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.
Highlights
Neuropathic pain arises due to a primary lesion or dysfunction affecting the somatosensory nervous system, which markedly impairs the patients’ quality of life and reduces individual productivity [1, 2]
These results indicated that constriction injury (CCI) induced a marked decrease in paw withdrawal threshold (PWT) and thermal withdrawal latency (TWL) in a pattern of a rapid-onset and long-lasting manner
And 1(h), the PWT and TWL were significantly upregulated on day 1 and day 3, but not on day 7 and day 14. These results suggest that early administration of RTA-408 (10 μg, i.t.) from day 0 to day 2 delayed the onset of CCI-induced mechanical allodynia and thermal hyperalgesia
Summary
Neuropathic pain arises due to a primary lesion or dysfunction affecting the somatosensory nervous system, which markedly impairs the patients’ quality of life and reduces individual productivity [1, 2]. Accumulating evidence indicates that oxidative stress and mitochondrial dysfunction are involved in various animal models of chronic pain [8,9,10,11]. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. We investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. RTA-408 increased the activity of Nrf and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Nrf activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction
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