Prenatal exposure to anti-HIV drugs: neurobehavioral effects of zidovudine (AZT) + lamivudine (3TC) treatment in mice.
ABSTRACT The new antiretroviral treatments that combine the zidovudine (AZT) regimen with lamivudine (3TC) appear as a cost-effective alternative to the current AZT monotherapy to prevent mother-to-fetus transmission of the HIV-1 virus. Recent evidence in uninfected children raised concern about the long-term effects of perinatal exposure to AZT and 3TC, especially when used in combination. Animal studies indicated behavioral changes in offspring exposed perinatally to both AZT and 3TC, whereas no animal data are available on the effects of the perinatal exposure to the AZT + 3TC combination on neurodevelopment.
Pregnant CD-1 mice received p.o. AZT + 3TC (160 and 500 mg/kg, respectively) or vehicle solution (NaCl 0.9%) twice daily from gestational day 10 to delivery. Maternal reproductive endpoints such as pregnancy length, abortion, litter size, sex ratio, and offspring viability were assessed. Pups were scored for different somatic and behavioral endpoints, including sensorimotor development, homing performance on postnatal day (PND) 10, passive-avoidance testing (PND 22-23), locomotor activity (PND 23), and social interaction (PND 35).
While no effects were observed on maternal reproductive endpoints, treated pups showed a long-lasting reduction of body weight and a slightly delayed maturation of placing and grasping reflexes and pole grasping. No effects on passive-avoidance or locomotor activity were found. AZT + 3TC-treated mice showed selective alterations in the social interaction test; the treated female offspring also displayed a significant reduction of affiliative interactions.
The combination of AZT and 3TC (1) induced small, but more marked, effects on somatic and sensorimotor development than either of these drugs administered separately; and (2) affected juvenile social behavior.
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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.PLoS ONE 10/2013; 8(2):e55753. · 3.53 Impact Factor
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ABSTRACT: Antagonists of group I metabotropic receptors exhibit anxiolytic action in adult rats. In immature animals we demonstrated anticonvulsant action of MPEP and AIDA, antagonists of group 5 and group 1, respectively. However, there are no developmental data on anxiolytic-like and learning actions of both compounds.This study investigated whether the anticonvulsant dose range of MPEP and AIDA affects anxiety-like behavior and learning ability in immature rats.Animals at 12, 18 and 25 postnatal (P) days received MPEP in doses of 10, 20 or 40 mg/kg i.p., AIDA in doses of 10 or 20 mg/kg i.p. In P18 and P25 rats anxiety-like behavior and locomotor activity were tested in the light–dark box and open-field test at 15 (1st session) and 60 (2nd session) minutes after drug administration. Learning ability of P12, P18, and P25 animals was examined in the homing response test 15 min after drug administration.Both antagonists exhibited anxiolytic-like action in the 1st session, effects in the 2nd session were less marked. In the open-field test both antagonists increased locomotion only in P18 animals. Age-dependent changes were found in the homing response test, the return latency being longer only in P12 animals. While MPEP in doses of 20- and 40-mg/kg in P12 and 40-mg/kg in P18 rats prolonged the homing response, AIDA did not affect the homing behavior.Both MPEP and AIDA exert anxiolytic-like effect also in immature rats. Except for the youngest animals no changes in learning ability in the homing response test were found.Behavioural brain research 12/2009; · 3.22 Impact Factor
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ABSTRACT: BACKGROUND:: This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants. METHODS:: HIV-exposed, uninfected infants (age 9-15 months) enrolled in SMARTT, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development, and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class), and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates. RESULTS:: As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black, 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (PIs; 9% of PI-containing regimens also included non-nucleoside reverse transcriptase inhibitors [NNRTIs]), 5% to regimens containing NNRTIs (without PI), and 14% to regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen, or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (p=0.01). CONCLUSIONS:: These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.The Pediatric Infectious Disease Journal 01/2013; · 3.14 Impact Factor