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Corrigendum to “Neuregulin-1 is neuroprotective and attenuates inflammatory responses induced by ischemic stroke” [Biochem. Biophys. Res. Commun. 322 (2004) 440–446]
... Neuregulin-1 (NRG-1) is a family of growth factors with multiple potent effects that include acetylcholine receptor inducing activity (ARIA), glial growth factor-2, heregulins and neu differentiation factors [4]. Its neuroprotective effects for ischemic brain injury have been reported [13,14,26,28] . In a rat model with transient middle cerebral artery occlusion (tMCAo), NRG-1 reduced cortical infarct volume by 90% if administered immediately after the onset of stroke and exhibited a therapeutic window of N13 h [26,28]. ...
... Its neuroprotective effects for ischemic brain injury have been reported [13,14,26,28] . In a rat model with transient middle cerebral artery occlusion (tMCAo), NRG-1 reduced cortical infarct volume by 90% if administered immediately after the onset of stroke and exhibited a therapeutic window of N13 h [26,28]. Such treatment efficacy of NRG-1 on stroke was evaluated previously using histological analysis within 24 h but not characterized longitudinally. ...
... To determine the effects of NRG-1 on ischemic stroke, rats were randomized and injected intra-arterially with a single bolus 50 μl dose of vehicle (1%BSA in PBS) or NRG-1β (20 μg/kg, EGF-like domain , R&D Systems, Minneapolis, Minnesota) through a Hamilton syringe as previously described [14,26]. NRG-1 (n = 10) or vehicle (n = 6) treated rats were administered by bolus injection into the ICA through ECA immediately before pMCAo. ...
The neuroprotective effects of neuregulin-1 (NRG-1) on stroke lesions were assessed longitudinally in rats with middle cerebral artery occlusion (MCAo) using MRI. Sprague-Dawley rats (n=16, 250±20g) underwent permanent MCAo surgery with cerebral blood flow (CBF) monitored by laser doppler flowmetry at ipsilateral side of bregma for 20min post-occlusion. A single 50μl bolus dose of NRG-1 or vehicle was administered into the left internal carotid artery immediately prior to MCAo. The expansion of the ischemic lesion into the cortex was attenuated by NRG-1 over a 48-hour (h) time span as measured by diffusion weighted imaging (DWI). The final infarct volumes of NRG-1 treated rats were significantly smaller than those of the vehicle treated rats at 48h (264.8±192.1 vs. 533.4±175.5mm(3), p<0.05). The NRG-1 treated rats were further subdivided into 2 subgroups according to their CBF reduction during stroke surgery: mild ischemia (<70% CBF reduction) or severe ischemia (>70% CBF reduction). In particular, ischemic infarction was not usually observed in the cortex of NRG-1 treated rats with mild ischemia at 3 and 48h post-occlusion. Histological results validated the imaging findings and demonstrated that NRG-1 treated rats had fewer injured neurons in peri-infarct areas 48h post-ischemia. In summary, the neuroprotective effect of NRG-1 in the pMCAo stroke model was demonstrated by prevention of ischemic lesion expansion, reduced infarct volume and protection of neurons from ischemic damage.
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... The studies reported here demonstrate that GGF2 can improve recovery when used acutely in the permanent MCAO model, as reported for other neuregulins in transient ischemia models (Xu et al., 2004Xu et al., , 2006). GGF2 was also effective in the permanent occlusive model when treatment was delayed for one, three and seven days after occlusion, long after the window for acute neuroprotection would be expected to have passed. ...
... factor 2 delivered acutely after permanent MCAO promotes functional recovery without altering lesion volume Neuregulins, and NRG-EGF specifically have been tested previously in an acute transient stroke model and demonstrated neuroprotection and functional improvements when blood flow was restored 90 min after MCAO (Xu et al., 2004Xu et al., , 2006). Neuregulins activate the PI3K/Akt pathway and stimulate anti-apoptotic signaling in CNS cells (Flores et al., 2000; Di Segni et al., 2005) and this mechanism could partially explain the neuroprotection seen when coupled with reperfusion after acute stroke. ...
