Oral Dimethyl Fumarate Reduces Peripheral Neuropathic Pain in Rodents via NFE2L2 Antioxidant Signaling

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Available treatments for neuropathic pain have modest efficacy and significant adverse effects, including abuse potential. Because oxidative stress is a key mechanistic node for neuropathic pain, the authors focused on the master regulator of the antioxidant response—nuclear factor erythroid 2-related factor 2 (NFE2L2; Nrf2)—as an alternative target for neuropathic pain. The authors tested whether dimethyl fumarate (U.S. Food and Drug Administration-approved treatment for multiple sclerosis) would activate NFE2L2 and promote antioxidant activity to reverse neuropathic pain behaviors and oxidative stress-dependent mechanisms. Methods Male Sprague Dawley rats, and male and female wild type and Nfe2l2-/- mice were treated with oral dimethyl fumarate/vehicle for 5 days (300 mg/kg; daily) after spared nerve injury/sham surgery (n = 5 to 8 per group). Allodynia was measured in von Frey reflex tests and hyperalgesia in operant conflict-avoidance tests. Ipsilateral L4/5 dorsal root ganglia were assayed for antioxidant and cytokine/chemokine levels, and mitochondrial bioenergetic capacity. Results Dimethyl fumarate treatment reversed mechanical allodynia (injury-vehicle, 0.45 ± 0.06 g [mean ± SD]; injury-dimethyl fumarate, 8.2 ± 0.16 g; P < 0.001) and hyperalgesia induced by nerve injury (injury-vehicle, 2 of 6 crossed noxious probes; injury-dimethyl fumarate, 6 of 6 crossed; P = 0.013). The antiallodynic effect of dimethyl fumarate was lost in nerve-injured Nfe2l2-/- mice, but retained in nerve-injured male and female wild type mice (wild type, 0.94 ± 0.25 g; Nfe2l2-/-, 0.02 ± 0.01 g; P < 0.001). Superoxide dismutase activity was increased by dimethyl fumarate after nerve injury (injury-vehicle, 3.96 ± 1.28 mU/mg; injury-dimethyl fumarate, 7.97 ± 0.47 mU/mg; P < 0.001). Treatment reduced the injury-dependent increases in cytokines and chemokines, including interleukin-1β (injury-vehicle, 13.30 ± 2.95 pg/mg; injury-dimethyl fumarate, 6.33 ± 1.97 pg/mg; P = 0.022). Injury-impaired mitochondrial bioenergetics, including basal respiratory capacity, were restored by dimethyl fumarate treatment (P = 0.025). Conclusions Dimethyl fumarate, a nonopioid and orally-bioavailable drug, alleviated nociceptive hypersensitivity induced by peripheral nerve injury via activation of NFE2L2 antioxidant signaling. Dimethyl fumarate also resolved neuroinflammation and mitochondrial dysfunction—oxidative stress-dependent mechanisms that drive nociceptive hypersensitivity after nerve injury.

The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids

“…142 The antinociceptive effects produced by the administration of different Nrf2 activators, such as sulforaphane, oltipraz, plumbagin, and dimethyl fumarate, have been evaluated. Several studies have shown that the pharmacological activation of Nrf2 reduces acute and chronic inflammatory pain 12,19,143 and neuropathic pain associated with diabetes 20,59 generated by nerve injury 75,93,144,145 or induced by chemotherapeutic drugs in rodents. 146 In contrast, the loss or disruption of Nrf2 signaling causes increased susceptibility to oxidative stress and inflammatory injuries.…”

“…140 The principal mechanisms involved in the antinociceptive effects of the Nrf2 transcription factor during acute and chronic pain are the enhancement and/or normalization of Nrf2, HO-1, NQO1, glutathione transferase or superoxide dismutase expression and the inhibition of microglial activation, NOS2 overexpression and MAPK phosphorylation in the spinal cord, dorsal root ganglia and/or paw tissues. 12,19,143,144 Other studies have revealed that the administration of Nrf2 inducers also reduces inflammatory responses by decreasing the synthesis of cyclooxygenase-2, TNF-α, IL-1β, and/or IL-6. 144,147,148 The prevailing oxidative stress conditions provoked by nerve injury in the peripheral and central nervous system, which are represented by reduced expression of Nrf2 and HO-1 in the spinal cords, amygdalas, prefrontal cortices, and hippocampi of animals with sciatic nerve injury-induced neuropathic pain, 54 are normalized by treatment with sulforaphane or oltipraz.…”

“…12,19,143,144 Other studies have revealed that the administration of Nrf2 inducers also reduces inflammatory responses by decreasing the synthesis of cyclooxygenase-2, TNF-α, IL-1β, and/or IL-6. 144,147,148 The prevailing oxidative stress conditions provoked by nerve injury in the peripheral and central nervous system, which are represented by reduced expression of Nrf2 and HO-1 in the spinal cords, amygdalas, prefrontal cortices, and hippocampi of animals with sciatic nerve injury-induced neuropathic pain, 54 are normalized by treatment with sulforaphane or oltipraz. 75,93 Both Nrf2 inducers prevent the decreased expression of Nrf2 and HO-1 in the spinal cords and brains of sciatic nerve-injured animals.…”

“…In contrast, the loss or disruption of Nrf2 signaling causes increased susceptibility to oxidative stress and inflammatory injuries 140 . The principal mechanisms involved in the antinociceptive effects of the Nrf2 transcription factor during acute and chronic pain are the enhancement and/or normalization of Nrf2, HO‐1, NQO1, glutathione transferase or superoxide dismutase expression and the inhibition of microglial activation, NOS2 overexpression and MAPK phosphorylation in the spinal cord, dorsal root ganglia and/or paw tissues 12,19,143,144 . Other studies have revealed that the administration of Nrf2 inducers also reduces inflammatory responses by decreasing the synthesis of cyclooxygenase‐2, TNF‐α, IL‐1β, and/or IL‐6 144,147,148 .…”

Protective effect of dimethyl fumarate on oxidative damage and signaling in cardiomyocytes

“…in addition, dMF has been reported to exert protective effects against i/r injury in the brain (18). dMF is recognized as a potent antioxidant (19) that exerts profound effects on the modulation of apoptosis (20). it has also been shown to activate the nuclear factor erythroid 2-related factor 2 (nrf2) signaling pathway.…”