Targeting Oxidative Stress and Neuroinflammation: Analgesic Effects of 4-(phenylsulfanyl)butan-2-one on Chronic Constriction Injury-Induced Peripheral Neuropathic Pain in Rats.

Neuropathic pain arises from complex pathological processes involving oxidative stress and neuroinflammation. Excessive production of reactive oxygen species (ROS) contributes critically to the initiation and persistence of neuropathic pain following nerve injury and inflammatory insults, and antioxidant-based interventions have shown consistent efficacy across multiple preclinical models. This study investigated the analgesic effects of 4-(phenylsulfanyl)butan-2-one (4-PSB-2), a compound with known anti-inflammatory properties, using the chronic constriction injury (CCI) rat model. Intrathecal administration of 4-PSB-2 significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days 3 to 28, without affecting baseline nociceptive responses in naïve rats. In the ipsilateral spinal cord dorsal horn (SCDH), 4-PSB-2 reduced oxidative stress, evidenced by decreased expression of tyrosinase and nitrotyrosine, particularly in astrocytes. Additionally, 4-PSB-2 modulated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway, as demonstrated by enhanced nuclear expression of Nrf2 and upregulation of HO-1 expression, along with reduced Kelch-like ECH-associated protein 1 (Keap1), phosphorylated P38 (p-P38), and tumor necrosis factor-alpha (TNF-α) levels. Glial cell activation was also attenuated. Notably, co-administration with zinc protoporphyrin (ZnPP), a pharmacological inhibitor of heme oxygenase activity, attenuated the analgesic, antioxidant, and anti-inflammatory effects of 4-PSB-2, suggesting that activation of the Nrf2/HO-1 pathway contributes to the protective effects of 4-PSB-2. These findings indicate that 4-PSB-2 confers sustained neuropathic pain relief by regulating oxidative stress and neuroinflammation via astrocytic Nrf2/HO-1 pathway activation, highlighting its potential as a promising therapeutic candidate for neuropathic pain management.