Nrf2 Activation in Peripheral Neuropathic Pain

Nrf2 Activation in Peripheral Neuropathic Pain: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Biology

Contributor:

Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors.

chemotherapy-induced peripheral neuropathy
chronic constriction injury
diabetic neuropathy
Nrf2
partial sciatic nerve ligation

1. Peripheral Neuropathic Pain and Erythroid 2 (NFE2)-Related Factor 2 (Nrf2)

Pharmacological and genetic studies report crosstalk between NF-κB and the transcription factor nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), such that the absence of Nrf2 can exacerbate NF-κB activity leading to the increased release of cytokine production. In turn, NF-κB can modulate the transcription and activity of Nrf2 [19]. Nrf2 is the product of the NFE2L2 gene and a member of the cap ‘n’ collar subfamily of basic region leucine zipper (bZip) transcription factors. Nrf2 contains a bZip domain at the C-terminus that is responsible for the formation of heterodimers with other bZip proteins, such as small muscle aponeurosis fibromatosis (MAF) K, G, and F [21,22]. These heterodimers are the regulators of 250 human genes located at the regulatory enhancer sequence known as the antioxidant response element (ARE), which resembles the NFE2-binding motif [23].

During normal physiological conditions, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. Keap1 was identified as a Nrf2-binding protein by employing the yeast two hybrid system in which the inhibitory Neh2 domain of Nrf2 was a bait [24]. Keap1 contains two protein binding domains, the BTB (bric-a-brac, tramtrack, broad-complex) domain in the N-terminal region and Kelch repeats in the C-terminal region, which is homologous to Drosophila actin-binding protein Kelch (Kelch repeat, double glycine repeat domain) that mediates the binding of Keap1 to the Neh2 domain of Nrf2 [25,26,27]. The BTB domain is responsible for the homodimerization and binding of Keap1 to Cullin (Cul) 3, which is a scaffold protein of Nrf2 ubiquitin ligase (E3). Nrf2 has a half-life of approximately 20 min before it is degraded by proteasomes, which is mediated by the polyubiquitination through the Keap1/Cul3 ubiquitin ligase. Therefore, the protein levels of Nrf2 remain low in many cell types under normal physiological conditions [28,29,30].

During stressful physiological conditions, Nrf2 is released from Keap1 and translocates into the nucleus where it heterodimerizes with the MAF proteins. The complex Nrf2–MAF binds to ARE, initiating the transcriptions of several cytoprotective genes, such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase1 (NQO1), superoxide dismutase (SOD), glutathione cysteine ligase, glutathione S-transferases, and catalase (Figure 1) [31,32,33]. Thus, Nrf2 provides protection against oxidative stress. In support, Nrf2 knockout mice are highly susceptible to oxidative stress-related chemical toxicity and disease [34,35,36,37,38,39,40,41], leading researchers to postulate that targeting Nrf2′s protective role against oxidative stress and mitochondrial dysfunction [42,43,44,45] may provide a novel target for alleviating neuropathic pain. Here, we discuss pre-clinical evidence across several animal models of neuropathic pain of the therapeutic potential of targeting Nrf2 signaling and Nrf2 inducers.

Figure 1. Illustrated working model of nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) signaling in rodent peripheral neuropathy (PN). Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, which ultimately leads to proteasomal degradation.

2. Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common neuropathies caused by antineoplastic agents [82], including platinum-based chemotherapeutic agents, taxanes, thalidomide and its analogues, and ixabepilone [83]. Oxaliplatin and paclitaxel are known to induce severe neuropathy during or immediately after the drug infusion [84]. The common symptoms of CIPN include “pins-and-needles” sensations, heat, burning, pain, as well as motor discoordination and muscle weakness [85]. Oxaliplatin is a third-generation platinum-derived chemotherapeutic agent that is used to treat colorectal and other cancers [86]. However, the beneficial effects of oxaliplatin and paclitaxel must be weighed against the risk of neurological side effects and peripheral neuropathic disorders, which affect 85–95% of the patients exposed to paclitaxel [87,88].

Nrf2^−/− knockout mice display severe mechanical and cold hypersensitivities. Yang et al. reported that oxaliplatin-induced neuropathy in Nrf2^−/− knockout mice resulted in greater production of ROS, decreased mitochondrial membrane potential with abnormal release of intracellular calcium, higher cytochrome C-related apoptosis, and overexpression of transient receptor potential (TRP) ion channels. All of these effects were attenuated by activating Nrf2 signaling with the Nrf2 inducer sulforaphane [89]. Similarly, Miao et al. reported that paclitaxel impaired Nrf-ARE and SOD in the dorsal root ganglia (DRG) in parallel with the production of oxidative stress markers (8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2′-deoxyguanosine (8-OHdG)) and proinflammatory cytokines (interleukin-1 beta (IL-1β), IL-6 and TNF-α), likely contributing to neuropathic pain [90]. Again, activation of the Nrf2/HO-1 signaling pathway alleviated paclitaxel-induced neuropathic pain, with a single dose of oltipraz attenuating pain while repeated administration abolished pain [91]. Remarkably, the antinociceptive effect of oltipraz was reversed by the Nrf2 inhibitor trigonelline, implicating a major role for Nrf2 signaling in chemotherapy-induced neuropathic pain.

