title: 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.
authors: Department of Physiology and Pharmacology Vittorio Erspamer, I Faculty of Medicine, Sapienza University of Rome, Rome, Italy.
authors: Anna Rita
authors: AR
authors: Zuena
authors: Chiara
authors: C
authors: Giuli
authors: Aldina
authors: A
authors: Venerosi Pesciolini
authors: Antonella
authors: A
authors: Tramutola
authors: Maria Antonietta
authors: MA
authors: Ajmone-Cat
authors: Carlo
authors: C
authors: Cinque
authors: Giovanni Sebastiano
authors: GS
authors: Alemà
authors: Angela
authors: A
authors: Giovine
authors: Gianfranco
authors: G
authors: Peluso
authors: Luisa
authors: L
authors: Minghetti
authors: Raffaella
authors: R
authors: Nicolai
authors: Gemma
authors: G
authors: Calamandrei
authors: Paola
authors: P
authors: Casolini
mesh_terms: D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001724:Birth Weight / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008431:Maternal-Fetal Exchange; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D013312:Stress, Physiological / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D018696:Neuroprotective Agents; D015215:Zidovudine; D000108:Acetylcarnitine