title: Effects of the analgesic acetaminophen (Paracetamol) and its para-aminophenol metabolite on viability of mouse-cultured cortical neurons.
abstract: Acetaminophen has been used as an analgesic for more than a hundred years, but its mechanism of action has remained elusive. Recently, it has been shown that acetaminophen produces analgesia by the activation of the brain endocannabinoid receptor CB1 through its para-aminophenol (p-aminophenol) metabolite. The objective of this study was to determine whether p-aminophenol could be toxic for in vitro developing mouse cortical neurons as a first step in establishing a link between acetaminophen use and neuronal apoptosis. We exposed developing mouse cortical neurons to various concentrations of drugs for 24 hr in vitro. Acetaminophen itself was not toxic to developing mouse cortical neurons at therapeutic concentrations of 10-250 μg/ml. However, concentrations of p-aminophenol from 1 to 100 μg/ml produced significant (p < 0.05) loss of mouse cortical neuron viability at 24 hr compared to the controls. The naturally occurring endocannabinoid anandamide also caused similar 24-hr loss of cell viability in developing mouse cortical neurons at concentrations from 1 to 100 μg/ml, which indicates the mechanism of cell death could be through the cannabinoid receptors. The results of our experiments have shown a detrimental effect of the acetaminophen metabolite p-aminophenol on in vitro developing cortical neuron viability which could act through CB1 receptors of the endocannabinoid system. These results could be especially important in recommending an analgesic for children or individuals with traumatic brain injury who have developing cortical neurons.
authors.affiliation: Naval Medical Research Unit San Antonio, San Antonio, TX, USAUniversity of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schultz
authors.forename: Mauris
authors.initials: M
authors.lastname: DeSilva
authors.forename: Ting Ting
authors.initials: TT
authors.lastname: Gu
authors.forename: Mei
authors.initials: M
authors.lastname: Qiang
authors.forename: Kyumin
authors.initials: K
authors.lastname: Whang
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000627:Aminophenols / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism
chemical_list: D000627:Aminophenols; D000700:Analgesics; D043884:Receptor, Cannabinoid, CB1; D000082:Acetaminophen; C026729:4-aminophenol