Simvastatin Therapy in the Acute Stage of Traumatic Brain Injury Attenuates Brain Trauma-Induced Depression-Like Behavior in Rats by Reducing Neuroinflammation in the Hippocampus

The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory. Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-alpha expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI. TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-alpha expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days. Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-alpha expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.