Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice

Zhang, Runji; Bao, Jing; Qiao, Jialu; Li, Wenshuang; Qian, Feng; Hu, Kanghong; Sun, Binlian

doi:10.1016/j.bbrc.2021.11.015

Cited by 4 publications

(3 citation statements)

References 40 publications

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“…A recent study in C57BL/6 mice showed that long-term use can be associated with dose-dependent cognitive deficits due to neuroinflammation. Mice who were given 40 mg/kg experienced impairment of short-term memory and those given 80 mg/kg experienced significant impairment of short-term memory and spatial learning ( Zhang et al, 2021 ) [E]. In rare cases, EFV may result in hepatic impairment which can be seen when monitoring LFTs.…”

Section: Drugs Active Against Human Immunodeficiency Virus (Hiv): Non...mentioning

confidence: 99%

Antiviral drugs

Samuel¹,

McNaught²,

Mulbah³

et al. 2022

Side Effects of Drugs Annual

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Section: Drugs Active Against Human Immunodeficiency Virus (Hiv): Non...mentioning

confidence: 99%

Antiviral drugs

Samuel¹,

McNaught²,

Mulbah³

et al. 2022

Side Effects of Drugs Annual

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“…Therefore, although EFV exerts a direct impact on neurons and glial cells 12 , we speculate that gut bacterial translocation contributes to the side effects of EFV and DTG. This hypothesis is supported by the upregulation of nuclear factor-kappa B (NF-κB) in EFV-treated individuals 13 . Therefore, we compared the impact of EFV and DTG on gut microbiota, as well as on the intestinal barrier function.…”

Section: Introductionmentioning

confidence: 96%

Alteration in Gut Microbiome and Intestinal Barrier Function caused by Efavirenz versus Dolutegravir Treatments in Mice

Tang,

Pan,

Liu

et al. 2023

Preprint

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Dolutegravir (DTG) is replacing efavirenz (EFV) as first-line antiretroviral therapy because of its better tolerance. However, DTG cause similar, but milder, gastrointestinal and neurological side effects as EFV does. We speculated that impaired gut barrier function contributes to their side effects. For this purpose, the mice were intragastrically administered EFV, DTG, or vehicle for 60 consecutive days. The plasma levels of FITC-dextran were determined to evaluate gut barrier integrity. Colonic contents were collected for 16S rRNA sequencing. Adipose, liver, ileum, and colon tissues were collected for pathological examination, and intestinal zona occludens-1 (ZO-1) immunofluorescence staining and goblet cell staining were performed. We found that EFV significantly retarded body weight gain, decreased glucose uptake, and caused lipodystrophy and hepatocyte necrosis. EFV also decreased species richness of gut microbiota, increased Verrucomicrobia and Proteobacteria, and decreased Patescibacteria and Cyanobacteria. Moreover, it caused crypt damage, goblet cell loss, reduced ZO-1 expression, impaired gut barrier function, and suppressed expressions of Pdha1 and Ndufv1. Interestingly, DTG impaired barrier function similar to EFV, but the impairment was milder. DTC also inhibited MPC1, MPC2, and Pdha1 expression. Our results suggest a link between abnormal energy metabolism, impaired gut barrier integrity and side effects of EFV and DTG.

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“…IL‐1β impaired LTP directly at the synapse and furthermore, sensitivity to IL‐1β was augmented in aged hippocampal synapses (Prieto et al, 2015). IL‐1β has been shown to have profound effects on synaptic transmission and synaptic plasticity (Chen et al, 2022; Patel et al, 2019; Zhang et al, 2021). IL‐1β administration in the CNS may affect structures and functions of neurons and synapses thereby impairing learning and memory (Lin, Shen, et al, 2019; Song et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Intrahippocampal injection of IL‐1β upregulates Siah1‐mediated degradation of synaptophysin by activation of the ERK signaling in male rat

Zhou

Lin

et al. 2023

J of Neuroscience Research

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Interleukin-1β (IL-1β) has been described to exert important effect on synapses in the brain. Here, we explored if the synapses in the hippocampus would be adversely affected following intracerebral IL-1β injection and, if so, to clarify the underlying molecular mechanisms. Adult male Sprague-Dawley rats were divided into control, IL-1β, IL-1β + PD98059, and IL-1β + MG132 groups and then sacrificed for detection of synaptophysin (syn) protein level, synaptosome glutamate release, and synapse ultrastructure by western blotting, glutamate kit and electron microscopy, respectively. These rats were tested by Morris water maze for learning and memory ability. It was determined by western blotting whether IL-1β exerted the effect of on syn and siah1 expression in primary neurons via extracellular regulated protein kinases (ERK) signaling pathway. Intrahippocampal injection of IL-1β in male rats and sacrificed at 8d resulted in a significant decrease in syn protein, damage of synapse structure, and abnormal release of neurotransmitters glutamate. ERK inhibitor and proteosome inhibitor treatment reversed the above changes induced by IL-1β both in vivo and in vitro. In primary cultured neurons incubated with IL-1β, the expression level of synaptophysin was significantly downregulated coupled with abnormal glutamate release. Furthermore, use of PD98059 had confirmed that ERK signaling pathway was implicated in synaptic disorders caused by IL-1β treatment. The present results suggest that exogenous IL-1β can suppress syn protein level and glutamate release. A possible

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Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice

Cited by 4 publications

References 40 publications

Antiviral drugs

Antiviral drugs

Alteration in Gut Microbiome and Intestinal Barrier Function caused by Efavirenz versus Dolutegravir Treatments in Mice

Intrahippocampal injection of IL‐1β upregulates Siah1‐mediated degradation of synaptophysin by activation of the ERK signaling in male rat

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