Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain

Ardizzone, Alessio; Fusco, Roberta; Casili, Giovanna; Lanza, Marika; Impellizzeri, Daniela; Esposito, Emanuela; Cuzzocrea, Salvatore

doi:10.3390/ijms22041967

Cited by 22 publications

(23 citation statements)

References 28 publications

(18 reference statements)

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“…OEA inhibits MCP-1 levels ( Montecucco et al, 2015 ; Antón et al, 2017 ; Zhao et al, 2018 ) and also reduces TNF levels ( Sayd et al, 2014 ; Chen et al, 2015 ; Xu et al, 2016 ; Antón et al, 2017 ). PEA reduces MCP-1 levels ( D’Aloia et al, 2021 ; Fusco et al, 2021 ) and TNF levels ( Costa et al, 2008 ; De Filippis et al, 2009 ; Hoareau et al, 2009 ; Cerrato et al, 2010 ; Di Paola et al, 2012 , 2016 ; Sayd et al, 2014 ; Impellizzeri et al, 2015 ; Rahimi et al, 2015 ; Orefice et al, 2016 ; Britti et al, 2017 ; Gugliandolo et al, 2017 ; D’amico et al, 2019 ; Puglia et al, 2020 ; Ardizzone et al, 2021 ; D’Aloia et al, 2021 ). PEA reduces inflammation in human colonic tissue (from patients with IBD, colon cancer and appendicitis), including levels of IL-6, IL-8, IL-17A, MCP-1, and GM-CSF ( Couch et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Vecchiarelli

Aukema

Hume

et al. 2021

Front. Cell. Neurosci.

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Cannabinoids, including cannabis derived phytocannabinoids and endogenous cannabinoids (endocannabinoids), are typically considered anti-inflammatory. One such endocannabinoid is N-arachidonoylethanolamine (anandamide, AEA), which is metabolized by fatty acid amide hydrolase (FAAH). In humans, there is a loss of function single nucleotide polymorphism (SNP) in the FAAH gene (C385A, rs324420), that leads to increases in the levels of AEA. Using a mouse model with this SNP, we investigated how this SNP affects inflammation in a model of inflammatory bowel disease. We administered 2,4,6-trinitrobenzene sulfonic acid (TNBS) intracolonically, to adult male FAAH SNP mice and examined colonic macroscopic tissue damage and myeloperoxidase activity, as well as levels of plasma and amygdalar cytokines and chemokines 3 days after administration, at the peak of colitis. We found that mice possessing the loss of function alleles (AC and AA), displayed no differences in colonic damage or myeloperoxidase activity compared to mice with wild type alleles (CC). In contrast, in plasma, colitis-induced increases in interleukin (IL)-2, leukemia inhibitory factor (LIF), monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF) were reduced in animals with an A allele. A similar pattern was observed in the amygdala for granulocyte colony stimulating factor (G-CSF) and MCP-1. In the amygdala, the mutant A allele led to lower levels of IL-1α, IL-9, macrophage inflammatory protein (MIP)-1β, and MIP-2 independent of colitis—providing additional understanding of how FAAH may serve as a regulator of inflammatory responses in the brain. Together, these data provide insights into how FAAH regulates inflammatory processes in disease.

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Section: Discussionmentioning

confidence: 99%

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Vecchiarelli

Aukema

Hume

et al. 2021

Front. Cell. Neurosci.

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“…Immunohistochemical staining was performed as previously described [ 19 , 20 ] and reported below. The brains were removed, fixed and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

“…Phospho-α-syn (p-α-syn) and CD68 were evaluated on brain tissues extracts for each experimental group as previously described [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

SUN11602, a bFGF mimetic, modulated neuroinflammation, apoptosis and calcium-binding proteins in an in vivo model of MPTP-induced nigrostriatal degeneration

Ardizzone

Bova

Casili

et al. 2022

J Neuroinflammation

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Background Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. PD etiopathogenesis is multifactorial and not yet fully known, however, the scientific world advised the establishment of neuroinflammation among the possible risk factors. In this field, basic fibroblast growth factor/fibroblast growth factor receptor-1 (bFGF/FGFR1) could be a promising way to treat CNS-mediated inflammation; unfortunately, the use of bFGF as therapeutic agent is limited by its side effects. The novel synthetic compound SUN11602 exhibited neuroprotective activities like bFGF. With this perspective, this study aimed to evaluate the effect of SUN11602 administration in a murine model of MPTP-induced dopaminergic degeneration. Methods Specifically, nigrostriatal degeneration was induced by intraperitoneal injection of MPTP (80 mg/kg). SUN11602 (1 mg/kg, 2.5 mg/kg, and 5 mg/kg) was administered daily by oral gavage starting from 24 h after the first administration of MPTP. Mice were killed 7 days after MPTP induction. Results The results obtained showed that SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory state via modulation of glial activation, NF-κB pathway, and cytokine overexpression. Furthermore, we demonstrated that SUN11602 treatment rebalanced Ca2+ overload in neurons by regulating Ca2+-binding proteins while inhibiting the apoptotic cascade. Conclusion Therefore, in the light of these findings, SUN11602 could be considered a valuable pharmacological strategy for PD.

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“…New insights such as these may allow for the design of targeted drugs for the treatment of peripheral neuropathies. Recent research on neuropathic pain and its pharmacological treatment resulted in the suggestion that compounds such as palmitoylethanolamide (and its derivatives), acetyl-l-carnitine, and berberine may be beneficial [ 39 , 40 , 41 , 42 , 43 ]. Hypotheses such as these may be complemented and advanced by experimental approaches based on human peripheral neurons.…”

Section: Introductionmentioning

confidence: 99%

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Holzer

Suciu

Karreman

et al. 2022

IJMS

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Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca2+-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50–200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons.

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Effect of Ultra-Micronized-Palmitoylethanolamide and Acetyl-l-Carnitine on Experimental Model of Inflammatory Pain

Cited by 22 publications

References 28 publications

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

Genetic Variants of Fatty Acid Amide Hydrolase Modulate Acute Inflammatory Responses to Colitis in Adult Male Mice

SUN11602, a bFGF mimetic, modulated neuroinflammation, apoptosis and calcium-binding proteins in an in vivo model of MPTP-induced nigrostriatal degeneration

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

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