Transplacental Exposure to AZT Induces Adverse Neurochemical and Behavioral Effects in a Mouse Model: Protection by L-Acetylcarnitine

Abstract

Maternal-fetal HIV-1 transmission can be prevented by administration of AZT, alone or in combination with other antiretroviral drugs to pregnant HIV-1-infected women and their newborns. In spite of the benefits deriving from this life-saving prophylactic therapy, there is still considerable uncertainty on the potential long-term adverse effects of antiretroviral drugs on exposed children. Clinical and experimental studies have consistently shown the occurrence of mitochondrial dysfunction and increased oxidative stress following prenatal treatment with antiretroviral drugs, and clinical evidence suggests that the developing brain is one of the targets of the toxic action of these compounds possibly resulting in behavioral problems. We intended to verify the effects on brain and behavior of mice exposed during gestation to AZT, the backbone of antiretroviral therapy during human pregnancy. We hypothesized that glutamate, a neurotransmitter involved in excitotoxicity and behavioral plasticity, could be one of the major actors in AZT-induced neurochemical and behavioral alterations. We also assessed the antioxidant and neuroprotective effect of L-acetylcarnitine, a compound that improves mitochondrial function and is successfully used to treat antiretroviral-induced polyneuropathy in HIV-1 patients. We found that transplacental exposure to AZT given per os to pregnant mice from day 10 of pregnancy to delivery impaired in the adult offspring spatial learning and memory, enhanced corticosterone release in response to acute stress, increased brain oxidative stress also at birth and markedly reduced expression of mGluR1 and mGluR5 subtypes and GluR1 subunit of AMPA receptors in the hippocampus. Notably, administration during the entire pregnancy of L-acetylcarnitine was effective in preventing/ameliorating the neurochemical, neuroendocrine and behavioral adverse effects induced by AZT in the offspring. The present preclinical findings provide a mechanistic hypothesis for the neurobehavioral effects of AZT and strongly suggest that preventive administration of L-acetylcarnitine might be effective in reducing the neurological side-effects of antiretroviral therapy in fetus/newborn.

In utero exposure to HIV and/or antiretroviral therapy: a systematic review of preclinical and clinical evidence of cognitive outcomes

“…Of the 20 preclinical articles, 15 evaluated exposure to ART monotherapy (either zidovudine or lamivudine) , two exposure to combination therapy (zidovudine and lamivudine) , two exposure to HIV‐derived proteins and one exposure to Simian Immunodeficiency Virus . Thirteen used a CD‐1 mouse model , five a Sprague‐Dawley rat model , one a pigtailed macaque model and one an undisclosed rat model . Sixteen studies looked at behaviour and development, while the remaining evaluated neurological biomarkers or structural differences in the brain.…”

High-throughput chinmedomics-based prediction of effective components and targets from herbal medicine AS1350

“…Nervous system diseases such as Alzheimer’s disease, depression, diabetes, and chronic fatigue syndrome were closely related to the reduction of acetylcarnitine323334. Therefore, long-term acetylcarnitine replacement therapy has been used for the treatment of these nervous system diseases35363738394041. The reduced levels of fatty acids in KYDS rats (Supplementary Figure 1a) suggested that the recovery of cells requires a lot of acetylcarnitine, α-linolenic acid, and other fatty acids.…”

Mitochondrial disturbances in HIV pregnancies

“…Subclinical mitochondrial molecular consequences from in-utero exposure of foetuses to HIV infection and antiretroviral drugs have not been completely elucidated as well as their association with the perinatal clinical outcomes in human pregnancies. Recently, adverse neurochemical and behavioural effects derived from transplacental exposure to zidovudine have been described in a mouse model together with a potential protector role of L-acetylcarnitine on mitochondrial function [17]. Recently, adverse neurochemical and behavioural effects derived from transplacental exposure to zidovudine have been described in a mouse model together with a potential protector role of L-acetylcarnitine on mitochondrial function [17].…”