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Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress.

Tripathy D, Grammas P - J Neuroinflammation (2009)

Bottom Line: Acetaminophen has pro-survival effects on neurons in culture.In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2 in brain neurons and decreases the menadione-induced elevation of the proapoptotic protein, cleaved caspase 3.We show that blocking acetaminophen-induced expression of Bcl2 reduces the pro-survival effect of the drug.

View Article: PubMed Central - HTML - PubMed

Affiliation: Garrison Institute on Aging, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. debjani.tripathy@ttuhsc.edu

ABSTRACT

Background: Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD), have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress.

Methods: Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 microM). Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES) release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots.

Results: Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p < 0.001) increase in neuronal cell death as well as in the release of tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES from cultured neurons. Pretreatment of neuronal cultures with acetaminophen (50 microM) increases neuronal cell survival and inhibits the expression of these cytokines and chemokines. In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2 in brain neurons and decreases the menadione-induced elevation of the proapoptotic protein, cleaved caspase 3. We show that blocking acetaminophen-induced expression of Bcl2 reduces the pro-survival effect of the drug.

Conclusion: These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.

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Primary cortical neurons were incubated with 100 μM of APAP (32 h) and neutralizing Bcl2 antibody for 2 h and then exposed to oxidative stress (5 μM menadione for 4 h). Cell survival assayed with MTT reagent. In each experiment, the number of control cells i.e. viable cells not exposed to any treatment, was defined as 100%. Inset shows the neutralization of protein expression of Bcl2 with neutralizing anti-human Bcl2 antibody. *** p < 0.001 vs. control. # p < 0.01 vs. menadione. δ p < 0.001 vs. m+APAP (menadione + APAP).
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Figure 7: Primary cortical neurons were incubated with 100 μM of APAP (32 h) and neutralizing Bcl2 antibody for 2 h and then exposed to oxidative stress (5 μM menadione for 4 h). Cell survival assayed with MTT reagent. In each experiment, the number of control cells i.e. viable cells not exposed to any treatment, was defined as 100%. Inset shows the neutralization of protein expression of Bcl2 with neutralizing anti-human Bcl2 antibody. *** p < 0.001 vs. control. # p < 0.01 vs. menadione. δ p < 0.001 vs. m+APAP (menadione + APAP).

Mentions: Using neutralizing antibodies to Bcl2 we determined that inhibition of Bcl2 expression prevented the increase in neuronal survival evoked by acetaminophen, suggesting that part of the neuroprotective effect of acetaminophen against menadione injury is mediated by an increase in Bcl2 (Fig. 7).


Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress.

Tripathy D, Grammas P - J Neuroinflammation (2009)

Primary cortical neurons were incubated with 100 μM of APAP (32 h) and neutralizing Bcl2 antibody for 2 h and then exposed to oxidative stress (5 μM menadione for 4 h). Cell survival assayed with MTT reagent. In each experiment, the number of control cells i.e. viable cells not exposed to any treatment, was defined as 100%. Inset shows the neutralization of protein expression of Bcl2 with neutralizing anti-human Bcl2 antibody. *** p < 0.001 vs. control. # p < 0.01 vs. menadione. δ p < 0.001 vs. m+APAP (menadione + APAP).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2662814&req=5

Figure 7: Primary cortical neurons were incubated with 100 μM of APAP (32 h) and neutralizing Bcl2 antibody for 2 h and then exposed to oxidative stress (5 μM menadione for 4 h). Cell survival assayed with MTT reagent. In each experiment, the number of control cells i.e. viable cells not exposed to any treatment, was defined as 100%. Inset shows the neutralization of protein expression of Bcl2 with neutralizing anti-human Bcl2 antibody. *** p < 0.001 vs. control. # p < 0.01 vs. menadione. δ p < 0.001 vs. m+APAP (menadione + APAP).
Mentions: Using neutralizing antibodies to Bcl2 we determined that inhibition of Bcl2 expression prevented the increase in neuronal survival evoked by acetaminophen, suggesting that part of the neuroprotective effect of acetaminophen against menadione injury is mediated by an increase in Bcl2 (Fig. 7).

Bottom Line: Acetaminophen has pro-survival effects on neurons in culture.In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2 in brain neurons and decreases the menadione-induced elevation of the proapoptotic protein, cleaved caspase 3.We show that blocking acetaminophen-induced expression of Bcl2 reduces the pro-survival effect of the drug.

View Article: PubMed Central - HTML - PubMed

Affiliation: Garrison Institute on Aging, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. debjani.tripathy@ttuhsc.edu

ABSTRACT

Background: Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD), have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress.

Methods: Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 microM). Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES) release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots.

Results: Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p < 0.001) increase in neuronal cell death as well as in the release of tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES from cultured neurons. Pretreatment of neuronal cultures with acetaminophen (50 microM) increases neuronal cell survival and inhibits the expression of these cytokines and chemokines. In addition, we document, for the first time, that acetaminophen increases expression of the anti-apoptotic protein Bcl2 in brain neurons and decreases the menadione-induced elevation of the proapoptotic protein, cleaved caspase 3. We show that blocking acetaminophen-induced expression of Bcl2 reduces the pro-survival effect of the drug.

Conclusion: These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.

Show MeSH
Related in: MedlinePlus