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Reviewer Article

Agricultural Reviews, volume 42 issue 4 (december 2021) : 359-370

Comparative Study of the Distribution and Localization of Neuroglobin Expression in the Mammalian Brain: A Literature Review

James Blackar Mawolo1,*, Caselia Akiti2
1College of Life Science and Technology, Gansu Agricultural University, Lanzhou City, Gansu Province, People’s Republic of China.
2Center for Endemic Disease Control, China Center for Disease Control and Prevention, Harbin Medical University, China.
Cite article:- Mawolo Blackar James, Akiti Caselia (2021). Comparative Study of the Distribution and Localization of Neuroglobin Expression in the Mammalian Brain: A Literature Review . Agricultural Reviews. 42(4): 359-370. doi: 10.18805/ag.R-153.

ABSTRACT

Neuroglobin (Ngb) was recently identified as a member of the vertebrate hemoglobin family. Several studies have been conducted on Ngb in mammals, but none have compared its expression and localization among different mammals. This review compared the distribution and localization of Ngb expression and explained the different functions of Ngb in the brains of mammals. Intel’s integrated performance primitive (IPP) analysis was employed to obtain the expression levels in each region of the mammalian brain. Ngb is widely expressed in the adult yak brain and distributed in different areas, similar to its expression in cattle. The relative expression of the Ngb gene in the cerebral cortex (262.69 ± 9.19) was significantly higher than that in the cerebellar cortex (137.00 ± 7.29), hippocampus (1.00 ± 0.22), medulla oblongata (3.43 ± 0.76), striatum (7.65 ± 0.61) and olfactory bulb (2.14 ± 1.22). Findings in the rat brain showed low Ngb protein expression. The mouse brain showed Ngb over expression in a transgenic variant (Ngb-Tg), while in the human brain, the level of Ngb was higher in the hypothalamus, amygdala and pontine tegmental nuclei than in other parts of the brain. The expression levels, distribution and localization of Ngb differ across the brains of different mammals, so it is appropriate to explore the precise distribution and localization of Ngb before comparison or analysis in these mammals.

INTRODUCTION

Neuroglobin (Ngb) was identified as a novel endogenous neuroprotectant by scientists but the regulatory role of this protein still remains under debate (Adelman et al., 2000). Although it is a hypoxia-inducible protein, Ngb has a cytoprotective effect in Alzheimer’s disease and related disorders in animal model of stroke (Adelman et al., 2000). Ngb binds reversibly to oxygen and has varying levels of expression in different areas of the brain (Burmester et al., 2000; Dewilde, 2001). Ngb in mammals protects neuronsin the brain from hypoxic-ischemic insults and experimentally induced stroke in vivo (Sun et al., 2001; Sun, 2003). Additionally, Ngb is 151 amino-acids long with a molecular mass of 17 kDa which has shown to promote neuron survival under hypoxia and could potentially limit brain damage (Burmester et al., 2000; Dewilde, 2001). It is an intracellular hemoprotein expressed in the central and peripheral nervous system, cerebrospinal fluid, retina and endocrine tissues (Pesce et al., 2002). It has hexa-coordinated heme-Fe atoms that display O2 affinities comparable to those of myoglobin (Pesce et al., 2002; Reuss et al., 2002). It is hypothesized that this protein enhances the O2 supply to the mitochondria of the metabolically active neurons and resides in metabolically active cells and subcellular compartments (Pesce et al., 2002). Also, the concentration of neuroglobin is closely correlated to the distribution of mitochondria; however, it is not entirely localized in specific organelle (Reuss et al., 2002). The exact localization of Ngb is still unclear. Several studies have demonstrated the expression of Ngb in mammalian brains, but no study has compared its expression level and localization in different mammals. Ngb has been found in the cerebral cortex, cerebellar cortex, hippocampus, medulla oblongata, striatum and olfactory bulb of the adult yak (Tong-fang et al., 2015). This research also showed the Ngb distribution in brain tissues (Tong-fang et al., 2015). In every area of the brain, Ngb decreases with increasing age, stabilizing at approximately 24 months (Ni et al., 1992). Research conducted on the rat brain showed that Ngb expression changed minimally in the control group than the subarachnoid hemorrhage (SAH) (Wei-De et al., 2013).
       
Ngb was shown to be highly expressed in the brains of mice with traumatic brain injury (TBI); specifically, TBI resulted in significantly increased expression of Ngb, with the post injury protein levels significantly higher than the pre injury levels (Zhao et al., 2012). According to this report (Zhao et al., 2012), higher expression of Ngb limits the volume of traumatic lesions, by reducing oxidative stress. Research has shown that human Ngb was previously present in uncharacterized cDNA databases (expressed sequence tags, ESTs), as shown in both the mouse and human brains (Burmester et al., 2000). Following this study, several other investigations were conducted involving Ngb in humans. The results mentioned here regarding the human brain showed that Ngb is highly expressed in various regions (the hypothalamus, amygdala and pontine tegmental nuclei), but not in the hippocampus (Hundahl et al., 2013). The expression of Ngb in the cerebral cortex is limited but it is enhanced and controls stroke in the human brain (Hundahl et al., 2013). In addition, scientists have shown that Ngb might be a target for pharmaceutical intervention because it is widely expressed in the human brain and plays a regulatory role in the peri-infarct zone of stroke patients (Jin et al., 2010). Ngb is also widely expressed in other animals, but this review focuses on the above mentioned mammals. Given the reported results, it is appropriate to explore the Ngb distribution and localization in detail before conducting a more thorough investigation.
 
