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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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Cerebral cortical cultures were pre-incubated (32 h) with acetaminophen (0–300 μM) (APAP) and oxidatively stressed with menadione (5 μM for 4 h). Chemokines (a) MIP-1α and (b) RANTES released into the supernatant were determined by indirect ELISA. Data are mean ± SD from 3 separate experiments. #p < 0.001 vs. control; **p < 0.01 vs. menadione alone; ***p < 0.001 vs. menadione alone.
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Figure 5: Cerebral cortical cultures were pre-incubated (32 h) with acetaminophen (0–300 μM) (APAP) and oxidatively stressed with menadione (5 μM for 4 h). Chemokines (a) MIP-1α and (b) RANTES released into the supernatant were determined by indirect ELISA. Data are mean ± SD from 3 separate experiments. #p < 0.001 vs. control; **p < 0.01 vs. menadione alone; ***p < 0.001 vs. menadione alone.

Mentions: Similar to the results obtained for the cytokines investigated, we showed that menadione caused a significant increase in release of chemokines MIP-1α (Fig. 5a) and RANTES (Fig. 5b). Pretreatment (32 h) of neuronal cultures with acetaminophen (25 – 300 μM) significantly (p < 0.01–0.001) reduced release of both chemokines.


Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress.

Tripathy D, Grammas P - J Neuroinflammation (2009)

Cerebral cortical cultures were pre-incubated (32 h) with acetaminophen (0–300 μM) (APAP) and oxidatively stressed with menadione (5 μM for 4 h). Chemokines (a) MIP-1α and (b) RANTES released into the supernatant were determined by indirect ELISA. Data are mean ± SD from 3 separate experiments. #p < 0.001 vs. control; **p < 0.01 vs. menadione alone; ***p < 0.001 vs. menadione alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Cerebral cortical cultures were pre-incubated (32 h) with acetaminophen (0–300 μM) (APAP) and oxidatively stressed with menadione (5 μM for 4 h). Chemokines (a) MIP-1α and (b) RANTES released into the supernatant were determined by indirect ELISA. Data are mean ± SD from 3 separate experiments. #p < 0.001 vs. control; **p < 0.01 vs. menadione alone; ***p < 0.001 vs. menadione alone.
Mentions: Similar to the results obtained for the cytokines investigated, we showed that menadione caused a significant increase in release of chemokines MIP-1α (Fig. 5a) and RANTES (Fig. 5b). Pretreatment (32 h) of neuronal cultures with acetaminophen (25 – 300 μM) significantly (p < 0.01–0.001) reduced release of both chemokines.

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