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Neuroglobin is a heme protein of which increased levels provide neuroprotection against amyloid proteinopathy and hemorrhagic damage. These cellular stressors involve the promotion of ferroptosis—an iron-dependent, lipid peroxide-accreting form of cell death. Hence, we questioned whether neuroglobin could oppose ferroptosis initiation. We detected human neuroglobin (hNgb)-EGFP-expressing SH-SY5Y cells to be significantly more resistant to ferroptosis induction, identifying 0.68-fold less cell death. To elucidate the underlying pathways, this study investigated hNgb-protein interactions with a Co-IP-MS/MS approach both under a physiological and a ferroptotic condition. hNgb binds to proteins of the cellular iron metabolism (e.g., RPL15 and PCBP3) in an unstressed condition and shows an elevated binding ratio towards cell death-linked proteins, such as HNRNPA3, FAM120A, and ABRAXAS2, under ferroptotic stress. Our data also reveal a constitutive interaction between hNgb and the longevity-associated heterodimer XRCC5/XRCC6. Disentangling the involvement of hNgb and its binding partners in cellular processes, using Ingenuity Pathway Analysis, resulted in the integration of hNgb in the ubiquitination pathway, mTOR signaling, 14-3-3-mediated signaling, and the glycolysis cascade. We also detected a previously unknown strong link with motor neuropathies. Hence, this study contributes to the elucidation of neuroglobin’s involvement in cellular mechanisms that provide neuroprotection and the upkeep of homeostasis.

Neuroglobin (Ngb) is a recently discovered heme protein in the vertebrate brain that can bind to oxygen molecules. Mammalian Ngb plays a crucial role in neuroprotection under conditions of oxidative stress. To investigate other potential functions of Ngb, we investigated the mouse retinal Ngb system following optic nerve injury. In the retina of control mice, Ngb immunoreactivity was limited to the retinal ganglion cell (RGC) layer, and this immunoreactivity rapidly decreased to less than 50% of the control level 5 days after optic nerve injury. On the basis of this decrease, we designed in vivo experiments with enhanced expression of Ngb using adult mouse retina. The enhanced expression of Ngb was achieved by injecting chimeric human Ngb protein, which included the cell membrane-penetrating module of fish Ngb. One-day pretreatment with chimeric Ngb increased immunoreactivity levels of Ngb two-fold in mouse RGCs and increased the number of surviving RGCs three-fold by 14 days after optic nerve injury compared with vehicle controls. Furthermore, in the mouse retinas showing enhanced Ngb expression, several regenerating central optic axons exhibited outgrowth and were found to pass through the nerve crush site 14 days after nerve injury. No such regenerating optic axons were observed in the control mouse optic nerve during the same time frame. The data obtained from in vivo experiments strongly indicate that mammalian Ngb has neuroprotective and neuroregenerative properties. [ABSTRACT FROM AUTHOR]

Retinal degeneration (RD) is a heterogeneous group of inherited dystrophies leading to blindness. The N-methyl-N-nitrosourea (MNU)-administered mouse is used as a pharmacologically induced RD animal model in various therapeutic investigations. The present study found the retinal neuroglobin (NGB) expression in the MNU-administered mice was significantly lower than in normal controls, suggesting NGB was correlated with RD. Subsequently, an adeno-associated virus (AAV)-2-mCMV-NGB vector was delivered into the subretinal space of the MNU-administered mice. The retinal NGB expression of the treated eye was upregulated significantly in both protein and mRNA levels. Further, we found NGB overexpression could alleviate visual impairments and morphological devastations in MNU-administered mice. NGB overexpression could rectify apoptotic abnormalities and ameliorate oxidative stress in MNU-administered mice, thereby promoting photoreceptor survival. The cone photoreceptors in MNU-administered mice were also sensitive to AAV-mediated NGB overexpression. Taken together, our findings suggest that manipulating NGB bioactivity via gene therapy may represent a novel therapeutic strategy against RD. Future elucidation of the exact role of NGB would advance our knowledge about the pathological mechanisms underlying RD. [ABSTRACT FROM AUTHOR]

Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ), against HO-induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ) typical of Huntington's disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics. [ABSTRACT FROM AUTHOR]

Neuroglobin (Ngb) is a heme protein expressed in the vertebrate brain. We previously engineered a chimeric Ngb protein, in which module M1 of human Ngb is replaced by that of zebrafish Ngb, and showed that the chimeric ZHHH Ngb has a cell membrane-penetrating activity similar to that of zebrafish Ngb and also rescues cells from death caused by hypoxia/reoxygenation as does human Ngb. Recently, it was reported that overexpression of mammalian Ngb in neuronal cells induces neurite outgrowth. In this study, we performed neurite outgrowth assays of chimeric Ngb using rat pheochromocytoma PC12 cells. Addition of chimeric Ngb, but not human or zebrafish Ngb, exogenously to the cell medium induces neurite outgrowth. On the other hand, the K7A/K9Q chimeric Ngb double mutant, which cannot translocate into cells, did not induce neurite outgrowth, suggesting that the cell membrane-penetrating activity of the chimeric Ngb is crucial for its neurite outgrowth-promoting activity. We also prepared several site-directed chimeric Ngb mutants and demonstrated that residues crucial for neurite outgrowth-inducing activity of the chimeric Ngb are not exactly the same as those for its neuroprotective activity. [ABSTRACT FROM AUTHOR]

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has no generally accepted treatment due to its complicated pathophysiology. Previously, we demonstrated the protective role of neuroglobin (Ngb) in SAE rats, but the exact mechanism has not been determined. To investigate the potential neuroprotective roles and mechanisms of Ngb, Sprague-Dawley rats were used. Overexpression of Ngb via intracerebroventricular injection with Ngb plasmids attenuated brain damage assessed by hematoxylin and eosin (HE) staining and neurological dysfunction assessed by Morris water maze test. Western blot analysis also showed that the phosphorylation of Akt increased and the protein level of Bax decreased. Furthermore, the protective effect can be abolished by PI3K/Akt pathway inhibitor LY294002. Our results demonstrate that Ngb can protect rats from SAE via a PI3K/Akt/Bax-dependent mechanism. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the mechanism underlying the neuroprotective effect of hemin in oxygen-glucose deprivation (OGD)-treated neurons. OGD-treated SH-SY5Y cells (human neuroblastoma cells) were used in the study. The cellular viability of SH-SY5Y cells was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the cell apoptosis rate was determined by flow cytometry analysis with Annexin V-fluorescein isothiocyanate and propidium iodide staining with or without hemin pretreatment. Cell viability and apoptotic activation were detected after hemin administration combined with neuroglobin (Nqb), thioredoxin-1, peroxiredoxin-2, or heme oxygenase-1 siRNA transient transfection. The release of cytochrome c from mitochondria and the interaction between Ngb and cytochrome c were examined with hemin pretreatment. Hemin had a neuroprotective effect in OGD-treated SH-SY5Y cells, which was mainly mediated by the upregulation of Ngb. Moreover, the release of cytochrome c from mitochondria was inhibited by hemin-induced Ngb expression through facilitating the interaction of Ngb with cytochrome c in mitochondria. The present findings provided new insights into the neuroprotective mechanisms of hemin. It was concluded that low-dose hemin pretreatment had a neuroprotective effect in OGD-treated SH-SY5Y cells, through inhibiting cell apoptosis. The neuroprotective effects of hemin following hypoxic-ischemic neuronal damage were mainly mediated by Ngb. One underlying mechanism was hemin-induced overexpression of mitochondrial Ngb, which inhibited endogenous apoptosis via the association with cytochrome c. [ABSTRACT FROM AUTHOR]