Survey methodology
 
Several studies have been conducted on the expression of Ngb in mammals. However, only a few of these studies have presented explanations for the distribution and localization of Ngb expression and none of them have compared the distribution and localization patterns across different mammals. Therefore, this study collected, documented and compared detailed results on Ngb in different mammals. The literature search was conducted by using the following search term: “The distribution and localization of neuroglobin expression in mammals’’. As there are few studies on the distribution and localization of Ngb expression, the authors included available information found in scientific databases, from reading available books and reports and from searching scholarly journals for research articles on the mammals involved in this study. In addition, Intel’s integrated performance primitives (IPP) analysis was employed to obtain the level of Ngb expression in each region of the mammalian brain. In this literature review, the authors respected the original authors’ definitions, descriptions, methodology and the reported results. During the literature review search, various information and results were obtained on the expression of Ngb, but the review’s objectives were prioritized.
       
The authors are aware that there might be doubts with regard to the analytical results presented in some of the figures or tables. It should be understood, however, that each laboratory uses a specific analytical tool and that it is practically impossible to streamline the results in such a way that they could be compared using the same standards. The readers are referred to the original articles for further details. Below are the methods used by the original authors to obtain specific results.
       
A study conducted on the adult yak showed the distribution of Ngb in the yak brain (Tong-fang et al., 2015) (Fig 1). The results showed that Ngb could be expressed in the following areas: A. Neurons of yak cerebral cortex, I and IV showed the laminae I, VI of cerebral cortex, M. indicates medulla, bar= 200 µm; B. Neurons of yak cerebellar cortex, ML. Indicates molecular, PCL, indicates Purkinje cell, GL. indicates granular layer, M. indicates medulla, bar= 100 µm; C. Neurons of yak hippocampus, bar= 20 µm; D. Striatum, bar= 200 µm; E. Olfactory bulb, bar= 100 µm; F. Medulla oblongata, bar= 100 µm; Arrow shows Ngb-positive cells.
 

Fig 1: Distribution of Ngb in different areas of the adult yak brain (Tong-fang et al., 2015).


       
According to a study done by Liang et al., (2013) on the distribution of Ngb in different neuronal regions of the adult yak (Fig 2). Ngb was mainly expressed in the following areas of the brain as compared to the study done by Tong et al., (2015). The quantities of expression and distribution pattern differ. The localization of distribution almost similar (Plate 1). The expression of NGB in neurons of yak cerebral cortex. I and VI represent the I and VI layers of the cerebral cortex, M. the medulla of the brain, Immunohistochemistry bar= 200 μm (Plate 2). The expression of NGB in Neurons of yak hippocampal shows the NGB positive-cells. Immunohistochemical staining bar= 20 μm (Plate 3). The expression of Ngb in neurons of the yak medulla oblongata. N-neurons show the NGB positive-cells. Immunohistochemical staining bar= 100 μm (Plate 4). The expression of Ngb in neurons of yak cerebellar cortex. ML-Molecular; PCL-Purkinje cell; GL-Granular layer; M-Medulla; shows the NGB positive-cells. Immunohistochemical staining bar= 100 μm (Plate 5). The expression of Ngb in neurons of yak spinal cord. VH-Ventral; WM-White matter; N-Neurons shows the NGB positive-cells. Immunohistochemical staining bar= 100 μm (Plate 6). The expression of Ngb in yak adrenal cortex. Co-Cortex; M-Medulla shows the NGB positive-cells. Immunohistochemical staining bar= 100 μm (Plate 7). The expression of NGB in neurons of the yak cerebral cortex. I and VI represent the I and VI layers of the cerebral cortex, M-the medulla of the brain, Immunohistochemistry bar= 200 μm (Plate 8). The expression of NGB in neurons of yak hippocampal shows the NGB positive-cells. Immunohistochemical staining bar= 20 μm (Plate 9). The expression of Ngb in neurons of the yak medulla oblongata. N neurons show the NGB positive-cells. Immunohisto- chemical staining bar= 100 μm (Plate 10). The expression of Ngb in neurons of the yak cerebellar cortex. ML-Molecular; PCL-Purkinje cell; GL-Granular layer; M-Medulla; shows the NGB positive-cells. Immunohisto- chemical staining bar= 100 μm (Plate 11). The expression of Ngb in neurons of yak spinal cord. VH-Ventral; WM-White matter; N-Neurons shows the NGB positive-cells. Immunohistochemical staining bar= 100 μm (Plate 12). The expression of Ngb in the yak adrenal cortex. Co-cortex; M-Medulla shows the NGB positive-cells. Immunohisto-chemical staining bar= 100 μm (Table 1a) comparison of the studies from Liang et al., (2013) and Tong-fang et al., (2015) showed the Ngb distribution in different regions of the adult yak brain. Expression was found mainly in the following areas: A. Yak cerebral cortex neurons: laminae; M indicates medulla (200 µm). B. Yak cerebellar cortex neurons: molecular, Purkinje cell and granular layers; medulla (100 µm). C. Yak hippocampus neurons (20 µm). D. Striatum (200 µm). E. Olfactory bulb (100 µm). F. Medulla oblongata (100 µm) (Tong-fang et al., 2015).
 

