Nrf2 Knockout Mice Incur Exacerbated Hippocampal Neuron Loss And Associate With Deteriorated Significant Cognitive Impairment After Free Drop Head Injury

Background and Purpose:Traumatic brain injury (TBI) is always associated with neuron apoptosis, the most vulnerable region is hippocampus, mechanism of this pathological process is not fully understood, and past research revealed the increased apoptosis is consequence of oxidative stress, inflammatory response et al. The endogenous antioxidative transcription factor Nrf2 has been revealed to have neuroprotective effect against TBI, however, if Nrf2 has the function of resistant to hippocampal dysfunction and neuron loss have not been investigated. The present study was designed to quantitatively describe metabolic change and pathological alteration in the hippocampus after brain injury, the cognitive impairment which is associated with hippocampal neuron loss was also investigated.Methods:In this study, Nrf2 knock-out and control wild type mice were subjedted to free drop TBI,72 hours after injury, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were examed using 7.0 T magnetic resonance image scanner of the brain and proton MRS in the right hippocampus. Hippocampal cellular density at the 7th day post injury was evaluated with Nissl staining. Morris Water Maze task was tested in other groups of Nrf2 (+/+) and Nrf2 (-/-) mice from 14th day post TBI or sham treatment.Results:In the free drop closed head injury model, no significant lacerations were detected at the site of impact, however, edema signal was seen at the bottom of both frontotemporal lobes, the hippocampi were apparently normal at T1, T2 and DWI images. Nevertheless, hippocampi of the injured mice had significant reduction in NAA relative to Cr ratio compared to uninjured mice; Nrf2 knockout mice had significant deteriorated reduction in NAA relative to Cr ratio compare to wild type littermates in the hippocampus. The metabolic consequence correlated with neuron loss in the hilus of hippocampus revealed in the pathological study. In the MWM study, Nrf2 knockout and wild type shame mice groups performed equally well in spatial learning task, both genotype animal showed impaired performance following TBI. Compare with Nrf2 (+/+) TBI mice, those mice null of Nrf2 had lengthier latency in finding the hidden platform and shortened time spent in target quadrant exploration during probe test (p< 0.05), however, both genotype groups had improved performance in visible platform test which indicated that the deficits were not due to visual impairment; and both groups had similar swim speed (p>0.05), which suggested cognition impairment rather than motor impairment caused the poorer MWM performance in mice deficient of Nrf2.Conclusion:This study highlights a crucial role for disruption of Nrf2 result in increased vulnerability of hippocampus and cognitive impairment to TBI, which indicated that neuroprotective effect of Nrf2 pathway for cognition in TBI.