The review summarizes current data on neuroglobin, the heme-containing protein discovered in mammalian nerve cells in 2000. It presents general characteristics of neuroglobin as well as data on its evolutionary changes and expression across different taxa. Neuroglobin distribution in specific brain structures and outside the brain is described. The issue of the occurrence of neuroglobin not only in neurons but also in astroglial cells is discussed. Subcellular localization of neuroglobin is characterized with a special focus on its detection in the nucleus of nerve cells, suggesting its involvement in nuclear functions. Current ideas on the probable functional significance of neuroglobin are reported. Neuroglobin is presumed to be involved in metabolism of reactive nitrogen and oxygen species as well as in intracellular signaling pathways. Besides, neuroglobin has neuroprotective and antiapoptotic functions. Since its expression changes during ontogenesis, its neuroprotective role in ageing is specifically highlighted. Changes in expression and localization of neuroglobin are suggested to influence the adaptive potential of an organism. [ABSTRACT FROM AUTHOR]

Oxygen (O 2 ) is a double-edged sword to cells, for while it is vital for energy production in all aerobic animals and insufficient O 2 (hypoxia) can lead to cell death, the reoxygenation of hypoxic tissues may trigger the generation of reactive oxygen species (ROS) that can destroy any biological molecule. Indeed, both hypoxia and hypoxia-reoxygenation (H/R) stress are harmful, and may play a critical role in the pathophysiology of many human diseases, such as myocardial ischemia and stroke. Therefore, understanding how animals adapt to hypoxia and H/R stress is critical for developing better treatments for these diseases. Previous studies showed that the neuroglobin GLB-5( Haw ) is essential for the fast recovery of the nematode Caenorhabditis elegans ( C. elegans ) from H/R stress. Here, we characterize the changes in neuronal gene expression during the adaptation of worms to hypoxia and recovery from H/R stress. Our analysis shows that innate immunity genes are differentially expressed during both adaptation to hypoxia and recovery from H/R stress. Moreover, we reveal that the prolyl hydroxylase EGL-9, a known regulator of both adaptation to hypoxia and the innate immune response, inhibits the fast recovery from H/R stress through its activity in the O 2 -sensing neurons AQR, PQR, and URX. Finally, we show that GLB-5( Haw ) acts in AQR, PQR, and URX to increase the tolerance of worms to Pseudomonas aeruginosa pathogenesis. Together, our studies suggest that innate immunity and recovery from H/R stress are regulated by overlapping signaling pathways. [ABSTRACT FROM AUTHOR]

Sensory receptor neurons match their dynamic range to ecologically relevant stimulus intensities. How this tuning is achieved is poorly understood in most receptors. The roundworm Caenorhabditis elegans avoids 21% O2 and hypoxia and prefers intermediate O2 concentrations. We show how this O2 preference is sculpted by the antagonistic action of a neuroglobin and an O2-binding soluble guanylate cyclase. These putative molecular O2 sensors confer a sigmoidal O2 response curve in the URX neurons that has highest slope between 15 and 19% O2 and approaches saturation when O2 reaches 21%. In the absence of the neuroglobin, the response curve is shifted to lower O2 values and approaches saturation at 14% O2. In behavioral terms, neuroglobin signaling broadens the O2 preference of Caenorhabditis elegans while maintaining avoidance of 21% O2. A computational model of aerotaxis suggests the relationship between GLB-5-modulated URX responses and reversal behavior is sufficient to broaden O2 preference. In summary, we show that a neuroglobin can shift neural information coding leading to altered behavior. Antagonistically acting molecular sensors may represent a common mechanism to sharpen tuning of sensory neurons. [ABSTRACT FROM AUTHOR]

