Prolonged perinatal exposure to AZT affects aggressive behaviour of adult CD-1 mice

Venerosi, Aldina; Cirulli, Francesca; Lilp, I. G.; Fiore, M.; Calamandrei, Gemma; Alleva, Enrico

doi:10.1007/s002130000455

Cited by 18 publications

(12 citation statements)

References 26 publications

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“…In a developmental perspective, AZT treatment could interfere with the physiological setting of HPA axis activity, thus reducing the capability to respond adaptively to environmental challenges. Previous studies from our laboratories indicate that mice exposed to AZT during development present abnormal reaction to novelty, and that pre- and/or postnatally AZT exposed adult male mice show maladaptive intraspecific social/aggressive behavior depending on the length of exposure [23], [24].…”

Section: Discussionmentioning

confidence: 89%

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

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 89%

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

et al. 2013

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“…In yet another study of prenatal exposure of 40 mg/day of ZDV in inpatas monkeys showed damage of cerebral mitochondria [28]. Neurobehavioural changes reported by different authors, revealed the cerebral effect of ZDV [29][30][31]. In-vitro study of brain cells from fetal mouse exposed to ZDV showed slightly more cytotoxic effect as compared to other tissues of the body [32].…”

Section: Discussionmentioning

confidence: 96%

Histochemical Changes in the Cerebellum of Wistar Rats Administered with Oral Doses of Zidovudine

Peter

Ekandem²,

Igiri³

et al. 2015

BIO

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Zidovudine is a drugs used in the management of Human Immunodeficiency Virus (HIV) and AcquiredImmunodeficiency Syndrome (AIDS) infection in sub-Saharan Africa in combination with other drugs. The objective of this research was to investigate the potential harmful effects of this drug on the histology of the cerebellum of Wistar rats. Twenty male Wistar rats were used for this study. The rats were divided into 2 groups of 10 rats each. Group A served as the control and was administered with 1 ml of distill water, while group B was administered with 8.57mg/kg of zidovudine daily for 30 days, after which the rats where sacrificed and each cerebellum was harvested, processed and stained using haematoxylin and Eosin (H/E), silver impregnation method. Paraffin impregnated Glial Fibrilar Acidic Protein (GFAP), Neuron Specific Enolase (NSE) and Neurofilament (NF) immunochemistry methods. Stained slides were viewed using light microscope. Results showed that, the cerebellum of Groups B animals were affected with moderate to severe shrinking and distortion of the Purkinje cells and granular cells, when compared with the control. Group B animals, also showed more expression of GFAP, NSE and NF staining in their cerebellum than the control. This suggests that zidovudine is harmful to the cerebellum and should be taken with caution.

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“…Alterations of intraspecific social/aggressive behavior were also evidenced either in adult mice prenatally exposed to AZT (0.4 or 0.8 mg/ml in drinking water from gestational day 10 to birth) or in mice subjected to a more extended AZT treatment (160 mg/kg AZT given to the mother per os twice daily, during pregnancy from gestation day 10, through delivery, and until lactation day 10). Specifically, perinatal AZT exposure reduced attack behavior of adult mice, while increasing the frequency of "submissive" behaviors [150,151]. Prenatal exposure to 3TC (125,250 or 500 mg/kg per os twice daily), a compound that shows lower toxicity than AZT, was also found to induce longterm behavioral effects in the offspring, namely decreased habituation when exploring a novel environment at weaning [152] alteration in locomotor behavior and in responding to the muscarinic antagonist scopolamine at adulthood [153].…”

Section: Nucleoside Analogue Antiretroviralsmentioning

confidence: 96%

Delayed Developmental Effects Following Prenatal Exposure to Drugs

Mantovani¹,

Calamandrei

2001

CPD

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Increasing evidence points to the possible risks of delayed effects upon prenatal exposure to chemicals; the evaluation of such effects may pose serious problems to clinicians, epidemiologists and toxicologists. In fact, several systems (e.g., nervous, excretory) show important developmental processes well after the organogenetic period, up to the postnatal phase; accordingly, these are also expected to be sensitive targets of developmental toxicants, resulting in impairment of the function and/or functional reserve. This review describes the effects of several groups of drugs on the functional maturation and histogenesis of the kidney (e.g., aminoglycosides, angiotensin-converting enzyme inhibitors, indomethacin) and brain (e.g., anticonvulsivants, antiretroviral compounds, benzodiazepines) upon exposure in utero of humans and laboratory animals. The available data stress the importance for risk assessment of an adequate knowledge of both developmental biology and mechanisms of toxicity. The design of developmental toxicity studies should allow an evaluation of targets most relevant for a given drug (or group of drugs); moreover, the analysis of functional development should receive the due attention within the safety assessment of chemicals.

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Prolonged perinatal exposure to AZT affects aggressive behaviour of adult CD-1 mice

Abstract: Overall, these data indicate that perinatal exposure to drugs such as AZT exerts selective effects on the developing CNS, resulting in long-term behavioural disturbances. Future studies will need to address the issue of the specific mechanisms underlying these effects.

Cited by 18 publications

References 26 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

Histochemical Changes in the Cerebellum of Wistar Rats Administered with Oral Doses of Zidovudine

Delayed Developmental Effects Following Prenatal Exposure to Drugs

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