Table 1: Quantitation of Ngb distribution in the adult yak brain.


 

Fig 2: Expression of Ngb in different regions of the yak brain Liang et al. (2013).


       
The results from Liang et al., (2013) showed that Ngb proteins are expressed in the following areas: the neurons of the cerebral cortex (200 µm), cerebral cortex layers I and IV (200 µm), medulla (200 µm), neurons of the hippocampus (20 µm), spinal cord (100 µm), ventral region (100 µm), white matter (100 µm), neurons (100 µm), adrenal cortex (100), cortex (100) and medulla (100 µm) (Liang et al., 2013).
       
Table 2 which was replicated from one of the included studies (Liang et al., 2013) on the adult yak, different lowercase letters in each column indicate a normal level of significance (P<0.05), while capital letters indicate a high level of significance (P<0.01). The Ngb expression levels in different areas of the adult yak brain were significantly different. The relative expression of the Ngb gene in the cerebral cortex was significantly higher than that in the cerebellar cortex, medulla oblongata, striatum and olfactory bulb. The expression level in the hippocampus was different from that in the other regions, with a high level of significance.
 

Table 2: Mean Ct values and relative content of neuroglobin (Ngb) in the brain of yak brain.


       
Table 3 shows positive (+) = expression of Ngb, negative (-) = no expression. This table shows that Ngb is widely expressed in different regions in mammals.
 

Table 3: Distribution and expression of neuroglobin (Ngb) in the brain of mammals.

  
 
Table 4 shows the results of double immunofluorescence staining to determine Ngb expression and distribution. The study reported that Ngb was expressed at a lower level in the control group and significantly more highly expressed in the SAH group after 24 h (Wei-De et al., 2013). Ngb was expressed in regions similar to those found in the yak study.
 

Table 4: Ngb expression in the control group/level of Ngb expression in the control group.


 
Expression levels after subarachnoid hemorrhage (SAH)
 
Study conducted on the rat brain reported that WB analysis was conducted to show the levels of Ngb protein found in the post-SAH temporal cortex (Wei-De et al., 2013). The level of Ngb expression was reported lower in the control group (Wei-De et al., 2013). Following induction of SAH, the levels of Ngb protein increased after 24 h and then decreased between 48 and 72 h after SAH (Wei-De et al., 2013). There was a significant difference in the expression level between the control group and the SAH group after 24 h. In addition, the quantitative real-time PCR analysis was performed to show the level of Ngb protein expression in the brain of rat (Wei-De et al., 2013). The level of Ngb in the control was low, while in the SAH groups (Wei-De et al., 2013),  the Ngb levels increased early after 3 h after SAH and reached a maximum at 6 h, which was three times than the control group. The Ngb rate gradually decreased after this time.
 
Immunohistochemical study of Ngb after subarachnoid hemorrhage (SAH)
 
In a study by Wei et al., (2013). immunohistochemical analysis was performed to locate Ngb in the control group and the SAH group after 24 h. Table 4 shows Ngb-positive cells in the temporal cortexes of the control group and the SAH group after 24 h. Less Ngb was observed in the control group. The SAH group showed significantly more Ngb-positive cells in the cerebral cortex after 24 h (Wei-De et al., 2013). Ngb expression was also observed in neurons (Wei-De et al., 2013). The semi-quantitative results demonstrated that the level of Ngb was significantly different in the temporal cortexes of the SAH group (80.5%) and the control group (55.3%) after 24 h (p<0.01).
 
Ngb expression among the mammals
 

According to the study performed by Hundahl et al., (2013). Ngb has a smaller distribution, weaker expression and fewer effects on neuronal morphology in the human brain than in the rodent brain. Low levels of Ngb expression were found in small neurons of the cerebral cortex and the protein was less widely distributed in the medium-sized neurons but had clear expression (Hundahl et al., 2013). As in yaks and mice, Ngb was also found in the cerebral cortex, but the relative expression level differed. Sections of the hypothalamus showed that Ngb-IR was scattered and observed in the processes of large neurons. As in yaks, Ngb was also found in the hypothalamus (Tong-fang et al., 2015). No Ngb-IR was observed in the striatum of humans, unlike yaks (Tong-fang et al., 2015). The greatest distribution was observed in the nuclei of the hindbrain pontine, while the strongest Ngb expression in the yak was in the cerebral cortex (Hundahl et al., 2013). Overall, Ngb was highly co-expressed in the laterodorsal tegmental area and weakly expressed in other brain areas (Hundahl et al., 2013).