Thiosulfate formation and biodegradation processes link aerobic and anaerobic metabolism of cysteine. In these reactions, sulfite formed from thiosulfate is oxidized to sulfate while hydrogen sulfide is transformed into thiosulfate. These processes occurring mostly in mitochondria are described as a canonical hydrogen sulfide oxidation pathway. In this review, we discuss the current state of knowledge on the interactions between hydrogen sulfide and hemoglobin, myoglobin and neuroglobin and postulate that thiosulfate is a metabolically important product of this processes. Hydrogen sulfide oxidation by ferric hemoglobin, myoglobin and neuroglobin has been defined as a non-canonical hydrogen sulfide oxidation pathway. Until recently, it appeared that the goal of thiosulfate production was to delay irreversible oxidation of hydrogen sulfide to sulfate excreted in urine; while thiosulfate itself was only an intermediate, transient metabolite on the hydrogen sulfide oxidation pathway. In the light of data presented in this paper, it seems that thiosulfate is a molecule that plays a prominent role in the human body. Thus, we hope that all these findings will encourage further studies on the role of hemoproteins in the formation of this undoubtedly fascinating molecule and on the mechanisms responsible for its biological activity in the human body. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (rh-EPO) has been reported to have protective effects against brain injury. The purpose of this study was to evaluate the levels of erythropoietin receptor (EPOR) and neuroglobin (Ngb) in a neonatal rat model of periventricular white matter damage (PWMD), and to identify the relationship between the two proteins. On postnatal day 3 (P3), rats underwent permanent ligation of the right common carotid artery followed by 6% O 2 for 4 h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, rats received a single intraperitoneal injection of rh-EPO (5 U/g) or saline. We assessed the expression level of Ngb and EPOR on postnatal days 5, 7, 10 and 14. EPOR in the HI rats was initially increased as compared to the sham rats at P5. Subsequently, EPOR expression decreased, but was maintained at a higher level than in sham rats from P7 to P14. In rh-EPO treated rats, the increase in EPOR was greater than in HI rats at P5. However, EPOR levels decreased sharply from P7 to P14. In HI rats, Ngb was increased compared to the sham rats from P5 to P14. Ngb levels were further upregulated after rh-EPO administration from P5 to P10 compared to HI rats. However, this upregulation decreased at P14. In conclusion, this study shows that EPOR and Ngb were upregulated, and both of them act as important coordinated neuroprotectors in rh-EPO treatment of PWMD. However, the two proteins exhibit different expression patterns. [ABSTRACT FROM AUTHOR]

Although neuroglobin confers neuroprotection against Alzheimer's disease ( AD) pathology, its expression becomes downregulated in late-stage AD. Here, we provide evidence that indicates that this decrease is associated with the AD-linked angiopathy. While wild-type mice of different ages show upregulated cerebral neuroglobin expression upon whole-body hypoxia, APP23 mice exhibit decreased cerebral transcription of neuroglobin. Interestingly, transcription of cytoglobin, whose involvement in amyloid pathology still needs to be elucidated, follows a similar pattern. To further unravel the underlying mechanism, we examined the expression levels of the RE-1-silencing transcription factor ( REST/ NRSF) after identifying a recognition site for it in the regulatory region of both globins. Neuroglobin-cytoglobin- REST/ NRSF expression correlations are detected mainly in the cortex. This raises the possibility of REST/ NRSF being an upstream regulator of these globins. [ABSTRACT FROM AUTHOR]

Significance: Erythrocyte hemoglobin (Hb) and myocyte myoglobin, although primarily oxygen-carrying proteins, have the capacity to do redox chemistry. Such redox activity in the wider family of globins now appears to have important associations with the mechanisms of cell stress response. In turn, an understanding of such mechanisms in vivo may have a potential in the understanding of cancer therapy resistance and neurodegenerative disorders such as Alzheimer's. Recent Advances: There has been an enhanced understanding of the redox chemistry of the globin superfamily in recent years, leading to advances in development of Hb-based blood substitutes and in hypotheses relating to specific disease mechanisms. Neuroglobin (Ngb) and cytoglobin (Cygb) have been linked to cell protection mechanisms against hypoxia and oxidative stress, with implications in the onset and progression of neurodegenerative diseases for Ngb and cancer for Cygb. Critical Issues: Despite advances in the understanding of redox chemistry of globins, the physiological roles of many of these proteins still remain ambiguous at best. Confusion over potential physiological roles may relate to multifunctional roles for globins, which may be modulated by surface-exposed cysteine pairs in some globins. Such roles may be critical in deciphering the relationships of these globins in human diseases. Future Directions: Further studies are required to connect the considerable knowledge on the mechanisms of globin redox chemistry in vitro with the physiological and pathological roles of globins in vivo. In doing so, new therapies for neurodegenerative disorders and cancer therapy resistance may be targeted. Antioxid. Redox Signal. 26, 763-776. [ABSTRACT FROM AUTHOR]

