Perinatal AZT exposure alters the acoustic and tactile startle response to 8-OH-DPAT and apomorphine in adult rats

Melnick, Susan M.; Weedon, Jeremy; Dow-Edwards, Diana

doi:10.1016/j.ntt.2005.05.010

Cited by 4 publications

(8 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, a recent study provided evidence that in utero exposure to the NRTI, AZT and Lamivudine, is associated with brain mitochondrial impairment, which progresses over time and might possibly end up in delayed neurobehavioral effects [32]. In laboratory rodents, developmental exposure to AZT produces both early and delayed behavioral changes in offspring including alteration in sensorimotor maturation, social/aggressive behavior, responses to environmental stressors and learning abilities [19]–[30]. Altogether, these data pointed to the potential risk of sub-clinical side effects of ARV therapy on the developing brain that may go undetected in clinical and epidemiological studies.…”

Section: Discussionmentioning

confidence: 99%

“…These studies have clearly shown that developmental exposure to AZT produces both early and delayed behavioral changes in offspring. The behavioral endpoints affected by transplacental exposure to AZT include sensor and motor maturation, learning abilities, social/aggressive behavior, exploration levels [19]–[30]. Knowledge of the neural bases of behavioral AZT toxicity is so far very limited, but it has been clearly shown that at doses comparable to those used in clinical practice, AZT acts as a mitochondrial toxin in rodents and non-human primates [31]–[36].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Perinatal zidovudine exposure enhanced startle responses following injection of amphetamine , apomorphine and serotonin agonist . These results may suggest abnormal nerve conduction velocity and long‐term functional alterations within the startle reflex pathways .…”

Section: Resultsmentioning

confidence: 90%

“…Exposure to zidovudine in utero was associated with a dose‐dependent increase in peak latency in the acoustic startle response and enhanced tactile stimuli response . Perinatal zidovudine exposure enhanced startle responses following injection of amphetamine , apomorphine and serotonin agonist .…”

Section: Resultsmentioning

confidence: 98%

“…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.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2019

View full text Add to dashboard Cite

Introducion With the increasing number of children exposed to HIV or antiretroviral therapy in utero, there are concerns that this population may have worse neurodevelopmental outcomes compared to those who are unexposed. The objective of this study was to systematically review the clinical and preclinical literature on the effects of in utero exposure to HIV and/or antiretroviral therapy ( ART ) on neurodevelopment. Methods We systematically searched OVID Medline, Psyc INFO and Embase, as well as the Cochrane Collaborative Database, Google Scholar and bibliographies of pertinent articles. Titles, abstracts, and full texts were assessed independently by two reviewers. Data from included studies were extracted. Results are summarized qualitatively. Results The search yielded 3027 unique titles. Of the 255 critically reviewed full‐text articles, 25 met inclusion criteria for the systematic review. Five articles studied human subjects and looked at brain structure and function. The remaining 20 articles were preclinical studies that mostly focused on behavioural assessments in animal models. The few clinical studies had mixed results. Some clinical studies found no difference in white matter while others noted higher fractional anisotropy and lower mean diffusivity in the brains of HIV ‐exposed uninfected children compared to HIV ‐unexposed uninfected children, correlating with abnormal neurobehavioral scores. Preclinical studies focused primarily on neurobehavioral changes resulting from monotherapy with either zidovudine or lamivudine. Various developmental and behavioural changes were noted in preclinical studies with ART exposure, including decreased grooming, decreased attention, memory deficits and fewer behaviours associated with appropriate social interaction. Conclusions While the existing literature suggests that there may be some neurobehavioral differences associated with HIV and ART exposure, limited data are available to substantially support these claims. More research is needed comparing neurobiological factors between HIV ‐exposed uninfected and HIV ‐unexposed uninfected children and using exposures consistent with current clinical care.

show abstract

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

Zuena¹,

Giuli²,

Venerosi³

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

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 lifesaving 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 sideeffects of antiretroviral therapy in fetus/newborn.

show abstract

Perinatal AZT exposure alters the acoustic and tactile startle response to 8-OH-DPAT and apomorphine in adult rats

Cited by 4 publications

References 73 publications

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

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

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

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

Contact Info

Product

Resources

About