 
Yak
 
The distribution and expression of Ngb in various regions of the adult yak brain were demonstrated by the immunohistochemical staining ISPs method and real-time fluorescence quantitative PCR as shown in Fig 1 (Tong-fang et al., 2015). The results indicated that Ngb was widely distributed in different regions of the adult yak brain (Tong-fang et al., 2015), while in the human brain (Hundahl et al., 2013), Ngb had a more limited levels of distribution, weaker expression and fewer effects on neuronal morphology (Tong-fang et al., 2015). These differences could be the result of the varied methods and laboratory procedures used in each study. Ngb participation in the uptake and storage of oxygen by nerve cells can improve the rate of oxygen usage by nerve cells (Sun et al., 2001). Ngb upregulation can protect nerve cells, improving the tolerance of brain tissue to ischemia and hypoxia and reducing damage to the brain under these conditions (Greenberg et al., 2001). As yaks live in a high-altitude hypoxic environment for a long period, the levels of Ngb in different regions of the brain perform key functions in enhancing the oxygen utilization rate (Zhang et al., 2008). The nervous system maintains the normal physiological function of the brain (Zhang et al., 2008). Due to the high expression of Ngb in functional nuclei, the function of oxygen storage may be closely related (Dewilde, 2001); however, this expression may also reflect the difference in activity and oxygen consumption in different areas of the brain. In addition, the distribution of Ngb in other regions of the brain and in the cells of the yak may also be related to the oxygen-consuming activities of these regions and cells (Zivin, 2008). First, the expression of the Ngb gene in different regions of the yak brain was found by fluorescence quantitative PCR and the results showed significant differences in the expression of Ngb in various areas of the yak brain. The level of Ngb quantity of expression in the cerebral cortexwas the most significant (Tong-fang et al., 2015). Compared to its expression in humans, a large amount of Ngb was observed in the hypothalamus, but the difference was not significant (Hundahl et al., 2013). Both yaks and mice showed Ngb in the cerebral cortex, but the levels of expression differed (Tong-fang et al., 2015; Wei-De et al., 2013). The rat brain also showed higher expression in the cerebral cortex, but the difference was not significantly different compared to the other brain regions (Guo et al., 2011). The positive expression of Ngb in the cerebral cortex of yaks was significantly higher than that in the cerebellar cortex, hippocampus, medulla oblongata, striatum and olfactory bulb (Wang et al., 2004).
 
Yaks and cattle
 
The study of the immunohistochemistry to show the distribution of Ngb in the brain of the adult yak (Liang et al., 2013) as shown in Fig 2. All twelve (12) layers of the cerebral cortex contained Ngb-positive cells that were distributed throughout the layers and the level of expression was significantly higher than that in the cerebellar cortex, hippocampus and striatum (Liang et al., 2013). Ngb-positive cells were also found in the medulla (Liang et al., 2013). The Ngb distribution and localization were similar in the cerebral cortexes of the cattle and yaks (Tong-fang et al., 2015). The overall levels of Ngb expression in the brains of cattle were lower than those in the brain of yaks (Liang et al., 2013). In the cerebellar cortex of the yak, Ngb-positive cells showed high levels of expression in purkinje cell layers and lower levels in the granular layers (Liang et al., 2013). The distribution and localization of Ngb-positive cells in the cerebellar cortex of cattle was similar to that in the yak, but the intensity of the reaction was weaker overall (Liang et al., 2013). In various regions of the hippocampus in the yak, Ngb-positive cells were mostly found in pyramidal cells, with positive reaction sites but weak Ngb expression found in nerve processes (Liang et al., 2013). The similarities of these results might be due to the identical methods and laboratory procedures used. In separate areas of the cattle hippocampus, the distribution and localization of Ngb-positive cells were similar to those of the yak, but the intensity of the reaction was weaker in the yak brain (Tong-fang et al., 2015). Additionally, in the medulla oblongata of cattle and yaks, the distribution and localization of Ngb-positive cells were weakly expressed and the overall intensity was weaker in the cattle than in the yak (Tong-fang et al., 2015). Ngb-positive cells in the striatum of the yak were widely distributed in the caudate nucleus and the Ngb-positive reactions were stronger than those in the hippocampus, medulla oblongata and olfactory bulb, but Ngb was more weakly expressed than in the cerebral cortex and cerebellar cortex (Liang et al., 2013). In the medulla oblongata of the yak, Ngb-positive cells were mainly distributed in the gray matter (Liang et al., 2013) and Ngb-positive cells were also scattered in the white matter (Liang et al., 2013). Ngb was also expressed in the mitral cell layer of the yak olfactory bulb, with notable staining and large cells (Liang et al., 2013); however, the staining intensity of the Ngb-positive cells was weaker than that of medulla oblongata and stronger than that of the hippocampus (Liang et al., 2013). The distribution and localization of Ngb-positive cells in the mitral cell layer of the olfactory bulb of the cattle was similar to that of the yak (Tong-fang et al., 2015); the staining intensity was higher than that of the hippocampus, weaker than that of the medulla oblongata and significantly weaker than that of yak (Tong-fang et al., 2015). Ngb-positive cells were distributed primarily in the peripheral nerve plexus and ganglia and mostly scattered in some of the nerve cells in the peripheral nervous system but at low quantities (Liang et al., 2013). In the peripheral nervous system of the cattle, the distribution and localization of the Ngb-positive cells were similar to those of the yak, but the intensity of the reactions was on average weaker than that of the yak (Tong-fang et al., 2015). Ngb is distributed in the cortex and medulla, similar to that observed in rats and human (Wei-De et al., 2013; Hundahl et al., 2013).
       
