In vitro and Ex vivo Neurotoxic Effects of Efavirenz are Greater than Those of Other Common Antiretrovirals
| Autor: | Iris Speigel, Courtney C. Elder, Edyta K. Bichler, William R. Tyor, Shavonne L Teng, Paul S. García, Vincent T. Ciavatta |
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| Rok vydání: | 2017 |
| Předmět: |
Cyclopropanes
Male 0301 basic medicine Efavirenz Anti-HIV Agents Cell Survival medicine.medical_treatment Pharmacology Biology Biochemistry Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Amprenavir chemistry.chemical_compound 0302 clinical medicine immune system diseases medicine Animals Cells Cultured Cerebral Cortex Neurons Protease Dose-Response Relationship Drug Reverse-transcriptase inhibitor Stavudine Neurotoxicity virus diseases General Medicine medicine.disease Reverse transcriptase Benzoxazines Rats 030104 developmental biology Animals Newborn Anti-Retroviral Agents chemistry Alkynes Reverse Transcriptase Inhibitors 030217 neurology & neurosurgery Ex vivo medicine.drug |
| Zdroj: | Neurochemical Research. 42:3220-3232 |
| ISSN: | 1573-6903 0364-3190 |
| DOI: | 10.1007/s11064-017-2358-x |
| Popis: | Although antiretroviral (ARV) therapy has reduced the incidence of severe dementia associated with HIV infection, there has been a rise in milder neurocognitive complaints. Data from HIV patients taking ARVs have shown measurable neurocognitive improvements during drug cessation, suggesting a neurotoxic role of the therapy itself. Mechanisms underlying potential ARV neurotoxicity have not been thoroughly investigated, however pathologic oxidative stress and mitochondrial dysfunction have been suspected. Using DIV 16 primary rat cortical neuron culture, we tested eight ARVs from the three most commonly prescribed ARV classes: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) for effects on neuron viability and morphology after 24 h of drug exposure. Of the tested NRTIs, only stavudine at nearly 100 times the target plasma concentration affected neuron viability with no appreciable change in morphology. Dideoxyinosine induced dendritic simplification at 100 times target plasma concentrations, but did not adversely affect viability. The sole NtRTI, tenofovir, induced dendritic simplification at approximately 3-4 times target plasma concentration, but did not affect viability. Of the tested PIs, only amprenavir decreased neuron viability at nearly 100 times the target plasma concentration. The non-nucleoside reverse transcriptase inhibitor, efavirenz, consistently reduced viability (at 50 µM) and induced dendritic simplification (at 20 µM) nearest the target plasma concentration. Probing mitochondrial energetics of DIV16 cortical neurons after exposure to 20 µM efavirenz showed rapid diminution of mitochondrial-dependent oxygen consumption. Further, 20 µM efavirenz decreased excitability in ex vivo slice culture whereas 2 µM had no effect. |
| Databáze: | OpenAIRE |
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