Silymarin Modulates 3-Nitropropionic Acid-Induced Oxidative Neurotoxicity and Apoptosis Through the Inhibition of...

The stimulation of the TRPV1 channel through capsaicin (CAP) and oxidative stress induces increases of 3-Nitropropionic acid (3NPA)-induced brain and hippocampus injury, whereas its inhibition by antioxidant silymarin (SIL) and capsazepine (CPZ) may suppress the increases in the brain and hippocampus injury. The antioxidant and antiapoptotic actions of SIL were investigated in the HT-22 mouse hippocampal cells and the brain of mice by diminishing the TRPV1 signaling pathways. A total of 32 mice were equally divided into four groups: control, SIL (100 mg/kg/day), 3NPA (12.5 mg/kg and single dose), and 3NPA + SIL. Mouse hippocampal HT-22 cells were also divided into four groups: control, SIL (10 µM for 24 h), 3NPA (1 mM for 24 h), and 3NPA + SIL. The 3NPA-induced increases of apoptotic (caspases-3, -8, and -9) and oxidant (mitochondrial reactive oxygen species (mROS), mitochondrial membrane dysfunction, and lipid peroxidation) markers were decreased through upregulation of glutathione, glutathione peroxidase, retinol, alpha-tocopherol, and beta-carotene in the brain of mice by the SIL and CPZ treatments. In the HT-22 cells, the 3NPA-induced increases of Ca²⁺, mROS, TRPV1 current densities, and death cell percentage were decreased in 3NPA + SIL and 3NPA + CPZ groups by the SIL and CPZ treatments, although the decreases of HT-22 viability were increased by the treatments. These findings suggest that silymarin-associated inhibition of TRPV1 signaling is consistent with a neuroprotective role against 3NPA-induced neurotoxicity, though TRPV1-independent mechanisms cannot be excluded.