Contribution of Nrf2 Modulation to the Mechanism of Action of Analgesic and Anti-inflammatory Drugs in Pre-clinical and Clinical Stages

Staurengo‐Ferrari, Larissa; Badaró-Garcia, Stephanie; Hohmann, Miriam S. N.; Manchope, Marília F.; Zaninelli, Tiago H.; Casagrande, Rúbia; Verri, Waldiceu A.

doi:10.3389/fphar.2018.01536

Cited by 108 publications

(48 citation statements)

References 239 publications

(274 reference statements)

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“…Therefore, the hydroxyl group at B ring seems to be important for ONOO − and superoxide anion scavenging activity and its reasonable that this scavenging activity accounts for flavonoids analgesic and anti-inflammatory activity. Flavonoids also present antioxidant effects by indirect mechanisms through activation of Nrf2 signaling pathway, for example [169]. Chalcones are more potent than other types of flavonoids, where the double bond at C2-C3 position of their structure are particularly important for Nrf2 induction.…”

Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

et al. 2020

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Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

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Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

et al. 2020

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“…Oxidative stress is also involved in the development and maintenance of neuropathic pain. Nuclear factor erythroid derived-2-related factor 2 (Nrf2) and its downstream pathway, the enzymes heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), are key to maintaining the homeostasis of organisms [20]. In vivo studies have demonstrated reduced Nrf2 and/or HO-1 levels in the spinal cord of animals with neuropathic pain [12,21] or diabetic neuropathy [22,23,24,25], in which the levels were restored by treatment with several pharmacological modulators of Nrf2 and HO-1 [12,26,27,28].…”

Section: Introductionmentioning

confidence: 99%

Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Díaz

Polo

Gallardo

et al. 2019

JCM

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Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain.

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“…Oxidative stress causes Nrf2 to dissociate from KEAP1 and, subsequently, to translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes [37,38]. We observed nuclear translocation of Nrf2 in the hypoxia group, which explains the upregulation of Prdx6, however, nuclear translocation of Nrf2 was not observed in reperfusion (Fig.…”

Section: Discussionmentioning

confidence: 68%

Regulation of Prdx6 by Nrf-2 is mediated through aiPLA2 in white matter reperfusion injury

Daverey

Agrawal

2020

Preprint

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Abstract BackgroundMechanisms involving upregulation of cytoprotective genes under the control of transcription factors, such as Prdx6 and Nrf2, exist to protect cells from permanent damage and dysfunction under hypoxic conditions. Hypoxia and reperfusion produces overproduction of ROS (reactive oxygen species), which may lead to mitochondrial dysfunction leading to cell death and apoptosis. Here, we explore the hypothesis that Prdx6 protects the spinal cord white matter from hypoxia-reperfusion injury and elucidate the possible mechanism by which Prdx6 elicits its protective effects.MethodsBriefly, rats were deeply anesthetized with 5% isoflurane and maintained at 1.5%-2.5% isoflurane. A 30 mm section of spinal cord was rapidly removed and placed in cold Ringer’s solution (2-4 °C), and then a dorsal column segment was micro-dissected from the spinal cord and adjacent gray matter after longitudinal sectioning. The dissected dorsal column was exposed to hypoxia by perfusing 95% N 2 /5% CO 2 for 1 h. For reperfusion experiments, the Ringer’s was reperfused with 95% O 2 and 5% CO 2 for 2 h and 4 h.ResultsOur results show that the expression of Prdx6 significantly upregulated in white matter after hypoxia compared to the sham group, whereas reperfusion caused a gradual decrease in Prdx6 expression after 2 h and 4 h of reperfusion injury. For the first time, our study revealed the novel expression and localized expression of Prdx6 in astrocytes after hypoxia, and possible communication of astrocytes and axons through Prdx6. Interestingly we observed a gradual increase in Nrf2 expression, which suggests a negative regulation of Prdx6 through Nrf2 signaling. Furthermore, inhibition of aiPLA2 activity of Prdx6 by MJ33 shows that the regulation of Prdx6 by Nrf2 is mediated through aiPLA2 activity.ConclusionThe present study uncovers a differential distribution of Prdx6 in axons and astrocytes under a hypoxic environment of white matter, and regulation of Prdx6 in hypoxia-reperfusion injury. Our data show that low levels of Prdx6 in reperfusion injury leads to increased inflammation and apoptosis in white matter, therefore the results of this study suggests that Prdx6 has a protective role in spinal hypoxia-reperfusion injury.

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Contribution of Nrf2 Modulation to the Mechanism of Action of Analgesic and Anti-inflammatory Drugs in Pre-clinical and Clinical Stages

Cited by 108 publications

References 239 publications

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Regulation of Prdx6 by Nrf-2 is mediated through aiPLA2 in white matter reperfusion injury

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