The 2-DDCt values of the Ngb gene in the adult yak cerebral cortex, cerebellar cortex, medulla oblongata, striatum, olfactory bulb, adrenal gland, abomasum and duodenum tissue were 262.69, 137.00, 3.43, 7.65, 2.14, 7.82, 16.26 and 30.23, respectively (Tong-fang et al., 2015). The Ngb gene expression levels in the above brain regions were 262.69 times, 137.00 times, 3.43 times, 7.65 times, 2.14 times, 7.82 times, 16.26 times and 30.23 times higher than the expression levels, respectively, of the hippocampus (Tong-fang et al., 2015).
       
The above reported results are similar to the results obtained with immunohistochemistry (Tong-fang et al., 2015). Ngb gene expression was significantly higher in the cerebral cortex and cerebellar cortex than in other areas. In contrast, the lowest expression levels were in the medulla oblongata, olfactory bulb and hippocampus (Tong-fang et al., 2015). The 2-DDCt values of the Ngb gene in the cerebral cortex, cerebellar cortex, medulla oblongata, striatum, olfactory bulb, adrenal gland, abomasum and duodenum tissue of the cattle were 165.53, 136.29, 1.53, 1.98, 2.19, 4.18, 12.91 and 20.29, respectively (Tong-fang et al., 2015). The Ngb gene expression in the cerebral cortex and the cerebellar cortex was the highest among and significantly higher than that in the other tissues (Tong-fang et al., 2015). The lowest expression levels were found in the striatum, medulla oblongata, olfactory bulb and hippocampus (Tong-fang et al., 2015).
 
Expression of Ngb in the nerve cells of the adult yak
 
Some researchers observed that positive expression of Ngb in the adult yak nervous system was mainly in the brain, which was basically consistent with the results of RNA dot hybridization in humans and mice (Burmester et al., 2000). Various parts of the brain showed significant Ngb expression (Tong-fang et al., 2015). In the cerebral cortex, positive expression was significantly higher than that in the hippocampus, cerebellum and thalamus (Tong-fang et al., 2015). This observation was consistent with the sensitivity of different regions of the brain (Zivin, 2008). Ngb participation in the uptake and storage of oxygen by nerve cells can improve the rate of oxygen usage by nerve cells (Greenberg et al., 2001). Ischemia and hypoxia (Greenberg et al., 2001) can also enable the upregulation of Ngb expression, protect nerve cells, improve the tolerance of brain tissue to ischemia and hypoxia and reduce damage to the brain under these conditions (Greenberg et al., 2001). Higher Ngb expression in the brain is important for enhancing the oxygen utilization rate of the yak nervous system and maintaining the normal physiological function of the brain (Tong-fang et al., 2015). Shang et al., (2006) used immunofluorescence double-labeling staining to identify the syndromes. Endogenous Ngb is specifically present in rat neurons, which was also observed in the study by Laufs et al., (2004). Positive Ngb expression was observed innerve cells, similar to what was reported in the studies by Shang et al., (2006) and (Shang et al., 2006; Laufs et al., 2004) and in astrocytes cultured in vitro, as reported by in the studies by Chen et al., 2012 and Aviv et al., (2010); Khan et al., 2008). The expression of Ngb in glial cells could be related to the oxygen-consuming physiological activity of these cells (Avivi et al., 2010; Khan et al., 2008). The specific location of Ngb needs further confirmation. The distribution and localization of Ngb in the adult yak spinal cord were mainly in poliomyelitis neurons, especially in anterior horn somatic motor neurons, similar to the results of the study by Shang et al., (2006) study. The distribution of Ngb in the spinal cord adapts to the function of the corresponding region. In addition, these results indicate that Ngb is widely involved in the physiological activities of the spinal cord. There was no positive expression of Ngb, which was similar to the results of the study by Reuss et al., (2002); (Hundahl et al., 2011).
 
