Neuropathic pain, which affects 7–10 % of the global population and decreases productivity and performance at work (Kawai et al., 2017; Wang and Zhao, 2018), has been a significant burden on society for decades. Its economic cost in society is markedly higher than that of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome, cardiovascular disease, and cancer (Ghazisaeidi et al., 2023). Unfortunately, most clinically used drugs have only 20–40 % clinically significant analgesic effects (Balanaser et al., 2023) and contain debilitating dose-limiting adverse effects (Balanaser et al., 2023; Cavalli et al., 2019). Therefore, it is necessary to develop novel and practical approaches for treating neuropathic pain.

Neuroinflammation, characterized by the release of pro-inflammatory mediators in the central nervous system (CNS), is a key factor in the initiation and maintenance of neuropathic pain. It effectively sensitizes nociceptors and enhances the plasticity of nociceptive transmission, thereby playing a crucial role in the pain experience (Matsuda et al., 2019; Shabab et al., 2017). During neuroinflammation, astrocytes and microglia are activated, which leads to a condition known as central sensitization (Ji et al., 2018). Moreover, neuroinflammation causes oxidative stress and antioxidant imbalance (Hsieh and Yang, 2013). Reactive oxygen species (ROS) play a crucial role in the development and maintenance of neuropathic pain, which results from inflammatory insults and nerve injury (Gao et al., 2007; Khattab, 2006; Kim et al., 2004; Yowtak et al., 2011). Kim and colleagues indicated that the antioxidants phenyl N-tert-butylnitrone (PBN), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and vitamin E have potent analgesic effects in rats with spinal nerve ligation-induced neuropathy (Kim et al., 2004, 2006). Nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the primary regulators of the oxidative stress response and can resist inflammatory conditions (He et al., 2020) and neurodegenerative disorders (Loboda et al., 2016). Heme oxygenase-1 (HO-1), a downstream target of Nrf2, is enhanced in the CNS under ischemic conditions (Paschen et al., 1994) and subarachnoid hemorrhage (Matz et al., 1996) and contributes to the regulation of inflammation and angiogenesis (Loboda et al., 2016). Moreover, the induction of Nrf2 expression can reduce gliosis and synthesis of pro-inflammatory cytokines (Jazwa et al., 2011). Several studies have indicated that activation of the Nrf2/HO-1 pathway is beneficial for ameliorating neuropathic pain (Chen et al., 2019; Liu et al., 2016; Shen et al., 2015).

WA25 is a Formosan soft coral Cladiella australis-derived compound (Fig. 1) and a precursor of austrasulfone. It exhibits potent anti-inflammatory and neuroprotective activities, which has been leveraged in treatments for cancer, atopic dermatitis (AD), and atherosclerosis (Chen et al., 2014; Hung et al., 2018; Wang et al., 2015). Huang and colleagues demonstrated that WA25 can alleviate nuclear factor-kappa B (NF-κB) nuclear translocation and upregulate nucleophosmin and HO-1 expressions. This mitigates inflammation in the cell culture and mouse models of AD (Hung et al., 2018). Additionally, one of our previous studies indicated that WA25 may have a therapeutic benefit for neuropathic pain and multiple sclerosis (Wen et al., 2010). However, the underlying mechanism needs to be clarified. Therefore, in this study, we attempted to determine the relationships between WA25, Nrf2/HO-1 pathway, and neuroinflammation. Further, we aimed to investigate the preventive analgesic effects of WA25 against neuropathic pain.

Current treatments for neuropathic pain often offer limited efficacy and are frequently accompanied by significant side effects. The Nrf2/HO-1 signaling pathway has emerged as a promising therapeutic target due to its role in mitigating neuroinflammation and oxidative stress. However, the effects of compounds on this pathway remain largely underexplored. WA25, a compound known for its anti-inflammatory properties, has demonstrated potential in the management of neuropathic pain. Nevertheless, the precise mechanisms by which WA25 modulates the Nrf2/HO-1 pathway remain unclear. Further investigation is warranted to elucidate this interaction and to evaluate the compound's potential preventive analgesic effects. However, the specific mechanism by which it influences the Nrf2/HO-1 pathway remains unclear. Further research is essential to elucidate this relationship and assess the preventive analgesic effects of WA25.