HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

Jin, Jingji; Grimmig, Bethany; Izzo, James; Brown, Lecia A M; Smith, Adam J. de; Tan, Jun; Bickford, Paula C.; Giunta, Brian

doi:10.3727/096368916x691457

Cited by 29 publications

(24 citation statements)

References 59 publications

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“…Consistent with our findings (Fig. 7), lower ATP levels have been reported previously upon efavirenz treatment (Blas-Garcia et al , 2010; Funes et al , 2014; Imaizumi et al , 2015; Jin et al , 2016; Purnell and Fox, 2014). Metabolites of efavirenz have also been implicated in dendritic spine injury in neurons (Tovar-y-Romo et al , 2012), but it is unlikely that such metabolites were present here.…”

Section: Discussionsupporting

confidence: 93%

“…impaired maximal mitochondrial respiration and SRC) represents a common pathway by which these ARV drugs may initiate neuronal dysfunction. Several of the ARV drugs tested here have been shown previously to dissipate the mitochondrial membrane potential, including efavirenz (Blas-Garcia et al , 2014; Funes et al , 2014; Jin et al , 2016; Purnell and Fox, 2014), emtricitabine (Groener et al , 2011), indinavir (Jiang et al , 2007), lopinavir (Groener et al , 2011), and zidovudine (Caron et al , 2004; Jiang et al , 2007; Nagiah et al , 2015). The mitochondrial membrane potential is a central regulator of cell health, it provides the charge gradient required for mitochondrial calcium sequestration and ATP generation, and also regulates ROS production (Perry et al , 2011).…”

Section: Discussionmentioning

confidence: 99%

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Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

et al. 2017

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The use of antiretroviral (ARV) drugs with central nervous system (CNS) penetration effectiveness (CPE) may be useful in the treatment of HIV-associated neurocognitive disorder (HAND) as well as targeting a CNS reservoir in strategies to achieve a functional cure for HIV. However, increased cognitive deficits are linked to at least one of these drugs (efavirenz). As mitochondrial dysfunction has been found with a number of ARVs, and as such can affect neuronal function, the objective of this study was to assess the effects of ARV with high CPE for toxicological profiles on presynaptic nerve terminal energy metabolism. This subcellular region is especially vulnerable in that a constant supply of ATP is required for the proper maintenance of neurotransmitter release and uptake supporting proper neuronal function. We evaluated the effects of acute treatment with ten different high CPE ARVs from five different drug classes on rat cortical and striatal nerve terminal bioenergetic function. While cortical nerve terminal bioenergetics were not altered, striatal nerve terminals exposed to efavirenz, nevirapine, abacavir, emtricitabine, zidovudine, darunavir, lopinavir, raltegravir, or maraviroc (but not indinavir) exhibit reduced mitochondrial spare respiratory capacity (SRC). Further examination of efavirenz and maraviroc revealed a concentration-dependent impairment of striatal nerve terminal maximal mitochondrial respiration and SRC as well as a reduction of intraterminal ATP levels. Depletion of ATP at the synapse may underlie its dysfunction and contribute to neuronal dysfunction in treated HIV infection.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

et al. 2017

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“…Nucleoside reverse transcriptase inhibitors have been reported to reduce neuronal axon length [79, 80] and mitochondrial DNA content [81, 82]. Recently, efavirenz which was found to promote amyloid-β (Aβ) production in vitro and in vivo [83], abrogate neural stem cell proliferation [84],and alter mitochondrial dynamics(i.e., increased mitochondrial depolarization, decreased mitochondrial DNA, and altered mitochondrial respiratory function) [81, 85, 86]. In addition, raltegravir was shown to enhance IL-8 production, providing further evidence for cART-mediated neurotoxicity [87].…”

Section: Hand In the Era Of Cartmentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Nookala

Mitra

Chaudhari

et al. 2017

JAD

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With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

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“…Enrollment cohort adjusts for socioeconomic differences and cART era exposure differences between enrollment waves (Walensky et al 2006). Efavirenz and Rilpivirine cause depressive symptoms (Panel on Antiretroviral Guidelines for Adults and Adolescents), and efavirenz may lead to susceptibility to cognitive impairment (Jin et al 2016). …”

Section: Methodsmentioning

confidence: 99%

Association of long-term patterns of depressive symptoms and attention/executive function among older men with and without human immunodeficiency virus

et al. 2017

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Older HIV-infected men are at higher risk for both depression and cognitive impairments, compared to HIV-uninfected men. We evaluated the association between longitudinal patterns of depressive symptoms and attention/executive function in HIV-infected and HIV-uninfected men aged 50+ years to understand whether HIV infection influenced the long-term effect of depression on attention/executive function. Responses to the Center for Epidemiologic Studies—Depression scale and attention/executive function tests (Trail Making Test Part B and Symbol Digit Modalities Test) were collected semiannually from May 1986 to April 2015 in 1611 men. Group-based trajectory models, stratified by HIV status, were used to identify latent patterns of depressive symptoms and attention/executive function across 12 years of follow-up. We identified three depression patterns for HIV-infected and HIV-uninfected men (rare/never 50.0 vs. 60.6%, periodically depressed 29.6 vs. 24.5%, chronic high 20.5 vs.15.0%, respectively) and three patterns of attention/executive function for HIV-infected and HIV-uninfected men (worst-performing 47.4 vs. 45.1%; average 41.9 vs. 47.0%; best-performing 10.7 vs. 8.0%, respectively). Multivariable logistic regression models were used to assess associations between depression patterns and worst-performing attention/executive function. Among HIV-uninfected men, those in the periodically depressed and chronic high depressed groups had higher odds of membership in the worst-performing attention/executive function group (adjusted odds ratio [AOR] = 1.45, 95% CI 1.04, 2.03; AOR = 2.25, 95% CI 1.49, 3.39, respectively). Among HIV-infected men, patterns of depression symptoms were not associated with patterns of attention/executive function. Results suggest that HIV-uninfected, but not HIV-infected, men with chronic high depression are more likely to experience a long-term pattern of attention/executive dysfunction.

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HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

Cited by 29 publications

References 59 publications

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

Central nervous system-penetrating antiretrovirals impair energetic reserve in striatal nerve terminals

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

Association of long-term patterns of depressive symptoms and attention/executive function among older men with and without human immunodeficiency virus

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