Expression of Ngb in the rat brain
 
A pilot study (Wei-De et al., 2013) conducted on the rat brain investigated the expression level and distribution pattern of Ngb in the temporal cortex of an SAH model. The key findings were as follows: (1) The expression of the Ngb protein in the control rat brain was low and it increased gradually after SAH until reaching a maximum 24 h later (Wei-De et al., 2013). (2) After SAH, the mRNA of Ngb increased at 3 h and reached a maximum at 6 h (Wei-De et al., 2013). (3) In the cerebral cortex, Ngb was highly expressed and the proportion of Ngb-positive cells in the temporal cortex was 80.5% (24 h after SAH group) which was greater than that of the control group (55.3%) (Wei-De et al., 2013). (4) In addition to astrocytes, Ngb was observed in neuronal and microglial cells (Wei-De et al., 2013). The results showed that Ngb plays an important role in protecting the brain (Wei-De et al., 2013). The results from different studies have shown that the Ngb protein increases immediately after injury caused by hypoxic ischemia (Sun et al., 2013). In addition, the proportion of Ngb increased dramatically, as indicated by WB, immunohistochemistry and double immunofluorescence staining (Sun et al., 2013). As suggested by neuronal expression, Ngb plays an important role following SAH (Sun et al., 2013). In 2000, a study conducted by Brumester et al., (2000) first identified Ngb in neurons, which was further confirmed in the studies reviewed here. Since its discovery, several studies have been conducted on the structure, molecular mechanisms and neuroprotective effect of Ngb. Some studies have confirmed that Ngb, as a heme proteins contains monomeric. The sequence identity of Ngb with vetebrate myoglobin and hemoglobin has been shown to be 21 and 25% respectively (Brumester et al., 2000; Pesce et al., 2003).             

In contrast to myoglobin and hemoglobin, the proximal and distal histidines located in the pocket of the heme in the Ngb protein can be bind directly to the heme iron (the Fe2 or Fe3 oxidation states) because of the his-histidine six-coordinate heme geometry (Dewilde, 2001). A study reported by Kriegl et al., (2002) rationalized the six-coordinate bond displacement with the distal histidine 64 residue. The binding of several ligands to heme iron can be enabled by Ngb, not excluding gaseous ligands of diatomic compounds such as nitric oxide (NO) and carbon monoxide (CO) (Kriegl et al., 2002; Capece et al., 2009). The P50 value reported for O2 binding to Ngb ranges from 1-2 mm Hg at 20°C (Kriegl et al., 2002; Capece et al., 2009). Because of its similar structure to hemoglobin and myoglobin and its ability to bind oxygen, Ngb functions in O2 storage and transportation (Kriegl et al., 2002). However, the concentration of Ngb is relatively low (11 M) (Brumester et al., 2000) and comparatively weak under O2-binding physiological conditions (Kriegl et al., 2002). The key functions of Ngb are O2 storage and transportation; however, Ngb may function as an O2 sensor, as reported by Krigel et al., (2002). Other results showed that Ngb performs other functions, such as reactive oxygen species (ROS) scavenging in the brain, due to NO binding enabled by Ngb (Dewilde, 2001; Fago et al., (2004). The idea that Ngb overexpression enables a decrease in NO-induced cell death was supported by Jin et al., (2008). In addition to its ability to function as an O2 sensor and a ROS scavenger, it is hypothesized that Ngb might also act as a signal transducer (Wakasugi et al., 2003). Ngb enables guanine nucleotide dissociation inhibitor (GDI) activity (Wakasugi et al., 2003), as reported by other studies, performing important functions for its protective role against hypoxia by interacting with the polarization of cytoskeletal and lipid raft-dependent death signaling through the Rho GTPase pathway (Khan et al., 2008), functioning as a redox-regulated nitrite reductase (Chen et al., 2012) and activating the Akt signaling pathway (Yu et al., 2013). In addition to themolecular mechanisms described above, the mitochondrial mechanisms of Ngb were recently discussed. As indicated by experimental studies, Ngb could interact with voltage-dependent anion channels (VDACs) and inhibit the depletion of hypoxia/oxygen-glucose (OGD), which induces the mitochondrial permeability transition pore (mPTP) to open and release cytochrome c from the mitochondria (Li et al., 2008) and the level of Ngb overexpression can attenuate beta-amyloid-induced mitochondrial dysfunction (Duong et al., 2009). Despite the controversy concerning the molecular mechanisms of Ngb and its role in neuroprotection has been supported by many in vivo and in vitro studies (Duong et al., 2009). The overexpression of Ngb in mice was reported to result in smaller infract volumes and fewer markers of oxidative stress in the brain after transient focal (Khan et al., 2008) or global (Duong et al., 2009) ischemia. In a similar manner, the intracerebral administration of an Ngb-expression-increasing adeno-associated virus vector reduced the infarct size in rats after focal cerebral ischemia, while Ngb downregulation worsened ischemic outcomes (Sun et al., 2003). The most important factor was the in vitro overexpression of Ngb, which reduced the sensitivity to hypoxic reoxygenation injury in a neuronal cell culture (Liu et al., 2009). Additionally, increasing evidence has demonstrated the important role of Ngb in protecting neurons against other related neurological disorders beyond hypoxic/ischemic brain injury. For instance, Ngb overexpression has shown protective effects against beta-amyloid and NMDA toxicity in both cultured neurons and an Alzheimer’s disease model in mice (Khan et al., 2008). All these results confirmed the neuroprotective functions of Ngb.
 
