Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

Tripathy, Debjani; Grammas, Paula

doi:10.1186/1742-2094-6-10

Cited by 66 publications

(38 citation statements)

References 46 publications

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“…Interestingly, FECDi demonstrated cleaved caspase-9 and caspase-3 bands without MN treatment, indicating activation of the apoptotic pathways at baseline. Similarly, MN induced caspase activation in MCF-9 cells, in cortical neurons, and pancreatic cells (1,14,40). Moreover, MN induced mtDNA damage, followed by cytochrome c release and caspase-dependent cell death in oligodendrocytes and microglia, with 100 lM MN treatment for 3 h, but did not cause significant cytochrome c release and caspase activation due to efficiently repaired mtDNA damage in astrocytes (17).…”

Section: Discussionmentioning

confidence: 98%

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in DCm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release.

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Section: Discussionmentioning

confidence: 98%

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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“…APAP has the capability to modulate the release of inflammatory molecules such as PGE2 and IL-6 by Aβ-stimulated astrocytes [58]. APAP also protects brain endothelial and neuronal cells against oxidative stress, and menadione-induced increase in chemokines and cytokines was reduced by APAP [25, 26]. Thus, APAP possesses the ability to block NF-κB activation and exert a neuroprotective effect, suggesting that the neuroprotective effects of APAP might be related to its anti-neuroinflammation effects.…”

Section: Discussionmentioning

confidence: 99%

“…can inhibit quinolinic acid (QA)-induced lipid peroxidation, superoxide anion generation, and cell damage in the rat hippocampus [24]. Tripathy et al [25, 26] showed that low-dose APAP reduces inflammatory protein release from cultured brain neuronal and endothelial cells exposed to oxidant stress and increases expression of the anti-apoptotic protein Bcl-2 in brain neurons. Naziroglu et al [27] also reported that APAP (5–100 mg/kg) can reduce brain and microsomal lipid peroxidation, while it also increases brain vitamin E levels and microsomal glutathione peroxidase (GSH-Px) activity.…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity

Zhao

Zhang

Cao

et al. 2017

J Neuroinflammation

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BackgroundConsiderable evidence has shown that neuroinflammation and oxidative stress play an important role in the pathophysiology of postoperative cognitive dysfunction (POCD) and other progressive neurodegenerative disorders. Increasing evidence suggests that acetaminophen (APAP) has unappreciated antioxidant and anti-inflammatory properties. However, the impact of APAP on the cognitive sequelae of inflammatory and oxidative stress is unknown. The objective of this study is to explore whether APAP could have neuroprotective effects on lipopolysaccharide (LPS)-induced cognitive impairment in mice.MethodsA mouse model of LPS-induced cognitive impairment was established to evaluate the neuroprotective effects of APAP against LPS-induced cognitive impairment. Adult C57BL/6 mice were treated with APAP half an hour prior to intracerebroventricular microinjection of LPS and every day thereafter, until the end of the study period. The Morris water maze was used to assess cognitive function from postinjection days 1 to 3. Animal behavioural tests as well as pathological and biochemical assays were performed to evaluate LPS-induced hippocampal damage and the neuroprotective effect of APAP.ResultsMice treated with LPS exhibited impaired performance in the Morris water maze without changing spontaneous locomotor activity, which was ameliorated by treatment with APAP. APAP suppressed the accumulation of pro-inflammatory cytokines and microglial activation induced by LPS in the hippocampus. In addition, APAP increased SOD activity, reduced MDA levels, modulated glycogen synthase kinase 3β (GSK3β) activity and elevated brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Moreover, APAP significantly decreased the Bax/Bcl-2 ratio and neuron apoptosis in the hippocampus of LPS-treated mice.ConclusionsOur results suggest that APAP may possess a neuroprotective effect against LPS-induced cognitive impairment and inflammatory and oxidative stress via mechanisms involving its antioxidant and anti-inflammatory properties, as well as its ability to inhibit the mitochondrial permeability transition (MPT) pore and the subsequent apoptotic pathway.

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“…The observed anti-oxidant effect of APAP at short periods of exposure was at odds with the abundant literature about its effects on hepatocytes, but consistent with reports that APAP acts as an anti-inflammatory and anti-oxidant compound in neurons both in vitro and in vivo. For example, APAP protects hippocampal neurons and PC12 cultures from oxidative stress by lowering cytoplasmic levels of peroxides and reducing of lipid peroxidation (Bisaglia et al, 2002), and cerebral cortical cultured neurons and brain endothelial cells exposed to the superoxide-generating compound menadione (Tripathy et al, 2009a; Tripathy et al, 2009b). In rats, APAP induces apoptosis of cortical neurons (Posadas et al, 2010), but significantly attenuates superoxide production by the neurotoxin quinolinic acid, a metabolite implicated in the pathogenesis of neurodegenerative diseases (Maharaj et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways

et al. 2014

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Pain relievers containing N-acetyl-para-aminophenol, also called APAP, acetaminophen or paracetamol, in combination with opioid narcotics are top-selling pharmaceuticals in the U.S. Individuals who abuse these drugs for as little as sixty days can develop tinnitus and progressive bilateral sensorineural hearing loss. Recently published studies indicate that APAP and its metabolic product N-acetyl-p-benzoquinoneimine (NAPQI) are the primary ototoxic agents in this type of pain relievers. However, the mechanisms underlying the deleterious effects of these drugs on auditory cells remain to be fully characterized. In this study, we report cellular, genomic, and proteomic experiments revealing that cytotoxicity by APAP and NAPQI involves two different pathways in Immortomouse™-derived HEI-OC1 cells, implicating ROS overproduction, alterations in ER morphology, redistribution of intra-cisternal chaperones, activation of the eIF2α-CHOP pathway, as well as changes in ER stress and protein folding response markers. Thus, both oxidative and ER stress are part of the cellular and molecular mechanisms that contribute to the cytotoxic effects of APAP and NAPQI in these cells. We suggest that these in vitro findings should be taken into consideration when designing pharmacological strategies aimed at preventing the toxic effects of these drugs on the auditory system.

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Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

Cited by 66 publications

References 46 publications

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Acetaminophen attenuates lipopolysaccharide-induced cognitive impairment through antioxidant activity

Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways

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