Background Neuroglobin (NGB) has been described as a neuroprotective agent in cerebral ischemia, hypoxia inducible factor (HIF) has shown an important role in modulating hypoxic and ischemic injury, and therefore they have the potential to impact outcomes after acute ischemic stroke (AIS). Thus, we investigated early changes in the concentrations of serum NGB and HIF-1α after AIS and evaluated the relations of both NGB and HIF-1α to stroke severity and prognosis. Methods We prospectively measured the serum concentrations of NGB and HIF-1α in 40 patients with AIS at 24, 48, 72, and 96 h after stroke. Correlation combined with infarct size and National Institutes of Health Stroke Scale (NIHSS) score of the patients was analyzed. Receiver operating characteristic (ROC) curve was used to appraise their value in predicting the 90-day outcome after AIS. Results Serum NGB concentrations increased and peaked at 72 h after AIS, whereas serum concentrations of HIF-1α increased for 48 h. Peak serum NGB concentration correlated significantly with both infarct size (R 2 = 0.484, p < 0.001) and admission NIHSS score (R 2 = 0.578, p < 0.001), while serum HIF-1α concentration was only correlated to a patient's infarct size (R 2 = 0.394, p < 0.001). ROC curve analysis suggested that the serum NGB concentration had a significantly better predictive power for poor outcome. Conclusions NGB level increased in serum after AIS accompanied by increases in serum HIF-1α, and was suggested as a predictor of stroke severity and poor prognosis. [ABSTRACT FROM AUTHOR]

Neuroglobin (Ngb) has been reported to be upregulated by hypoxia and plays an anti-apoptotic function. Previous studies have reported that Ngb is expressed in human glioblastoma cells and up-regulated in hypoxic microregions of glioblastoma tumor xenografts. While, the clinical significance of Ngb and its function in human glioma keep unknown. Ngb expression was analyzed in 86 glioma tissues and 20 normal brain tissues. Results showed that Ngb was significantly overexpressed in glioma tissues compared to normal brain tissues. In addition, increased levels of Ngb also observed in glioma cell lines. Clinicopathological analysis verified that the positive expression of Ngb was associated with histological type and world health organization (WHO) grade of glioma. Moreover, Kaplan–Meier analysis found that Ngb overexpression led to a shorter survival. Multivariate Cox regression analysis demonstrated that Ngb expression was an independent prognostic marker. Further experiments illustrated that Ngb knockdown significantly inhibited proliferation and facilitated apoptosis in U251 cells. In vivo experiments further confirmed that Ngb silencing notably prohibited the tumor growth of glioma in nude mice. While, Ngb overexpression prominently promoted proliferation and suppressed apoptosis in U87 cells. Taken together, this work support the first evidence that Ngb can be potentially used as a promising biomarker and target for novel treatment of human glioma. [ABSTRACT FROM AUTHOR]

ABSTRACT The side stream cigarette smoke (SSCS) is a contributing factor in the pathogenesis of cigarette smoking-induced toxicity. Hemoglobin (Hb), myoglobin (Mb), neuroglobin (Ngb), and cytoglobin (Cygb) are globins with different distributions and functions in the tissues and have similar actions by providing O2 (oxygen) for respiratory chain, detoxification of ROS and nitric oxide (NO), and protect tissues against irreversible lesions. We aimed to investigate the effects of SSCS exposure on gene and protein expression of Ngb, Cygb, and Mb in different tissue. The Ngb and Cygb gene and protein expression in the cerebral cortex increased after 1 week of rat exposure to SSCS. In hippocampus, the Ngb gene and protein expression increased after 1 week or more of exposure and no change was observed in Cygb gene and protein expression. In myocardium, Mb and Cygb gene expression increased at 1 and 4 weeks of exposure, while protein expression of both increased at 1, 2, 3, and 4 weeks. In lung, observed an increase in Cygb gene and protein expression after 2, 3, and 4 weeks of exposure. The findings suggest that SSCS modulates Ngb, Cygb, and Mb in central and peripheral tissue © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1252-1261, 2017. [ABSTRACT FROM AUTHOR]