Expression of Ngb in the mouse brain
 
Studies have shown that Ngb plays an important role in neuroprotection against hypoxic/ischemic brain injury, stroke and other related neurological disorders (Lin et al., 2010; Chuang et al., 2010; Shang et al., 2012). Other studies have demonstrated that a reduction in tissue infarction volume and markers of oxidative stress is induced by Ngb overexpression in a mouse model of focal stroke (Lin et al., 2010). Recently, researchers reported that after TBI, the gene expression of Ngb was increased, but the results were not investigated in detail (Wei et al., 2011; Jain, 2008). In this brief study, the hypothesis was tested and the outcomes indicated that Ngb overexpression might play a protective role against traumatic injury in the mouse brain. In addition, three sets of experiments were conducted to examine the following: (1) Ngb protein expression in the brain following TBI; (2) the effects of Ngb overexpression on mechanistic endpoint-oxidative tissue damage and (3) the neurological outcomes of neurobehavioral deficits and traumatic lesion size three weeks after TBI (Wei et al., 2011; Jain, 2008).
       
During the first experiments, the researchers found that the Ngb protein level significantly increased in the brains of Ngb-Tg and WTmice, similar to the sham controls, 6 h after TBI. The results of this immunohistochemistry and WB examination were similar to the transient increase in Ngb brain expression found in rat, which showed a peak 6 h after TBI (Jain, 2008). In the mouse study, WB showed that the baseline levels of both Ngb protein expression (149% of WT sham control mice) and CCI-induced Ngb protein levels at 6 h after TBI (196% of WT sham control mice) were increased, which was highly significant than the Ngb-Tg mouse brains and the WT TBI controls (147% of WT sham control mice) (Jain, 2008). Despite the different levels of expression demonstrated after TBI, Ngb protein expression was induced. Both baseline and TBI conditions also induced Ngb protein levels, which are still reported to be significant in the Ngb-Tg mouse brains, validating the association between the various levels of brain Ngb protein expression and the numerous neurological results after TBI in Ngb-Tg and WT control mice (Jain, 2008). Other studies have demonstrated that the overexpression of Ngb enables a reduction in hypoxia/ischemia that induces oxidative damage in cultured neurons and focal cerebral ischemia in mice (Lin et al., 2010; Jin et al., 2011). The second experiment recorded a common oxidative tissue damage biomarker, 3NT, in TBI-injured brains of Ngb-Tg and WT control mice (Lin et al., 2010; Jin et al., 2011). The study reported a significant reduction in the level of 3 NT 6 h after TBI in the Ngb-Tg mouse brains compared to the WT controls, indicating that TBI-induced oxidative tissue damage could be diminished by Ngb overexpression (Lin et al., 2010; Jin et al., 2011). During the third experiment, the researchers focused on the neurological outcomes of neurobehavioral deficits and the sizes of brain lesions for a period of three weeks after TBI (Lin et al., 2010; Jin et al., 2011). At 0, 1, 3, 5, 7, 10, 14 and 21 days after TBI, the functions of Ngb were assessed by neurological scores and the hanging wire tests. Body weight loss was recorded on each day (Lin et al., 2010; Jin et al., 2011). Data from the experiment were reported to be significantly different across the 7-day deficits after TBI (Lin et al., 2010; Jin et al., 2011). By day 21 after CCI, all deficits recovered close to pre-injury baselines (Lin et al., 2010; Jin et al., 2011). However, no significant differences between the Ngb-Tg and WT mice were observed in any of the assessments during the 3-week TBI recovery period (Lin et al., 2010; Jin et al., 2011). The morris water maze was used to assess spatial acquisition memory between 15 and 21 days after TBI, but no significant difference was observed between Ngb-Tg and WT mice in the latency on the hidden and visible platform trials, or for the probe trials (Lin et al., 2010; Jin et al., 2011). Last, the researchers quantitatively examined traumatic brain lesion volumes and found that they were reduced significantly in Ngb-Tg mice compared to WT mice 21 days after TBI (Lin et al., 2010; Jin et al., 2011). Over the past two decades, neuroprotectants designed to block or inhibit a specific step in the TBI cascade have not been medically successful (Xin et al., 2012). TBI triggering of endogenous protective mechanism scan prevent or limit damage to the brain. New methodologies that seek to augment the endogenous protection of the brain and its repair signals can lead to new therapeutic strategies for stroke and related disorders (Hundahl et al., 2008a). Ngb is among the few unique molecules that could be utilized for endogenous neuroprotection according to the above experiments, functioning to stabilize neuronal function and prosurvival genes under both normal resting and hypoxic/ischemic conditions, protect against oxidative stress and preserve mitochondrial function (Hundahl et al., 2008b; Hundahl et al., 2010a; Hundahl et al., 2010b). Investigators have further attempted to explain the gene regulation mechanisms of Ngb, detecting small molecules that can specifically upregulate endogenous Ngb protein expression for the development of a group of strategies called novel endogenous neuroprotection, for treating neurological disorders (Jin et al., 2011; Bederson et al., 1995). The researchers first examined whether Ngb overexpression affects neuroprotection in the TBI model of mice (Jin et al., 2011; Bederson et al., 1995) and the results showed the following: (1) there was a significant increase in Ngb in the peri lesion areas of the ipsilateral cortex 6 h after TBI in both WT and Ngb-Tg mice compared to the sham mice, but the levels of Ngb increased significantly more in the Ngb-Tg mice than in the WT controls; (2) a significant reduction in the levels of the oxidative damage marker 3 NT was observed 6 h after TBI in Ngb-Tg mice compared to WT controls; (3) compared to WT mice, at 3 weeks, Ngb-Tg mice exhibited smaller lesion volumes; (4) no significant differences were observed in neurobehavioral deficits between the WT and Ngb-Tg mice for during the three-week period after TBI (Jin et al., 2011; Bederson et al., 1995).
 
