Neuronal Bioenergetics and Acute Mitochondrial Dysfunction: A Clue to Understanding the Central Nervous System Side Effects of Efavirenz

Funes, Haryes A.; Apostolova, Nadezda; Alegre, Fernando; Blas‐García, Ana; Álvarez, Ángeles; Martı́-Cabrera, Miguel; Esplugues, Juan V.

doi:10.1093/infdis/jiu273

Cited by 72 publications

(69 citation statements)

References 40 publications

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“…Several other studies have provided direct evidence that antiretroviral drugs can exert neurotoxic effects in connection with oxidative stress, dysregulation of Ca 2ϩ homeostasis, and alteration of mitochondrial respiration (14,17,62,(73)(74)(75)(76)(77)(78). Furthermore, similar to HIV-1 gp120, the earliest antiretroviral drug, AZT, has been shown to impair neurogenesis (79-81), besides affecting cerebrocortical mitochondria (82).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, similar to HIV-1 gp120, the earliest antiretroviral drug, AZT, has been shown to impair neurogenesis (79-81), besides affecting cerebrocortical mitochondria (82). Efavirenz (EFV) and NVP, which are currently FDA approved and used in NNRTI regimens (http://aidsinfo.nih.gov/guidelines), have been suggested to exert neurotoxicity (14,62,83). One study found that EFV caused a loss of ATP, depolarization and fragmentation of mitochondria, and increased mitophagy and autophagy, in general, in neuron-like SHSY-5Y cells and primary rat striatal neurons, suggesting a disturbance of energy homeostasis as a mechanism of toxicity (84).…”

Section: Discussionmentioning

confidence: 99%

“…Two recent studies investigated drug combinations and cell culture models different from those in the present study (17,62), and one of the studies assessed only the effects of cART for up to 48 h (17). However, HIV treatment regimens commonly consist of combinations of three and sometimes more drugs (8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

“…However, several ARVs have been linked to mitochondrial injury (61,62). In addition, measurement of cellular ATP has been used to assess cytotoxicity in large-scale screening and neuroprotection studies (46,63).…”

Section: Short-term Exposure To Arv Drugs Does Not Alter Dendritic Mamentioning

confidence: 99%

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Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

Sánchez

Varano

Rozieres

et al. 2016

Antimicrob Agents Chemother

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b HIV-1 infection frequently causes HIV-associated neurocognitive disorders (HAND) despite combination antiretroviral therapy (cART).Evidence is accumulating that components of cART can themselves be neurotoxic upon long-term exposure. In addition, abuse of psychostimulants, such as methamphetamine, seems to aggravate HAND and compromise antiretroviral therapy. However, the combined effect of virus and recreational and therapeutic drugs on the brain is poorly understood. Therefore, we exposed mixed neuronal-glial cerebrocortical cells to antiretrovirals (ARVs) (zidovudine [AZT], nevirapine [NVP], saquinavir [SQV], and 118-D-24) of four different pharmacological categories and to methamphetamine and, in some experiments, the HIV-1 gp120 protein for 24 h and 7 days. Subsequently, we assessed neuronal injury by fluorescence microscopy, using specific markers for neuronal dendrites and presynaptic terminals. We also analyzed the disturbance of neuronal ATP levels and assessed the involvement of autophagy by using immunofluorescence and Western blotting. ARVs caused alterations of neurites and presynaptic terminals primarily during the 7-day incubation and depending on the specific compounds and their combinations with and without methamphetamine. Similarly, the loss of neuronal ATP was context specific for each of the drugs or combinations thereof, with and without methamphetamine or viral gp120. Loss of ATP was associated with activation of AMP-activated protein kinase (AMPK) and autophagy, which, however, failed to restore normal levels of neuronal ATP. In contrast, boosting autophagy with rapamycin prevented the long-term drop of ATP during exposure to cART in combination with methamphetamine or gp120. Our findings indicate that the overall positive effect of cART on HIV infection is accompanied by detectable neurotoxicity, which in turn may be aggravated by methamphetamine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Short-term Exposure To Arv Drugs Does Not Alter Dendritic Mamentioning

confidence: 99%

See 2 more Smart Citations

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

Sánchez

Varano

Rozieres

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…EFV also inhibits mitochondrial complex IV activity in mice (Streck et al, 2011). The bioenergetic effects of EFV in neurons have recently been demonstrated (Funes et al, 2014). Because of the critical role that autophagy plays in postmitotic cells, such as neurons (Nixon, 2013), we sought to determine the effect of EFV on neuronal autophagy.…”

Section: Introductionmentioning

confidence: 99%

Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations

Purnell

Fox

2014

J Pharmacol Exp Ther

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Efavirenz (EFV) is a non-nucleoside reverse-transcriptase inhibitor in wide use for the treatment of human immunodeficiency virus infection. Although EFV is generally well tolerated, neuropsychiatric toxicity has been well documented. The toxic effects of EFV in hepatocytes and keratinocytes have been linked to mitochondrial perturbations and changes in autophagy. Here, we studied the effect of EFV on mitochondria and autophagy in neuronal cell lines and primary neurons. In SH-SY5Y cells, EFV induced a drop in ATP production, which coincided with increased autophagy, mitochondrial fragmentation, and mitochondrial depolarization. EFV-induced mitophagy was also detected by colocalization of mitochondria and autophagosomes and use of an outer mitochondrial membrane tandem fluorescent vector. Pharmacologic inhibition of autophagy with 3-methyladenine increased the cytotoxic effect of EFV, suggesting that autophagy promotes cell survival. EFV also reduces ATP production in primary neurons, induces autophagy, and changes mitochondrial morphology. Overall, EFV is able to acutely induce autophagy and mitochondrial changes in neurons. These changes may be involved in the mechanism leading to central nervous system toxicity observed in clinical EFV use.

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New Potential Axes of HIV Neuropathogenesis with Relevance to Biomarkers and Treatment

Angelovich

Churchill

Wright

et al. 2020

Neurocognitive Complications of HIV-Infection

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Neuronal Bioenergetics and Acute Mitochondrial Dysfunction: A Clue to Understanding the Central Nervous System Side Effects of Efavirenz

Cited by 72 publications

References 40 publications

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

Antiretrovirals, Methamphetamine, and HIV-1 Envelope Protein gp120 Compromise Neuronal Energy Homeostasis in Association with Various Degrees of Synaptic and Neuritic Damage

Efavirenz Induces Neuronal Autophagy and Mitochondrial Alterations

New Potential Axes of HIV Neuropathogenesis with Relevance to Biomarkers and Treatment

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