... Infarct volume measurements at 21 days post-occlusion confirmed observations at 2 days post-occlusion (Table 2) that there was no significant rescue or protection of tissue in any of the neuregulin treatment groups compared to vehicle. In an effort to begin to understand the mechanisms that may be involved with the enhanced functional recovery in all GGF2 treatment groups, the tissue was examined for specific histological markers known to be involved in neuregulin biology including modulation of myelin formation, inflammation and apoptosis (Dimayuga et al., 2003; Xu et al., 2004; Lemke, 2006). As expected and reported previously there was astrogliosis (GFAP) in the ipsilateral hemisphere (Fig. 4AeE). ...
Neuregulins are a family of growth factors essential for normal cardiac and nervous system development. The EGF-like domain of neuregulins contains the active site which binds and activates signaling cascades through ErbB receptors. A neuregulin-1 gene EGF-like fragment demonstrated neuroprotection in the transient middle cerebral artery occlusion (MCAO) stroke model and drastically reduced infarct volume (Xu et al., 2004). Here we use a permanent MCAO rat model to initially compare two products of the neuregulin-1 gene and also assess levels of recovery with acute versus delayed time to treatment. In the initial study full-length glial growth factor 2 (GGF2) and an EGF-like domain fragment were compared with acute intravenous delivery. In a second study GGF2 only was delivered starting at 24h, 3 days or 7 days after permanent ischemia was induced. In both studies daily intravenous administration continued for 10 days. Recovery of neurological function was assessed using limb placing and body swing tests. GGF2 had similar functional improvements compared to the EGF-like domain fragment at equimolar doses, and a higher dose of GGF2 demonstrated more robust functional improvements compared to a lower dose. GGF2 improved sensorimotor recovery with all treatment paradigms, even enhancing recovery of function with a delay of 7 days to treatment. Histological assessments did not show any associated reduction in infarct volume at either 48 h or 21 days post-ischemic event. Neurorestorative effects of this kind are of great potential clinical importance, given the difficulty of delivering neuroprotective therapies within a short time after an ischemic event in human patients. If confirmed by additional work including additional data on mechanism(s) of improved outcome with verification in other stroke models, one can make a compelling case to bring GGF2 to clinical trials as a neurorestorative approach to improving outcome following stroke injury.
... Indeed, endothelial cells have a remarkable capacity to respond to stressors (Dauphinee and Karsan 2006; Magder, Neculcea et al. 2006). Neuregulins (NRGs) play important roles during fetal brain (Bernstein, Lendeckel et al. 2006), heart (Gassmann, Casagranda et al. 1995) and lung development (Dammann, Nielsen et al. 2003), and are involved in inflammatory processes (Xu, Jiang et al. 2004; Xu, Ford et al. 2005). Several NRG isoforms (Meyer, Yamaai et al. 1997) are produced by alternative splicing (Wen, Suggs et al. 1994; Falls 2003). ...
... Several NRG isoforms (Meyer, Yamaai et al. 1997) are produced by alternative splicing (Wen, Suggs et al. 1994; Falls 2003). One of these, NRG1, appears to help signal the onset of surfactant synthesis in the fetal lung (Dammann, Nielsen et al. 2003) and might qualify as a brain protector in experimental ischemia (Xu, Jiang et al. 2004; Xu, Ford et al. 2005). We have recently suggested that NRG1 might play a role not only in adult (Deadwyler, Pouly et al. 2000; Gerecke, Wyss et al. 2004), but also in neonatal brain disorders (Dammann, Bueter et al. 2007). ...
... The goal of our study was to explore a potentially protective role for NRG1 in neonatal brain damage (Dammann, Bueter et al. 2007) based on experimental evidence from other groups obtained in several damage models (Xu, Jiang et al. 2004; Xu, Ford et al. 2005; Li, Xu et al. 2007; Lok, Wang et al. 2007). Our results suggest that NRG1 is expressed and might even be systemically released by human umbilical venous endothelial cells in response to LPS challenge. ...
To assess the potential role for Neuregulin-1 (NRG1) as a systemic endogenous protector in the setting of perinatal inflammatory brain damage.
