4-(Phenylsulfanyl) Butan-2-One Reduces Mechanical Hypersensitivity in an STZ-Induced Rat Model of Diabetic Neuropathy via TGF-β Associated Suppression of Spinal Neuroinflammation

Diabetic neuropathy is a common complication of diabetes and is associated with persistent spinal neuroinflammation, glial activation, and maladaptive intracellular signaling that contribute to pain-like behaviour. This study investigated the antinociceptive efficacy and associated spinal mechanisms of 4-(phenylsulfanyl)butan-2-one (4-PSB-2) in a streptozotocin (STZ)-induced rat model of diabetic pain-like behaviour. STZ administration produced persistent mechanical allodynia accompanied by time-dependent activation of spinal microglia and astrocytes, characterized by early microglial reactivity followed by sustained astrocytic activation in the dorsal horn. Intrathecal administration of 4-PSB-2 produced robust, dose-dependent attenuation of mechanical hypersensitivity without impairing motor coordination. 4-PSB-2 rapidly reduced STZ-induced phosphorylation of p38 MAPK, ERK, and mTOR in the spinal dorsal horn. In parallel, 4-PSB-2 markedly reduced the expression of the pro-inflammatory cytokine interleukin-1β and increased transforming growth factor-β1 (TGF-β1) immunoreactivity across microglial, astrocytic, and neuronal populations. Pharmacological blockade of TGF-β type I receptors with SB431542 attenuated the effects of 4-PSB-2 on spinal glial activation and cytokine regulation and significantly reduced its antinociceptive effect. These findings suggest that the antinociceptive effects of 4-PSB-2 are associated with attenuation of spinal neuroinflammatory responses and reduced phosphorylation of p38, ERK, and mTOR, and may be partly dependent on TGF-β receptor-associated signaling. These results provide preclinical evidence supporting further investigation of 4-PSB-2 as a potential therapeutic approach for diabetic neuropathy.