Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the N-Methyl-d-Aspartate (NMDA) Receptors

Casili, Giovanna; Lanza, Marika; Filippone, Alessia; Cucinotta, Laura; Paterniti, Irene; Repici, Alberto; Capra, Anna Paola; Cuzzocrea, Salvatore; Esposito, Emanuela; Campolo, Michela

doi:10.3390/antiox11091774

Cited by 4 publications

(4 citation statements)

References 63 publications

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“…Therefore, considering the notable role played by the p-IKBα-NF-kB pathway in the devel-opment of chronic pain and mood disorders, our data suggest that the normalization of the overexpression of p-IKBα in the DRG and HIP produced by UFP-512 might be involved in the inhibition of allodynia as well as of the emotional and/or mechanical deficits produced by this DOR agonist. In accordance with this suggestion, other treatments such as berberine and dimethyl fumarate also relieve gouty arthritis, neuropathy or post-operative pain by blocking the activation of p-IKBα-NF-kB pathway [59][60][61].…”

Section: Discussionmentioning

confidence: 94%

The Impact of UFP-512 in Mice with Osteoarthritis Pain: The Role of Hydrogen Sulfide

Batallé,

Bai,

Balboni

et al. 2023

Antioxidants

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The pain-relieving properties of opioids in inflammatory and neuropathic pain are heightened by hydrogen sulfide (H2S). However, whether allodynia and functional and/or emotional impairments related to osteoarthritis (OA) could be reduced by activating δ-opioid receptors (DOR) and the plausible influence of H2S on these actions has not been completely established. In female C57BL/6J mice with OA pain generated via monosodium acetate (MIA), we analyze: (i) the effects of UFP-512 (a DOR agonist), given alone and co-administered with two H2S donors, on the symptoms of allodynia, loss of grip strength (GS), and anxiodepressive-like comportment; (ii) the reversion of UFP-512 actions with naltrindole (a DOR antagonist), and (iii) the impact of UFP-512 on the expression of phosphorylated NF-kB inhibitor alpha (p-IKBα) and the antioxidant enzymes superoxide dismutase 1 (SOD-1) and glutathione sulfur transferase M1 (GSTM1); and the effects of H2S on DOR levels in the dorsal root ganglia (DRG), amygdala (AMG), and hippocampus (HIP) of MIA-injected animals. Results showed that systemic and local administration of UFP-512 dose-dependently diminished the allodynia and loss of GS caused by MIA, whose effects were potentiated by H2S and reversed by naltrindole. UFP-512 also inhibited anxiodepressive-like behaviors, normalized the overexpression of p-IKBα in DRG and HIP, and enhanced the expression of SOD-1 and GSTM1 in DRG, HIP, and/or AMG. Moreover, the increased expression of DOR triggered by H2S might support the improved analgesic actions of UFP-512 co-administered with H2S donors. This study proposes the use of DOR agonists, alone or combined with H2S donors, as a new treatment for OA pain.

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Section: Discussionmentioning

confidence: 94%

The Impact of UFP-512 in Mice with Osteoarthritis Pain: The Role of Hydrogen Sulfide

Batallé,

Bai,

Balboni

et al. 2023

Antioxidants

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“…The neuroprotective effects of DMF in neurodegenerative disorders [7], as well as in osteoarthritis pain, post-operative pain, and neuropathic pain caused by spare nerve injury or by chemotherapeutic agents, have been demonstrated [22,23,39,40]. Other studies also revealed that another Nrf2 activator, sulforaphane, as well as the HO-1 inducer, CoPP, both inhibited neuropathic pain provoked by CCI or associated with diabetes [24,25,41,42] and inflammatory pain caused by CFA injection [27].…”

Section: Discussionmentioning

confidence: 95%

The Inhibition of Neuropathic Pain Incited by Nerve Injury and Accompanying Mood Disorders by New Heme Oxygenase-1 Inducers: Mechanisms Implicated

Suárez-Rojas,

Pérez-Fernández,

Bai

et al. 2023

Antioxidants

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Neuropathic pain is a type of pain that persists for a long time and becomes pathological. Additionally, the anxiodepressive disorders derived from neuropathic pain are difficult to palliate with the current treatments and need to be resolved. Then, using male mice with neuropathic pain provoked by chronic constriction of the sciatic nerve (CCI), we analyzed and compared the analgesic actions produced by three new heme oxygenase 1 (HO-1) inducers, 1m, 1b, and 1a, with those performed by dimethyl fumarate (DMF). Their impact on the anxiety- and depressive-like comportments and the expression of the inflammasome NLRP3, Nrf2, and some antioxidant enzymes in the dorsal root ganglia (DRG) and amygdala (AMG) were also investigated. Results revealed that the administration of 1m, 1b, and DMF given orally for four days inhibited the allodynia and hyperalgesia caused by CCI, while 1a merely reduced the mechanical allodynia. However, in the first two days of treatment, the antiallodynic effects produced by 1m were higher than those of 1a and DMF, and its antihyperalgesic actions were greater than those produced by 1b, 1a, and DMF, revealing that 1m was the most effective compound. At four days of treatment, all drugs exerted anxiolytic and antidepressant effects, decreased the NLRP3 levels, and increased/normalized the Nrf2, HO-1, and superoxide dismutase 1 levels in DRG and AMG. Data indicated that the dual modulation of the antioxidant and inflammatory pathways produced by these compounds, especially 1m, is a new promising therapeutic approach for neuropathic pain and related emotional illnesses.

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“…Transforming growth factor β (TGF-β), an important profibrotic growth factor and vascular endothelial growth factor (VEGF), a key angiogenic mediator of pulmonary fibrosis were determined by immunohistochemistry in lung tissues as previously described [ 33 ]. Lung sections were incubated overnight with anti-TGF-β (Santa Cruz Biotechnology; 1:100 sc-130348 in PBS, v/v, MA, USA) and anti-VEGF polyclonal antibody (Santa Cruz Biotechnology; 1:100 sc-7269 in PBS, v/v, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro

Cucinotta,

Mannino,

Casili

et al. 2023

Respir Res

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Background Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis. Methods The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. Results The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. Conclusion In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways. Graphical abstract

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Dimethyl Fumarate (DMF) Alleviated Post-Operative (PO) Pain through the N-Methyl-d-Aspartate (NMDA) Receptors

Cited by 4 publications

References 63 publications

The Impact of UFP-512 in Mice with Osteoarthritis Pain: The Role of Hydrogen Sulfide

The Impact of UFP-512 in Mice with Osteoarthritis Pain: The Role of Hydrogen Sulfide

The Inhibition of Neuropathic Pain Incited by Nerve Injury and Accompanying Mood Disorders by New Heme Oxygenase-1 Inducers: Mechanisms Implicated

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro

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