Journal
NEUROCHEMICAL RESEARCH
Volume 42, Issue 11, Pages 3220-3232Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-017-2358-x
Keywords
Antiretroviral; Efavirenz; Neurotoxicity; Neuron morphology; Mitochondria; Excitability
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Funding
- Department of Veterans Affairs [CDA BX001677, 1I01BX001506-01A2]
- James S. McDonnell Foundation [220023046]
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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 A mu M) and induced dendritic simplification (at 20 A mu M) nearest the target plasma concentration. Probing mitochondrial energetics of DIV16 cortical neurons after exposure to 20 A mu M efavirenz showed rapid diminution of mitochondrial-dependent oxygen consumption. Further, 20 A mu M efavirenz decreased excitability in ex vivo slice culture whereas 2 A mu M had no effect.
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