| Background and objectiveTraumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunction. TBI is accompanied by neuroinflammation, a process medicated largely by microglia/macrophages and astrocytes. In the central nervous system, neuroinflammation is generally beneficial and allows the brain to response to changes in its environment and to dispose of damage tissue or undesirable substances. However, this beneficial process sometimes gets out of balance. Uncontrolled neuroinflammation is considered to play an important role in the pathogenesis of secondary brain injury following traumatic brain injury (TBI). Recent researches have demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that regulates the cellular antioxidant response, plays a broader role in modulating acute inflammatory response.Under basal conditions, Nrf2 is sequestered in the cytoplasm by the cytosolic regulatory protein Keapl. In conditions of oxidative or xenobiotic stress, Nrf2 translocates from the cytoplasm to the nucleus, and sequentially binds to a promoter sequence called the antioxidant response element (ARE), resulting in a cytoprotective response which is characterized by upregulation of a group of antioxidant enzymes and decreased sensitivity to oxidative damage. These antioxidant enzymes have also been shown to protect cells against acute inflammatory response. Numerous studies have reported that Nrf2 plays a critical role in counteracting inflammation in a variety of experimental models. Nrf2 protects against cigarette smoke-induced emphysema, dextran sulfate sodium (DSS)-mediated colitis, and inflammation-mediated colonic tumorigenesis. Furthermore, Nrf2 has also been reported as a crucial regulator of the innate immune response and survival during experimental sepsis. In one of our previous studies, we have also demonstrated that TBI could induce Nrf2-ARE pathway activation in brain, and nuclear Nrf2 localization was observed mainly in glial cells. So we hypothesize that Nrf2 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of Nrf2 on microglia and astrocytes responses.MethodsNrf2-deficient and wild-type (WT) mice were confirmed by PCR. Nrf2-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurological status was assessed by the Neurological Severity Score (NSS) at various time points post-injury. In addition, the amount of activated microglia and astrocytes in the vicinity of the injured area was also observed.ResultsThe neurological deficits of the Nrf2-deficient mice from the injury were aggravated compared with wild-type mice. A significant and substantial increase in the amount of activated microglia was observed in Nrf2-/-mice, compared with WT mice, as early as 1 day post-injury, the extent of this difference risen on day 3(P<0.01), and still has statistical differences until 7 days post-injury. Moreover, the activation of astrocytes marked by GFAP was also significantly exacerbated in Nrf2 (-/-) mice than in Nrf2 (+/+) mice on day 3 (P<0.05) and day 7(P<0.01) after TBI.ConclusionsThe disruption of Nrf2 aggravates neuropathology after CHI and that this effect is medicated, at least in part, via the effect of Nrf2 on glial responses. |
