Progesterone Provides the Pleiotropic Neuroprotective Effect on Traumatic Brain Injury Through the Nrf2/ARE Signaling Pathway.

OBJECTIVE: This study was to investigate the role of Nrf2/ARE signaling pathway in the pleiotropic neuroprotective effect of progesterone (PROG) on traumatic brain injury (TBI).

METHODS: The Nrf2-knockout (Nrf2-/-) and C57 mice were respectively subjected to a lateral cortical impact injury caused by a free-falling object and randomly divided into three groups: sham-operated, trauma, and trauma + PROG treatment group. The PROG treatment group was given PROG (32 mg/kg of body weight, intraperitoneal injection) immediately after injury. For all groups, a series of brain samples were obtained after trauma at 24 and 72 h, respectively. The cerebral edema was evaluated; the expression of IL-1β, IL-6, and TNF-α was measured using ELISA array, and the apoptosis index was detected by TUNEL. Flow cytometry was used to detect the intracellular calcium concentration.

RESULTS: The water content, the apoptosis index, the levels of inflammatory cytokine, and the intracellular calcium ion were significantly decreased with the PROG treatment in C57 mice with TBI model. However, the effect of PROG on TBI was not found in the Nrf2-/- mouse model of TBI.

CONCLUSIONS: PROG reduced cerebral edema, apoptosis, inflammatory reaction, and intracellular calcium ion overload effects after TBI. These beneficial effects were not seen in the Nrf2-/- mouse model of TBI. The results from this study suggested that the Nrf2/ARE signal pathway may be involved in the pleiotropic neuroprotective effect of PROG on TBI.