<i>N</i>-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition

Piomelli, Daniele; Scalvini, Laura; Fotio, Yannick; Lodola, Alessio; Spadoni, Gilberto; Tarzia, Giorgio; Mor, Marco

doi:10.1021/acs.jmedchem.0c00191

Cited by 62 publications

(79 citation statements)

References 116 publications

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“…Moreover, dual FAAH/cholinesterase inhibitors which might be beneficial for neurodegenerative diseases are currently under development [ 218 ]. In addition, an increasing number of studies have characterized the beneficial effects of NAAA inhibitors, which prevent the degradation of NAEs, in preclinical studies of pain and (neuro-) inflammation [ 219 , 220 , 221 ] ( Table 3 ). However, in a phase I study, the FAAH inhibitor BIA 10-2474 resulted in severe adverse events such as lethal toxic cerebral syndrome [ 222 ], leading to the discontinuation of several clinical studies employing FAAH inhibitors.…”

Section: Neuroinflammation-induced Synaptopathy and Neurodegenerative Diseasesmentioning

confidence: 99%

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Kasatkina

Rittchen

Sturm

2021

IJMS

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Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.

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Section: Neuroinflammation-induced Synaptopathy and Neurodegenerative Diseasesmentioning

confidence: 99%

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Kasatkina

Rittchen

Sturm

2021

IJMS

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“…PEA has been reported to cross the blood brain barrier after an oral administration, although at very low concentrations (<1%) ( Artamonov et al, 2005 ) and unpublished pilot data from our lab suggest that PEA levels were not elevated in the hypothalamus 1 h following administration. It should be noted that in addition to FAAH, OEA and PEA are also hydrolysed by NAAA, the inhibition of which has been shown to elicit potent immunosuppressive activity ( Alhouayek et al, 2015 ; Piomelli et al, 2020 ; Skaper et al, 2015 ; Solorzano et al, 2009 ). NAAA is highly expressed in cells of the immune system and thus, the lack of effect of PEA on hypothalamic gene expression may be due to low central tissue distribution due to its rapid metabolism by NAAA under inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

“…AEA attenuates TLR4-induced production of pro-inflammatory cytokines and mediators such as TNF-α, IL-1β, prostaglandins (PG) and nitric oxide (NO) ( Facchinetti et al, 2003 ; Molina-Holgado et al, 1997 ; Puffenbarger et al, 2000 ), while concurrently increasing anti-inflammatory mediators such as IL-10 ( Correa et al, 2010 ; Krishnan and Chatterjee, 2012 ). N-acylethanolamine acid amidase (NAAA) is a further metabolic pathway for OEA and PEA, inhibition of which elicits potent immunosuppressive effects ( Alhouayek et al, 2015 ; Piomelli et al, 2020 ; Skaper et al, 2015 ; Solorzano et al, 2009 ). PEA reduces TLR4-induced increases in TNF-α production and IL-6 and iNOS expression in macrophages ( Li et al, 2012 ; Solorzano et al, 2009 ) and inhibits TLR4-induced pro-inflammatory M1 microglia while augmenting anti-inflammatory M2a microglia ( D'Aloia et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα

Flannery

Kerr

Hughes

et al. 2021

Journal of Neuroimmunology

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Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N -oleoylethanolamide (OEA), N -palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes ( IL-1β, iNOS, COX2 and m-PGES ) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.

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“…A large body of evidence indicates that activating directly or indirectly PPAR‐α receptors by administering PEA or inhibiting the NAAA enzyme, is an important approach to control inflammation and/or providing antinociception in several types of injuries. A recent review by Piomelli et al (2020) summarized the potential molecular changes mediating the effects of endogenous lipids such as PEA and OEA, in controlling nociception and inflammation. In the absence of insults or injuries to the nociceptive neurons in the dorsal root ganglion (DRG), PEA and OEA provide a tonic inhibition on the immune cells such as macrophages and the excitability of the nociceptors.…”

Section: Discussionmentioning

confidence: 99%

N‐acylethanolamine‐hydrolysing acid amidase: A new potential target to treat paclitaxel‐induced neuropathy

Toma

Caillaud

Patel

et al. 2021

European Journal of Pain

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Background Although paclitaxel is an effective chemotherapeutic agent used to treat multiple types of cancer (e.g. breast, ovarian, neck and lung), it also elicits paclitaxel‐induced peripheral neuropathy (PIPN), which represents a major dose‐limiting side effect of this drug. Methods As the endogenously produced N‐acylethanolamine, palmitoylethanolamide (PEA), reverses paclitaxel‐induced mechanical hypersensitivity in mice, the main goals of this study were to examine if paclitaxel affects levels of endogenous PEA in the spinal cord of mice and whether exogenous administration of PEA provides protection from the occurrence of paclitaxel‐induced mechanical hypersensitivity. We further examined whether inhibition of N‐acylethanolamine‐hydrolysing acid amidase (NAAA), a hydrolytic PEA enzyme, would offer protection in mouse model of PIPN. Results Paclitaxel reduced PEA levels in the spinal cord, suggesting that dysregulation of this lipid signalling system may contribute to PIPN. Consistent with this idea, repeated administration of PEA partially prevented the paclitaxel‐induced mechanical hypersensitivity. We next evaluated whether the selective NAAA inhibitor, AM9053, would prevent paclitaxel‐induced mechanical hypersensitivity in mice. Acute administration of AM9053 dose‐dependently reversed mechanical hypersensitivity through a PPAR‐α mechanism, whereas repeated administration of AM9053 fully prevented the development of PIPN, without any evidence of tolerance. Moreover, AM9053 produced a conditioned place preference in paclitaxel‐treated mice, but not in control mice. This pattern of findings suggests a lack of intrinsic rewarding effects, but a reduction in the pain aversiveness induced by paclitaxel. Finally, AM9053 did not alter paclitaxel‐induced cytotoxicity in lung tumour cells. Conclusions Collectively, these studies suggest that NAAA represents a promising target to treat and prevent PIPN. Significance The present study demonstrates that the chemotherapeutic paclitaxel alters PEA levels in the spinal cord, whereas repeated exogenous PEA administration moderately alleviates PIPN in mice. Additionally, targeting NAAA, PEA's hydrolysing enzyme with a selective compound AM9053 reverses and prevents the PIPN via the PPAR‐α mechanism. Overall, the data suggest that selective NAAA inhibitors denote promising future therapeutics to mitigate and prevent PIPN.

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N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition

Cited by 62 publications

References 116 publications

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα

N‐acylethanolamine‐hydrolysing acid amidase: A new potential target to treat paclitaxel‐induced neuropathy

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