Interactions with other inflammatory mediators have also been implicated. Crosstalk between the peroxisome proliferator-activated receptor gamma (PPARγ) and Nrf2/HO-1 signaling pathway has also been reported and may inform therapy development. Zhou et al. found the PPARγ selective agonist rosiglitazone reduced pain and upregulated the expression of Nrf2 and HO-1 in the spinal cord of paclitaxel-treated rats [92]. Moreover, the analgesic activity of rosiglitazone was abolished by the application of the Nrf2 inhibitor trigonelline. In addition, the Nrf2-ARE signaling pathway can also be targeted by microRNA (miRNA) treatment. Treatment with an inhibitor of miR-155, a miRNA that regulates inflammation, restored the oxaliplatin-induced impairment of the Nrf2-antioxidant response and Nrf2-regulated NQO1 protein expression in the dorsal horn of male rats [93]. Inhibition of miR-155 led to the attenuation of NOX4 protein expression, other oxidative stress products (8-iso PGF2α/8-OHdG), and TRPA1 in the dorsal horn of oxaliplatin-treated rats [93]. These data support the potential inhibitory effect of miR-155 in chemotherapy-induced PN via the Nrf2-ARE signaling pathway.

Alkaloid levo-corydalmine [94], antioxidant alphalipoic acid [95], mitoquinone [96], endogenous fatty acid amide palmitoylethanolamide (PEA) in association with oxazoline forming the 2-pentadecyl-2-oxazoline of palmitoylethanolamide (PEA-OXA) [97], curcumin [98], quercetin [99], resveratrol [100], formononetin [101], berberine [102], dimethyl fumarate and its metabolite monomethyl fumarate [103], and oleuropein [104] can reduce pain and inflammation associated with CIPN by activating the Nrf2 pathway. In addition to these Nrf2 inducers, Zhang and Xu shed light on the effects of bromodomain-containing protein 4 (BRD4) on the alleviation of vincristine-induced PN [105]. The study reported that BRD4 inhibition significantly reduced oxidative stress in sciatic nerve tissues by activating Nrf2. They postulate that the reducing expression of BRD4 by genetic therapy or drug intervention could inhibit macrophage infiltration and reduce inflammation and oxidative stress, providing a novel therapeutic target to be developed for the treatment of CIPN.

In addition to the aforementioned preclinical studies, Zhao et al. reported that electroacupuncture intervention restored the impairment of Nrf2-ARE/SOD, Nrf2-regulated NQO1, inhibited oxidative stress products (8-iso PGF2α/8-OHdG), and thereby attenuated the mechanical and thermal hypersensitivities in rats treated with paclitaxel [106]. Therefore, the study confirms the use of electropuncture as an alternative treatment strategy to treat CIPN [106].

Table 1. Evidence of the effects of Nrf2 inducers in rodent models of chemotherapy-induced peripheral neuropathy (CIPN).

Nrf2 Inducer	Animals (Sex, Strain)	Dose (mg/kg), Route of Administration	Mechanism of Action	Reference
PEA-OXA	Male Wistar rats	10 mg/kg, oral	NF-κB/Nrf-2 pathway	[97]
Oleuropein	Male Wistar rats	Oleuropein—20 mg/kg, oral Combination—Oleuropein—20 mg/kg, oral + suvorexant—an orexin receptor antagonist—20 mg/kg, oral	Nrf2 pathway	[104]
Curcumin	Male Sprague Dawley rats	100 and 200 mg/kg, oral	Nrf2/HO-1 pathway	[98]
Mitoquinone	Male ICR mice	2.5, 5 and 10 mg/kg, intragastric	Nrf2 pathway	[96]
Formononetin	Male C57BL/6 mice	10 mg/kg, i.p. 10 µM on mouse ND7/23 neuron cells, colon cancer cells (CT-26), human colorectal carcinoma cells (Caco-2, DLD-1, and HCT-116), human lung adenocarcinoma cells (PC9, A649, H1975, and HCC8827), human lung squamous cell carcinoma cells (H520), and human pancreatic cancer cells (BxPC3 and Panc1)—in vitro	Keap1-Nrf2-GSTP1 pathway	[101]
Resveratrol	Male Sprague Dawley rats	7 and 14 mg/kg, oral	Nrf2/HO-1 pathway	[100]
Quercetin	Male Sprague Dawley rats	25 and 50 mg/kg, oral	Nrf2/HO-1 pathway	[99]
Oltipraz	Male Sprague Dawley rats	10, 50, 100 mg/kg/day, i.p.	Nrf2/HO-1 pathway	[91]
Rosiglitazone	Male Sprague Dawley rats	5, 25, and 50 mg/kg, i.p.	Nrf2/HO-1 pathway	[92]
Levo-corydalmine	Male ICR mice	5, 10, and 20 mg/kg, intragastric	Nrf2/HO-1/CO pathway	[94]
Berberine	Male Wistar rats	10 and 20 mg/kg, i.p.	Nrf2 pathway	[102]
Alphalipoic acid	Male Sprague Dawley rats	15, 30, and 60 mg/kg, i.p.	Nrf2 pathway	[95]
L-carnosine	Male and female Egyptian patients	500 mg, oral in patients—clinical trial	Nrf2 pathway	[107]
Dimethyl fumarate and its metabolite monomethyl fumarate	Rat	0.3, 1, 3, or 10 mM dimethyl fumarate or monomethyl fumarate on PC12 cell—a rat pheochromocytoma cell	Nrf2 pathway	[103]
Sulforaphane	Nrf2^+/+ and Nrf2^−/− C57BL/6 mice	5 mg/kg, i.p. 10 µM on DRG neurons	Nrf2 pathway	[89]

Note. Table is organized based on the most recent to oldest publications.

This entry is adapted from the peer-reviewed paper 10.3390/antiox11020430

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.