Trifluoro-icaritin attenuates neuropathic pain-associated anxiety-like behaviors and hippocampal oxidative stress in rats.

Neuropathic pain is frequently accompanied by anxiety-like symptoms. Trifluoro-icaritin (ICTF), an icaritin derivative with reported central nervous system activity, has analgesic and anti-inflammatory effects, but its actions in neuropathic pain-associated anxiety remain unclear. We examined whether changes in sigma-1 receptor (Sigma-1R) expression and hippocampal oxidative stress accompany the behavioral effects of ICTF in spared nerve injury (SNI) rats. Mechanical hypersensitivity and anxiety-related behavior were assessed using the paw withdrawal threshold, open field test, and elevated plus maze. Sigma-1R expression, oxidative stress, and hippocampal cellular changes were evaluated in vivo, and complementary experiments were performed in H2O2-treated HT22 cells and LPS-stimulated primary astrocytes. ICTF (5 mg/kg, i.p.) attenuated mechanical allodynia and improved several anxiety-related behavioral measures in SNI rats, together with reduced hippocampal malondialdehyde, increased superoxide dismutase activity, and improved neuronal morphology. CA1 Sigma-1R knockdown reduced oxidative stress and improved mechanical hypersensitivity and selected anxiety-related measures. In HT22 cells, H2O2 reduced Sigma-1R expression, whereas ICTF restored Sigma-1R expression and reduced ROS; these effects were attenuated by the Sigma-1R antagonist BD-1047. In LPS-stimulated astrocytes, ICTF reduced the increases in Sigma-1R and ROS, and these effects were attenuated by the Sigma-1R agonist PRE-084. These findings support context-dependent involvement of Sigma-1R-associated redox regulation in the effects of ICTF. They do not establish direct ICTF-Sigma-1R binding, pharmacological selectivity, or an anxiolytic effect independent of analgesia.