We measured NRG1-protein and mRNA levels in human umbilical venous endothelial cells (HUVECs) of different gestational ages at various durations of exposure to lipopolysaccharide (LPS). In parallel, we genotyped the donor individuals for SNP8NRG221533, a disease-related single nucleotide polymorphism in the 5' region upstream of the NRG1 sequence. Intracellular NRG1 localization was visualized by confocal microscopy. Furthermore we analyzed the relationship between SNP8NRG221533 genotype and neurodevelopmental outcome in children born preterm.
We observed a positive dose-response-relationship between NRG1-mRNA and intracellular protein levels with both advancing gestational age and duration of LPS exposure in HUVECs. The presence of allele C at the SNP8NRG221533 locus was associated with an increased cellular production of NRG1 in HUVECs, and with a significantly reduced risk for cerebral palsy and developmental delay in children born preterm.
In conclusion, our data indicate that gestational age, duration of LPS exposure, and the SNP8NRG221533 genotype affect NRG1 levels. Our results support the hypothesis that NRG1 may qualify as an endogenous protector during fetal development.
... The neuregulins are a family of multipotent growth factors that includes acetylcholine receptor inducing activities (ARIAs), glial growth factors (GGFs), heregulins and neu differentiation factors (NDFs) [11,19,20,25,33]. A number of recent reports from our laboratory and others have shown that administration of NRG-1 reduces delayed ischemic cortical damage following transient middle cerebral artery occlusion (tMCAO) when administered before the onset of ischemia in rats [16,30,37] or after tMCAO with an extended therapeutic window [35] neuroprotective effects of the single administration of NRG-1 were seen up to 2 weeks following treatment. NRG-1 was neuroprotective if administered either before or 13.5 hours after transient MCAO and resulted in a significant improvement of functional neurological outcome. ...
... We previously demonstrated that administration of NRG-1 prior to tMCAO prevented neuronal death by up to 90% following ischemia and reperfusion [34,37]. However, no further protection was conferred in the pMCAO model even when a twofold higher dose of NRG-1 was administered (data not shown). ...
... It is plausible that NRG-1 was not equally effective in the pMCAO model due to additional mechanisms that may be involved in pMCAO that are not available to NRG-1 treatment. Previous results from our laboratory using EASE software [12] showed that tMCAO/reperfusion was associated with apoptotic cell death and inflammation, which have been shown to be blocked by NRG-1 [16,36,37]. EASE identified distinct pathways upregulated in the pMCAO model that were related to excitotoxicity, including neurotransmission and ion channel function. ...
Neuregulin-1 (NRG-1) is a growth factor with potent neuroprotective capacity in ischemic stroke. We recently showed that NRG-1 reduced neuronal death following transient middle cerebral artery occlusion (tMCAO) by up to 90% with an extended therapeutic window. Here, we examined the neuroprotective potential of NRG-1 using a permanent MCAO ischemia (pMCAO) rat model. NRG-1 reduced infarction in pMCAO by 50% when administered prior to ischemia. We previously demonstrated using gene expression profiling that pMCAO was associated with an exaggerated excitotoxicity response compared to tMCAO. Therefore, we examined whether co-treatment with an inhibitor of excitotoxicity would augment the effect of NRG-1 following pMCAO. Both NRG-1 and the N-methyl-D-aspartate (NMDA) antagonist MK-801 similarly reduced infarct size following pMCAO. However, combination treatment with both NRG-1 and MK-801 resulted in greater neuroprotection than either compound alone, including a 75% reduction in cortical infarction compared to control. Consistent with these findings, NRG-1 reduced neuronal death using an in vitro ischemia model and this effect was augmented by MK-801. These results demonstrate the efficacy of NRG-1 in pMCAO rat focal ischemia model. Our findings further indicate the potential clinically relevance of NRG-1 alone or as a combination strategy for treating ischemic stroke.
... Moreover, our own unpublished observations suggest differential erbB-heterodimerization patterns in lung type-II cells in pro-versus antiinflammatory contexts. In the brain, the neuroprotective effect of NRG-exposure prior to middle cerebral artery occlusion (v.i.) is accompanied by a prominent reduction in microglia activation and interleukin-1 mRNA expression in the penumbra, indicating a down-regulation of periinfarct inflammation by NRG [65]. The hypothesis that NRG might have anti-inflammatory and antioxidative properties in the brain is further supported by the finding that recombinant human NRG attenuates the production of superoxide and nitrite by stimulated N9 microglial cells [66]. ...
