Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress.
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.


CONCLUSIONS
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.
Tripathy
Debjani
D
Garrison Institute on Aging, Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. debjani.tripathy@ttuhsc.edu
Grammas
Paula
P
D000082:Acetaminophen / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D024483:Vitamin K 3 / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D018925:Chemokines; D016207:Cytokines; D016877:Oxidants; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; D000082:Acetaminophen; D024483:Vitamin K 3