Expression of Ngb in the human brain
 
During the study, an investigation was conducted to test whether the level of Ngb expression play a role in global neuroprotection (Hundahl et al., 2012a). Whether plays an important role in total brain protection, the requirement of both global and overt expression is essential. Observations by researchers have shown that both the co-localization and localization of Ngb in the human brain are identical to those in the brains of rats and mice, particularly in the regions heavily involved in sleep (DellaValle et al., 2010; Hundahl et al., 2012a; Nornes, 1973; Schubert et al., 2011). There is still some controversy regarding the Ngb expression patterns found in the brains of rodents. Several studies have reported that Ngb has a ubiquitous expression pattern (Tiso et al., 2011). Human stroke predominantly affects the middle territory of the cerebral artery (MCA), which supplies blood to almost all of the neocortex (Hundahl et al., 2011). In relation to phylogenetics, the neocortex and the MCA are considerably than the diencephalic and mesencephalic brain structures where Ngb expression is found (Hundahl et al., 2011). The Ngb distribution thus results in the majority of the brain lacking protection against ischemic injury (Hundahl et al., 2011). Despite its anatomical distribution, Ngb plays a substantial role in general defense against ischemic cell death (Hundahl et al., 2011). If Ngb functions as a neuroprotectant, then an investigation is needed to determine why it is that only the specific neurons that highly express Ngb require protection (Hundahl et al., 2011). The anatomical function of Ngb could serve as a preliminary guide to begin this investigation (Hundahl et al., 2011). Except for the normal function of Ngb in the brain, studies have reported that Ngb may be involved in cellular processes related to basic homeostatic functions such as sleep, the circadian rhythm and the central regulation of appetite (Nornes, 1973; Schubert et al., 2011). Ngb-null mice showed an altered light-induced phase shift of the circadian rhythm (Capece et al., 2009), but no difference was observed in overt appearance, such as home-cage behavior and body weight (Hundahl et al., 2011).

CONCLUSION

This literature review show that despite the different methods used by researchers, Ngb was found to be widely expressed in the brains of mammals. The distribution of Ngb expression and function in various regions differs. The expression levels in some areas of the brain are significantly higher than those in others, while in other areas, the expression levels are nearly identical. Studies on the expression of Ngb have indicated that Ngb is involved in neuroprotective functions or mechanisms in the brains of mammals and that its overexpression reduces tissue infarction volume and markers of oxidative stress in a focal stroke mouse model. Additionally, overexpression of Ngb in mouse brains decreased mechanical injury-induced neuronal death and reduced hypoxia/ischemia-induced oxidative cell damage in cultured neurons and focal cerebral ischemia. The expression of Ngb in mammalian brains is presented in this study and the patterns and levels of expression vary among different mammals. In addition, diverse conditions can increase or decrease the proportion of Ngb-positive cells in mammals, so it is appropriate to assess the exact pattern of distribution and localization before conducting Ngb investigations in mammals.

ACKNOWLEDGEMENT

The researchers acknowledged the Gansu Agricultural University Library Team for their technical support and advice during the literature review.

FUNDING

The author received no funding.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS

James Blackar Mawolo and Caselia Akiti contributed to the literature search. James Blackar Mawolo and Caselia Akiti organized, investigated and interpreted the data. James Blackar Mawolo and Caselia Akiti wrote the first draft of the manuscript. James Blackar Mawolo and Caselia Akiti performed the study methodology and formal analysis. James Blackar Mawolo and Caselia Akiti designed the study concept. Both authors contributed to this manuscript revision and read and approved the submitted version.

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