... In adult rat brain, erbB-4 (but not erbB-2 and erbB-3) protein was up-regulated in neurons and macrophages/microglia in ischemic areas after MCAO [74]. From the same group comes the most interesting finding that " a single intravascular injection of NRG-1beta (approximately 2.5 ng/kg) reduced cortical infarct volume by >98% when given immediately before MCAO " [65]. Based on their observations, these authors speculate that " the induction of erbB receptors … is an adaptive response … to prevent neuronal injury " [74]. ...
... Direct NRG administration might be feasible for animal studies designed to protect the animal's brain in the context of perinatal inflammatory, hypoxic-ischemic, and/or excitotoxic insults. The proof of principle has recently been published: NRG-1 can enter the brain after intra-venous [87] and intra-arterial [65] administration. In experimental autoimmune encephalitis (one laboratory model for multiple sclerosis), systemic treatment with NRG reduces demyelination and enhances remyelination [88]. ...
Brain white matter damage, an important antecedent of long-term disabilities among preterm infants, has both endogenous and exogenous components. One of the endogenous components is the paucity of developmentally regulated protectors. Here we expand on this component, discussing the potential roles of one putative protector, neuregulin (NRG)-1, in brain development and damage. We outline how NRG-1 might be involved in perinatal brain damage pathomechanisms and suggest that NRG-1 might be one target for intervention.
... The neuropathological and neuroinflammatory sequelae of acute OP poisoning are similar to those observed in other acute CNS injuries, such as stroke, brain trauma, and status epilepticus151617181947,48]. Studies from our laboratory and others demonstrated that administration of NRG-1 reduced delayed ischemic brain damage and improved functional recovery in a rat middle cerebral artery occlusion (MCAO) stroke model [32,49505152. NRG-1 prevented macrophage/microglial activation, reactive astrogliosis, neuronal apoptosis, and pro-inflammatory cytokine expression following stroke [41,50,52]. Taken together, these studies suggest that the neuroprotective efficacy of NRG-1 in DFP-induced brain injury, ischemic stroke, and cerebral malaria might be explained, at least in part, by regulating the immune response and inflammatory mediators. ...
... Studies from our laboratory and others demonstrated that administration of NRG-1 reduced delayed ischemic brain damage and improved functional recovery in a rat middle cerebral artery occlusion (MCAO) stroke model [32,49505152. NRG-1 prevented macrophage/microglial activation, reactive astrogliosis, neuronal apoptosis, and pro-inflammatory cytokine expression following stroke [41,50,52]. Taken together, these studies suggest that the neuroprotective efficacy of NRG-1 in DFP-induced brain injury, ischemic stroke, and cerebral malaria might be explained, at least in part, by regulating the immune response and inflammatory mediators. ...
Background
Neuregulin-1 (NRG-1) has been shown to act as a neuroprotectant in animal models of nerve agent intoxication and other acute brain injuries. We recently demonstrated that NRG-1 blocked delayed neuronal death in rats intoxicated with the organophosphate (OP) neurotoxin diisopropylflurophosphate (DFP). It has been proposed that inflammatory mediators are involved in the pathogenesis of OP neurotoxin-mediated brain damage.
Methods
We examined the influence of NRG-1 on inflammatory responses in the rat brain following DFP intoxication. Microglial activation was determined by immunohistchemistry using anti-CD11b and anti-ED1 antibodies. Gene expression profiling was performed with brain tissues using Affymetrix gene arrays and analyzed using the Ingenuity Pathway Analysis software. Cytokine mRNA levels following DFP and NRG-1 treatment was validated by real-time reverse transcription polymerase chain reaction (RT-PCR).
