Ninjinyoeito Prevents Onset of Depression-Like Behavior and Reduces Hippocampal iNOS Expression in Senescence-Accelerated Mouse Prone 8 Mice

Late-life depression is a globally prevalent disorder. Ninjinyoeito (NYT), a traditional Japanese herbal medicine, attenuates depressive symptoms in older patients. However, the mechanisms underlying the antidepressive effect of NYT are unknown. In this study, we investigated the mechanism of the action of NYT using senescence-accelerated mouse prone 8 (SAMP8) mice, which exhibit accelerated aging. SAMP8 mice were treated with NYT starting at 12 weeks of age. Twelve-week-old SAMP8 mice did not show prolonged immobility time in the tail suspension test compared with age-matched SAMR1 mice (normal aging control). At 34 weeks of age, vehicle-treated SAMP8 mice displayed prolonged immobility time compared with SAMR1 mice. NYT-treated SAMP8 mice showed a shorter immobility time than that of vehicle-treated SAMP8 mice. Notably, NYT decreased hippocampal inducible nitric oxide synthase (iNOS) expression in SAMP8 mice. There was no difference in iNOS expression between SAMR1 and vehicle-treated SAMP8 mice. Subchronic (5 days) administration of an iNOS inhibitor, 1400 W, shortened the immobility time in SAMP8 mice. These results suggest that NYT prevents an increase in immobility time of SAMP8 mice by decreasing iNOS levels in the hippocampus. Therefore, the antidepressive effect of NYT in older patients might be mediated, at least in part, by the downregulation of iNOS in the brain. Our data suggest that NYT is useful to prevent the onset of depression with aging.