, differentiation, survival, and in the neuronal migration pathway, and EFV, as a 5-HT receptor (ant)agonist, could directly interfere with these processes, consequently leading to neuronal cell death.…”

“…Moreover, EFV induces neuronal damage dosedependently in vitro [14,15]. EFV-exposed rats showed delayed maturation (delayed eyelid opening), delayed reflex and motor development, and reduced body weights throughout the course of their lives [20]. EFV exposure also causes structural changes to the motor cortical layers, with reductions in the number of mature neurons observed probably due to neuronal apoptosis [20].…”

“…EFV-exposed rats showed delayed maturation (delayed eyelid opening), delayed reflex and motor development, and reduced body weights throughout the course of their lives [20]. EFV exposure also causes structural changes to the motor cortical layers, with reductions in the number of mature neurons observed probably due to neuronal apoptosis [20]. Acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior, with both effects having been found to be dose-related in mice.…”

“…Swimming behavior is a result of the activity of the nervous system, which is necessary for fish to survive and reproduce in the wild. Considering the above results on the effects of DOR and EFV on the hatching rate and apoptosis in the developing head region, the dose-dependent neuropsychological symptoms associated with EFV treatment [19,20], the described association between the in utero exposure to EFV and the lower behavioral self-regulatory abilities and motor skills of exposed children [7], but the less frequent and milder adverse effects of DOR associated with the nervous system in humans [2,3], we decided to assess swimming behavior of our treated…”