Oxidative stress, resulting from accumulation of reactive oxygen species, plays a critical role in astroglial cell death occurring in diverse neuropathological conditions. Numerous studies indicate that neuroglobin (Ngb) promotes neuron survival, but nothing is known regarding the action of Ngb in astroglial cell survival. Thus, the purpose of this study was to investigate the potential glioprotective effect of Ngb on hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in cultured mouse astrocytes. Incubation of cells with subnanomolar concentrations of Ngb (10−14-10−10 M) was found to prevent both H2O2-evoked reduction in surviving cells number and accumulation of reactive oxygen species in a concentration-dependent manner. Furthermore, Ngb treatment abolishes H2O2-induced increase in mitochondrial oxygen consumption rates. Concomitantly, Ngb treatment rescues H2O2-associated reduced expression of endogenous antioxidant enzymes (superoxide dismutases and catalase) and prevents the stimulation of the expression of pro-inflammatory genes (inducible nitric oxide synthase, cyclooxygenase-2, and interleukin ( IL) IL-6 and IL-33). Moreover, Ngb blocks the stimulation of Bax (pro-apoptotic) and the inhibition of Bcl-2 (anti-apoptotic) gene expression induced by H2O2, which in turn abolishes caspase 3 activation. The protective effect of Ngb upon H2O2 induced activation of caspase 3 activity and cell death can be accounted for by activation of protein kinase A and mitogen-activated protein kinase transduction cascade. Finally, we demonstrate that Ngb increases Akt phosphorylation and prevents H2O2-provoked inhibition of ERK and Akt phosphorylation. Taken together, these data demonstrate for the first time that Ngb is a glioprotective agent that prevents H2O2-induced oxidative stress and apoptotic astroglial cell death. Protection of astrocytes from oxidative insult may thus contribute to the neuroprotective effect of Ngb. [ABSTRACT FROM AUTHOR]

In 2000, the third member of the globin family was discovered in human and mouse brain and named neuroglobin (Ngb). Ngb is a monomeric 3/3 globin structurally similar to myoglobin and to the α- and β-chains of hemoglobin, however it displays a bis-histidyl six-coordinate heme-Fe atom. Therefore, ligand binding to the Ngb metal center is limited from the dissociation of the distal His(E7)64-Fe bond. From its discovery, more than 500 papers on Ngb structure, expression, reactivity, and localization have been published to highlight its biochemical properties and its role(s) in health and disease. In vivo experiments have shown that increased levels of Ngb significantly protect both heart and brain from hypoxic/ischemic and oxidative stress-related insults, whereas decreased Ngb levels lead to an exacerbation of tissue injuries. Although some contradictory data emerged, human Ngb overexpression has been hypothesized to protect neurons from mitochondrial dysfunctions and neurodegenerative disorders such as Alzheimer's disease, and to play a shielding role in cancer cells. Recently, the recognition of Ngb interactors and inducers enlarges the functions of this stress-inducible globin, opening new therapeutic approaches to prevent neuronal cell death. Here, structural and functional aspects of human Ngb are examined critically to highlight its roles in health and disease. [ABSTRACT FROM AUTHOR]

Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen–glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co-immunoprecipitation (Co-IP) and immunocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb–VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD+ release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD+ release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD+ release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection.

Astrocytes play an important role in physiological, metabolic and structural functions and, when impaired, they can be involved in various pathologies including Alzheimer, focal ischemic stroke and traumatic brain injury. These disorders involve an imbalance in the blood flow and nutrients such as glucose and lactacte, leading to biochemical and molecular changes that cause neuronal damage, which is followed by loss of cognitive and motor functions. Previous studies have shown that astrocytes are more resilient than neurons during brain insults as a consequence of their more effective antioxidant systems, transporters and enzymes, which made them less susceptible to excitotoxicity. In addition, astrocytes synthesize and release different protective molecules for neurons, including neuroglobin, a member of the globin family of proteins. After brain injury neuroglobin expression is induced in astrocytes. Since neuroglobin promotes neuronal survival, its increased expression in astrocytes after brain injury may represent an endogenous neuroprotective mechanism. Here, we review the role of neuroglobin in the CNS, its relationship with different pathologies, and the role of different factors that regulate its expression in astrocytes.

