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Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture.
Biochem Pharmacol. 2020 Aug; 178:114050.BP

Abstract

Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior.

Authors+Show Affiliations

Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands.Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands.Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands.Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands.Department of General Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Psychiatry, Donders Institute for Brain, Cognition, and Behaviour, Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Centre for Medical Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: judith.homberg@radboudumc.nl.Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands; Department of Molecular Neurobiology, Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University, Nijmegen, The Netherlands. Electronic address: s.kolk@donders.ru.nl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32446887

Citation

Garcia, L P., et al. "Perinatal Exposure of Rats to the HIV Drug Efavirenz Affects Medial Prefrontal Cortex Cytoarchitecture." Biochemical Pharmacology, vol. 178, 2020, p. 114050.
Garcia LP, Van de Wijer L, Hanswijk SI, et al. Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture. Biochem Pharmacol. 2020;178:114050.
Garcia, L. P., Van de Wijer, L., Hanswijk, S. I., Rando, J., Witteveen, J. S., Middelman, A., Ter Heine, R., de Mast, Q., Martens, G. J. M., van der Ven, A. J. A. M., Schellekens, A. F. A., Homberg, J. R., & Kolk, S. M. (2020). Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture. Biochemical Pharmacology, 178, 114050. https://doi.org/10.1016/j.bcp.2020.114050
Garcia LP, et al. Perinatal Exposure of Rats to the HIV Drug Efavirenz Affects Medial Prefrontal Cortex Cytoarchitecture. Biochem Pharmacol. 2020;178:114050. PubMed PMID: 32446887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Perinatal exposure of rats to the HIV drug efavirenz affects medial prefrontal cortex cytoarchitecture. AU - Garcia,L P, AU - Van de Wijer,L, AU - Hanswijk,S I, AU - Rando,J, AU - Witteveen,J S, AU - Middelman,A, AU - Ter Heine,R, AU - de Mast,Q, AU - Martens,G J M, AU - van der Ven,A J A M, AU - Schellekens,A F A, AU - Homberg,J R, AU - Kolk,S M, Y1 - 2020/05/22/ PY - 2020/03/24/received PY - 2020/05/19/accepted PY - 2020/5/25/pubmed PY - 2020/5/25/medline PY - 2020/5/25/entrez KW - Antiretroviral therapy KW - Corticogenesis KW - Efavirenz KW - PFC KW - Perinatal KW - Serotonin SP - 114050 EP - 114050 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 178 N2 - Efavirenz (EFV) is used for antiretroviral treatment of HIV infection, and successfully inhibits viral replication and mother-to-child transmission of HIV during pregnancy and childbirth. Unfortunately, the drug induces neuropsychiatric symptoms such as anxiety and depressed mood and potentially affects cognitive performance. EFV acts on, among others, the serotonin transporter and serotonin receptors that are expressed in the developing brain. Yet, how perinatal EFV exposure affects brain cytoarchitecture remains unclear. Here, we exposed pregnant and lactating rats to EFV, and examined in the medial prefrontal cortex (mPFC) of their adult offspring the effects of the maternal EFV exposure on cortical architecture. We observed a significant decrease in the number of cells, mainly mature neurons, in the infra/prelimbic and cingulate cortices of adult offspring. Next, we found an altered cortical cytoarchitecture characterized by a significant reduction in deep- and superficial-layer cells. This was accompanied by a sharp increase in programmed cell death, as we identified a significantly higher number of cleaved Caspase-3-positive cells. Finally, the serotonergic and dopaminergic innervation of the mPFC subdomains was increased. Thus, the perinatal exposure to EFV provoked in the mPFC of adult offspring cell death, significant changes in cytoarchitecture, and disturbances in serotonergic and dopaminergic innervation. Our results are important in the light of EFV treatment of HIV-positive pregnant women, and its effect on brain development and cognitive behavior. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/32446887/Perinatal_exposure_of_rats_to_the_HIV_drug_efavirenz_affects_medial_prefrontal_cortex_cytoarchitecture L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(20)30284-7 DB - PRIME DP - Unbound Medicine ER -
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