Neuroglobin overexpression improves sensorimotor outcomes in a mouse model of traumatic brain injury

Abstract

There is a significant need for novel treatments that will improve traumatic brain injury (TBI) outcomes. One potential neuroprotective mechanism is to increase oxygen binding proteins such as neuroglobin. Neuroglobin has a high affinity for oxygen, is an effective free radical scavenger, and is neuroprotective within the brain following hypoxia and ischemia. The purpose of this study was to determine whether neuroglobin overexpression improves sensorimotor outcomes following TBI in transgenic neuroglobin overexpressing (NGB) mice. Additional study aims were to determine if and when an endogenous neuroglobin response occurred following TBI in wild-type (WT) mice, and in what brain regions and cell types the response occurred. Controlled cortical impact (CCI) was performed in adult (5 month) C57/BL6 WT mice, and NGB mice constitutively overexpressing neuroglobin via the chicken beta actin promoter coupled with the cytomegalovirus distal enhancer. The gridwalk task was used for sensorimotor testing of both WT and NGB mice, prior to injury, and at 2, 3, and 7 days post-TBI. NGB mice displayed significant reductions in the average number of foot faults per minute walking at 2, 3, and 7 days post-TBI when compared to WT mice at each time point. Neuroglobin mRNA expression was assessed in the injured cortex of WT mice prior to injury, and at 1, 3, 7, and 14 days post-TBI using quantitative real time polymerase chain reaction (qRT-PCR). Neuroglobin mRNA was significantly increased at 7 days post-TBI. Immunostaining showed neuroglobin primarily localized to neurons and glial cells in the injured cortex and ipsilateral hippocampus of WT mice, while neuroglobin was present in all brain regions of NGB mice at 7 days post-TBI. These results showed that overexpression of neuroglobin reduced sensorimotor deficits following TBI, and that an endogenous increase in neuroglobin expression occurs during the subacute period. Increasing neuroglobin expression through novel therapeutic interventions during the acute period after TBI may improve recovery.

Diagnostic and Prognostic Interests of Plasmatic Neuroglobin during Stroke in Adult at the Acute Phase

“…Thus, despite the fact that we have not been able to monitor the CmNgb early (that is to say from the installation of the initial symptomatology until admission to the service), our results support the idea that elevation of CmNgb is a function of the duration of stroke [11] [53]. This elevation of Ngb in the acute phase of stroke may be explained by the ischemic nature of the initial lesion and/or because stroke (ischemic or hemorrhagic) is usually complicated by initial or secondary cerebral ischemia, with cell lysis, favoring the progressive overexpression of Ngb at the cerebral level and secondarily the release in the plasma [24] [53]. In this case, this result suggests CmNgb as a biological element of monitoring, at least during the early and critical phase of stroke [11] [12] [13].…”

“…In the human, two studies done by Jin et al in 2010 and 2013 had noted overexpression of Ngb, respectively in infarcted area of CI, and in peri-hematoma area during ICH secondary to a rupture of venous arterial malformations. According to them, these results supported the neuroprotective role of Ngb during ischemic events in the central nervous system, including stroke [13] [23] [24] [25] [26] [27]. Stroke (Cerebral infarction or CI, and intracerebral hemorrhage or ICH) is a common pathology in Africa World Journal of Neuroscience [28]- [33].…”

“…As part of neuroprotection during acute cerebral infarction, Ngb has been widely evaluated from other vertebrates, but very little in humans [13] [23] [24] [25] [26] [27]. Indeed, in rodents, it has been shown that stroke induced after carotid occlusion is responsible for high plasmatic concentration of Ngb.…”

Amyloid-β Protein and Neuroglobin Protein as Biomarkers on Brainstem Following Traumatic Brain Injury in Rats

“…NGB was a novel discovered globin in 2000, which is an oxygen-binding protein that supplies oxygen to hypoxic tissue [66]. Evidence exists to support that NGB play an important role, which is upregulated after TBI to assist in promoting cell survival [67].…”

“…Hypoxia commonly occurs as a secondary injury response to TBI, NGB expression protects neurons from cell death and reactive oxygen species damage [30,31]. Multiple neuroprotective effects operate by different mechanisms, including inhibit calcium in ux, reduce cellular uptake of iron, copper, and zinc, suppress necrosis and apoptosis, and several studies suggest that NGB may positively affect TBI outcomes [32,33]. The reported results indicated that there was a late, but signi cant, increase in NGB mRNA expression 7 days post-TBI in WT mice and the subacute increase occurred later that were known to be upregulated at 3 days post-TBI [32].The previous work in the rat and mouse also showed increased NGB expression levels with peak time of 6 hours after TBI [34].…”