Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord.
Oxid Med Cell Longev
; 2021: 9577874, 2021.
Article
in En
| MEDLINE
| ID: mdl-34721761
ABSTRACT
BACKGROUND:
Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms.METHODS:
Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB.RESULTS:
RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor.CONCLUSIONS:
Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Spinal Cord
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Triterpenes
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Organelle Biogenesis
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Sciatic Neuropathy
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NF-E2-Related Factor 2
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Analgesics
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Mitochondria
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Neuralgia
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Oxid Med Cell Longev
Year:
2021
Document type:
Article