Testosterone is a hormone that has been shown to confer neuroprotection from different insults affecting the central nervous system (CNS). Testosterone induces this protection by different mechanisms that include the activation of anti-apoptotic pathways that are directly implicated in neuronal survival. However, little attention has been devoted to its actions on glial cells. In the present study, we have assessed whether testosterone exerts protection in a human astrocyte cell model, the T98G cells. Our results indicate that testosterone improves cell survival and mitochondrial membrane potential and reduces nuclear fragmentation and reactive oxygen species (ROS) generation. These effects were accompanied by a positive regulation of neuroglobin, an oxygen-binding and sensor protein, which may serve as a regulator of ROS and nitrogen reactive species (NOS), and these protective effects of testosterone may be at least in part mediated by estradiol and DHT. In conclusion, these findings suggest that astroglia may mediate some of the protective actions of testosterone in the brain upon pathological conditions.

Estrogens are neuroprotective factors in several neurological diseases. Neuroglobin (NGB) is one of the estrogen target gene involved in neuroprotection, but little is known about its transcriptional regulation. Estrogen genomic pathway in gene expression regulation is mediated by estrogen receptors (ERα and ERβ) that bind to specific regulatory genomic regions. We focused our attention on E2-induced NGB expression in human differentiated neuronal cell lines (SK-N-BE and NT-2). Previously, using bioinformatics analysis we identified a putative enhancer in the first intron of NGB locus. Therefore, we observed that E2 increased the enrichment of the H3K4me3 epigenetic marks at the promoter and of the H3K4me1 and H3K27Ac at the intron enhancer. In these NGB regulatory regions, we found estrogen receptor alpha (ER) binding suggesting that ER may mediate chromatin remodeling to induce NGB expression upon E2 treatment. Altogether our data show that NGB expression is regulated by ERa binding on genomic regulatory regions supporting hormone therapy applications for the neuroprotection against neurodegenerative disease.

The small heme-protein neuroglobin is expressed at high concentrations in certain brain neurons and in the rod cells of the retina. This paper reviews the many studies which have recently identified a protective role for neuroglobin, in a wide range of situations involving apoptotic cell death. The origins of this protective mechanism are discussed in terms of both experimental results and computational modeling of the intrinsic pathway of apoptosis, which shows that neuroglobin can intervene in this process by a reaction with released mitochondrial cytochrome c. An integrated model, based on the various molecular actions of both neuroglobin and cytochrome c, is developed, which accounts for the cellular distribution of neuroglobin.

Durante mucho tiempo se asumió que la hemoglobina y la mioglobina eran las únicas globinas de los vertebrados. En el año 2000 se descubrió un tercer tipo de globina, que sobre la base de su ubicación preferencial en el sistema nervioso fue denominada neuroglobina. Aunque aún se desconoce su función específica, se han planteado varias hipótesis entre las que se destaca la que sugiere que puede destoxificar las especies reactivas del oxígeno y el nitrógeno. Otros estudios proponen que es parte de una cadena de transducción de señales que transmite el estado redox de la célula o que inhibe la apoptosis. Aunque algunas funciones son más probables que otras, aún no se ha establecido definitivamente cuál es la función fisiológica de la neuroglobina en los vertebrados. No obstante, no hay dudas de que esta globina tiene una función esencial, conservada y que es beneficiosa para las neuronas.For a long time, it was taken for granted that hemoglobin and mioglobin were the only vertebrate globins. In 2000, a third type of globins was discovered on the basis of its preferential location in the nervous system and it was called neuroglobin. Although its specific function is still unknown, a number of hypotheses has been put forward, mainly the one suggesting that it may detoxify the reactive oxygen species and the nitrogen. On the other hand, other studies state that neuroglobin is part of a signal transduction chain that transmits the redox state of the cell or inhibits apoptosis. Though some functions are more probable than others, the real physiological function of neuroglobin in vertebrae has not been finally established. Nevertheless, this globin has undoubtedly an essential preserved function that is useful for neurons.