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Page 2 of 15 Slattery et al. Neuroimmunol Neuroinflammation 2018;5:11 I http://dx.doi.org/10.20517/2347-8659.2018.05

Keywords: Acetaminophen, p-aminophenol, AM404, neuroinflammation, pharmacodynamics, microglia

INTRODUCTION
[1,2]
Inflammation is believed to contribute to the pathogenesis of Alzheimer’s disease (AD) . Complement
protein cascades, cyclooxygenases (COX), oxygen free radical species, cytokines, chemokines, and other
inflammatory factors such as acute phase proteins have been linked to the development and progression of
[2,3]
AD . Release of pro-inflammatory mediators by microglia, the main effector cells of inflammation within the
central nervous system (CNS), could be sufficient to cause AD pathology independently of other pathological
[4,5]
events, such as deposition of the amyloid b protein (Ab) and neurofibrillary tangles (NFT) . Elevated
nitric oxide (NO) released by astrocytes and microglia during neurodegenerative disease is both necessary
and sufficient to induce primary microglial phagocytosis of neurons and leads to neurotoxic effects
resulting from perturbed mitochondrial respiration . Down-regulation of inducible nitric oxide synthase
[6-8]
(iNOS) in AD-model mice, and subsequent decrease in NO, has been associated with rescue of cognitive
function, reduction in Ab and NFT load, decreased glial activation, and attenuated neuronal loss [9-11] . As
dysregulated activation of microglia resulting from inflammatory insult has been closely associated with
AD brain regions exhibiting extensive deterioration, Ab deposition, and markers of NO-mediated protein
damage [8,12,13] , it has been suggested that reducing microglial activation may be an effective means of treating
neurodegenerative diseases. Epidemiological studies indicate that long-term use of non-steroidal anti-
inflammatory drugs (NSAIDs), which inhibit microglial COX and their select immune functions, reduces
the relative risk of developing AD [13,14] ; however, several clinical trials have failed to identify protective
activity of NSAIDs in AD patients [15-17] .

While not generally considered an anti-inflammatory drug, acetaminophen (paracetamol, N-acetyl-
para-aminophenol, APAP) has similar clinical indications to NSAIDs due to its analgesic and antipyretic
[18]
properties . Acetaminophen inhibits the synthesis of prostaglandin (PG) E2, PGF2, and thromboxane
B2 by lipopolysaccharide (LPS)-stimulated microglia, yet has no effect on the levels of pro-inflammatory
mediators such as tumor necrosis factor (TNF)-α and NO [19,20] . These effects are attributed to the inhibition
of COX enzymatic activity, as the expression of the enzymes involved in PG synthesis, including COX,
is not affected nor does the concentration of the PG precursor, arachidonic acid, significantly vary with
[20]
acetaminophen treatment . Moreover, the inhibition of COX by acetaminophen has been shown to be
more efficacious in microglia than in peripheral macrophages [20,21] . It has been suggested that the low levels
of oxidants in the CNS potentiate the ability of acetaminophen to reduce the catalytically active oxidized
[21]
form of COX to its inactive state . It has, therefore, been proposed that acetaminophen may be a good
[20]
agent for treating neuroinflammation in the CNS, without compromising peripheral PG levels .
In addition to COX inhibition, the cannabinoid system has been suggested as the possible pharmacological
target of acetaminophen. Antagonists of cannabinoid receptors inhibited the analgesic activity of
acetaminophen by reducing the responsiveness of mice to nociceptive stimuli, attributable to the
modulation of cytokine and NO pathways [22,23] . These studies suggest that the therapeutic activity of
acetaminophen could be mediated, at least in part, through the effects of the parent drug or its metabolites
[24]
on the cannabinoid system . Studies on pharmacokinetics have indicated that acetaminophen undergoes
extensive phase I and phase II metabolism prior to excretion. Initially, it was postulated that acetaminophen
is metabolized by sulfotransferases (30%-44%) and uridine-5’-diphospho-glucuronosyltransferases
(52%-57%) in the liver to inactive secondary compounds . In 2005, however, an alternative metabolic
[25]
pathway was described in which acetaminophen undergoes deacetylation to a lipid-soluble intermediate
p-aminophenol, catalyzed to some extent by liver acylamidase and N-deacetylase [26-28] . Following
distribution to the CNS, p-aminophenol is conjugated to arachidonic acid via fatty acid amide hydrolase
(FAAH) to form the bioactive N-acylphenolamine, N-arachidonoylaminophenol (AM404) [27-29] . A single
dose of acetaminophen commonly used to induce analgesia in rats (300 mg/kg body weight) leads to