Nrf2 Deficiency Exacerbates Cognitive Impairment and Reactive Microgliosis in a Lipopolysaccharide-Induced Neuroinflammatory Mouse Model.

The transcription factor Nrf2 is a central regulator of anti-inflammatory and antioxidant mechanisms that contribute to the development and progression of various neurological disorders. Although the direct and indirect Nrf2 regulatory roles on inflammation have been reviewed in recent years, the in vivo evidence of Nrf2 function on lipopolysaccharide (LPS)-induced cognitive decline and characteristic alterations of reactive microglia and astrocytes remains incomplete. During the 3-5 days after LPS or saline injection, 5-6-month-old wildtype (WT) and Nrf2-/- C57BL/6 mice were subjected to the novel object recognition task. Immunohistochemistry staining was employed for analyses of brain cells. The Nrf2-/- mice displayed exacerbated LPS-induced cognition impairment (28.1 ± 9.6% in the discrimination index of the novel object recognition task), enhanced hippocampal reactive microgliosis and astrogliosis, and an increased expression level of the water channel transmembrane protein aquaporin 4 when compared with WT controls. In addition, similar overt effects of Nrf2 deficiency on LPS-induced characteristic alterations of brain cells were observed in the cortex and striatum regions of mice. In summary, this transgenic loss-of-function study provides direct in vivo evidence that highlights the functional importance of Nrf2 activation in regulating LPS-induced cognitive alteration, glial responses, and aquaporin 4 expression. This finding provides a better understanding of the complex nature of Nrf2 signaling and neuroprotection.

Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury.

Recently, dimethyl fumarate (DMF) and Korean red ginseng (ginseng), based on their purported antioxidative and anti-inflammatory properties, have exhibited protective potential in various neurological conditions. Their effects on cerebral ischemia and underlying mechanisms remain inconclusive; however, increasing evidence indicates the involvement of the transcriptional factor Nrf2. This study evaluated the preventive effects of DMF and ginseng on hippocampal neuronal damage following hypoxia-ischemia (HI) and assessed the contributions of reactive gliosis and the Nrf2 pathway. Adult wild type (WT) and Nrf2-/- mice were pretreated with DMF or ginseng for 7 days prior to HI. At 24 h after HI, DMF or ginseng significantly reduced infarct volume (52.5 ± 12.3% and 47.8 ± 10.7%), brain edema (61.5 ± 17.4% and 39.3 ± 12.8%), and hippocampal CA1 neuronal degeneration, and induced expressions of Nrf2 target proteins in WT, but not Nrf2-/-, mice. Such hippocampal neuroprotective benefits were also observed at 6 h and 7 days after HI. The dynamic attenuation of reactive gliosis in microglia and astrocytes correlated well with this sustained neuroprotection in an Nrf2-dependent manner. In both early and late stages of HI, astrocytic dysfunctions in extracellular glutamate clearance and water transport, as indicated by glutamine synthetase and aquaporin 4, were also attenuated after HI in WT, but not Nrf2-/-, mice treated with DMF or ginseng. Together, DMF and ginseng confer robust and prolonged Nrf2-dependent neuroprotection against ischemic hippocampal damage. The salutary Nrf2-dependent attenuation of reactive gliosis may contribute to this neuroprotection, offering new insight into the cellular basis of an Nrf2-targeting strategy for stroke prevention or treatment.

Nrf2 Plays an Essential Role in Long-Term Brain Damage and Neuroprotection of Korean Red Ginseng in a Permanent Cerebral Ischemia Model.

Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation, and therefore represents a promising target for stroke intervention. However, the long-term effects of Nrf2 and the standardized Korean red ginseng (ginseng), a potent Nrf2 natural inducer, on permanent cerebral ischemic damage have not yet been reported. Wildtype (WT) and Nrf2-/- adult mice were pretreated with either vehicle or ginseng, and were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrocytes and microglia, and the water regulatory protein aquaporin 4 (AQP4) were examined at 28 days after stroke. When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume (40.4 ± 10.1%) and exacerbated the progression of reactive gliosis and AQP4 protein levels after pdMCAO. In contrast, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3 ± 6.9%), but not in the Nrf2-/- mice (25.5 ± 5.6%). In conclusion, Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and the neuroprotection of ginseng.