Abstract
Reduction in Nrf2-mediated antioxidant response in the central nervous system plays an important role in the development and maintenance of neuropathic pain (NP). However, the mechanisms regulating Nrf2 activity in NP remain unclear. A recent in vitro study revealed that Sirt2, a member of the sirtuin family of proteins, affects antioxidant capacity by modulating Nrf2 activity. Here we examined whether central Sirt2 regulates NP through Nrf2-mediated oxidative stress pathway. In a rat model of spared nerve injury (SNI)-induced NP, mechanical allodynia and thermal hyperalgesia were observed on day 1 and up to day 14 post-SNI. The expression of Sirt2, Nrf2 and its target gene NQO1 in the spinal cord in SNI rats, compared with sham rats, was significantly decreased from day 7 and remained lower until the end of the experiment (day 14). The mechanical allodynia and thermal hyperalgesia in SNI rats were ameliorated by intrathecal injection of Nrf2 agonist tBHQ, which normalized expression of Nrf2 and NQO1 and reversed SNI-induced decrease in antioxidant enzyme superoxide dismutase (SOD) and increase in oxidative stress marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the spinal cord. Moreover, intrathecal injection of a recombinant adenovirus expressing Sirt2 (Ad-Sirt2) that upregulated expression of Sirt2, restored expression of Nrf2 and NQO1 and attenuated oxidative stress in the spinal cord, leading to improvement of thermal hyperalgesia and mechanical allodynia in SNI rats. These findings suggest that peripheral nerve injury downregulates Sirt2 expression in the spinal cord, which inhibits Nrf2 activity, leading to increased oxidative stress and the development of chronic NP.
Highlights
Neuropathic pain (NP), which is redefined as a “pain caused by lesion or disease of the somatosensory system,” is an underestimated socioeconomic health problem affecting millions of people worldwide (Carrasco et al, 2018)
To explore the potential role of Nuclear factor erythroid derived-2-related factor 2 (Nrf2) pathway in regulation of NP, we first examined the expression of Nrf2 and NQO1, a downstream target of Nrf2 that plays a protective role in various cells against oxidative stress, in the spinal cord of spared nerve injury (SNI) rats
The main findings of the present study are: 1) Nrf2 activity and its downstream target NQO1 expression in the spinal cord are downregulated in rats with SNI-induced chronic NP; 2) upregulation of Nrf2 activity restores NQO1 expression and prevents oxidative stress in the spinal cord, ameliorating mechanical allodynia and thermal hyperalgesia in rats with SNI-induced chronic NP; 3) Sirt2 expression in the spinal cord is reduced in rats with SNI-induced chronic NP; 4) overexpression of Sirt2 prevents reductions in Nrf2 activity and NQO1 expression as well as increase in oxidative stress in the spinal cord, leading to improvement of thermal hyperalgesia and mechanical allodynia
Summary
Neuropathic pain (NP), which is redefined as a “pain caused by lesion or disease of the somatosensory system,” is an underestimated socioeconomic health problem affecting millions of people worldwide (Carrasco et al, 2018). A better understanding of the molecular mechanism underlying NP may lead to improvements in pain relief and quality of life in patients with NP
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