Results
DFP administration resulted in microglial activation in multiple brain regions, and this response was suppressed by treatment with NRG-1. Using microarray gene expression profiling, we observed that DFP increased mRNA levels of approximately 1,300 genes in the hippocampus 24 h after administration. NRG-1 treatment suppressed by 50% or more a small fraction of DFP-induced genes, which were primarily associated with inflammatory responses. Real-time RT-PCR confirmed that the mRNAs for pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly increased following DFP exposure and that NRG-1 significantly attenuated this transcriptional response. In contrast, tumor necrosis factor α (TNFα) transcript levels were unchanged in both DFP and DFP + NRG-1 treated brains relative to controls.
Conclusion
Neuroprotection by NRG-1 against OP neurotoxicity is associated with the suppression of pro-inflammatory responses in brain microglia. These findings provide new insight regarding the molecular mechanisms involved in the neuroprotective role of NRG-1 in acute brain injuries.
... Neuregulin-1 (NRG-1) is a member of the neuregulin family of growth factors that promotes survival and function of neuronal cells28293031. Studies have shown that NRG-1 attenuates tissue damage and immunopathology in animal models of acute brain injury (ABI) such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and nerve agent poisoning323334353637. There are clear pathophysiological similarities between CM and AIS, including an exaggerated host expression of pro-inflammatory factors that lead to increased vascular endothelial activation with upregulation of adhesion molecules, glial activation, focal inflammation, activation of apoptotic pathways and eventually brain damage and death383940. ...
... brain injury [32,33,37]. Using a PbA ECM model that mimics significant features of human CM, we have demonstrated the effectiveness of NRG-1 therapy against ECM pathophysiology, and associated mortality. ...
Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM).
We tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria.
Treatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels.
This study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.
... e l s e v i e r . c o m / l o c a t e / y t a a p Xu et al., 2004 Xu et al., , 2005 Xu et al., , 2006). The neuropathological sequelae of acute OP poisoning are similar to those observed in other acute CNS injuries, such as stroke, brain trauma and status epilepticus (Deshpande et al., 2010; Lemercier et al., 1983; McDonough et al., 1987; McLeod et al., 1984; Petras, 1994). ...
... Both acute OP intoxication and ischemia are characterized by neuronal injury that is associated with common mechanisms and neuropathology (Deshpande et al., 2010; Lemercier et al., 1983; McDonough et al., 1987; McLeod et al., 1984; Petras, 1994). Thus, as observed in these studies of acute DFP intoxication, NRG-1 prevented delayed neuronal injury in rodent models of ischemic stroke and inhibited ischemia-induced apoptotic and oxidative stress mechanisms (Guo et al., 2006; Li et al., 2007 Li et al., , 2009 Shyu et al., 2004; Xu et al., 2004 Xu et al., , 2005). To determine whether the effects of NRG-1 were due to direct activation of the NRG-erbB signaling pathway in the brain, we first confirmed that NRG-1 reached the brain. ...
... In addition to being expressed in the brain, some NRG1 isoforms are also widely expressed in the periphery303132. In particular, NRG1b, the most widespread NRG1 isoform in the brain, is found in the circulation, from which it can readily cross the adult BBB via carrier-mediated transport and affect brain activity33343536. Studies of NRG1 signaling in the brain indicate prominent roles for this protein during development, such as cell fate determina- tion [37], axon guidance [38], radial glia elongation394041, neuronal migration [42,43] and dendritic growth [44]. ...
... Mice hypomorphic for NRG1 or ErbB4 show behavioral abnormalities consistent with existing animal models for schizophrenia, including abnormal prepulse inhibition and enhanced response to cannabinoid and dopaminergic agonists929394. Studies of clinical populations have revealed decreased peripheral expression of NRG1b in schizophrenic patients that increased with antipsychotic treatment [30,31], which is particularly interesting as NRG1b can cross the adult BBB and affect brain activity and behavior33343536. Schizophrenia has been associated with both abnormal NRG1 type-I signaling in the prefrontal cortex959697 and decreased hippocampal neurogenesis [98,99]. ...
Adult hippocampal neurogenesis has been implicated in the mechanism of antidepressant action, and neurotrophic factors can mediate the neurogenic changes underlying these effects. The neurotrophic factor neuregulin-1 (NRG1) is involved in many aspects of brain development, from cell fate determination to neuronal maturation. However, nothing is known about the influence of NRG1 on neurodevelopmental processes occurring in the mature hippocampus.
Adult male mice were given subcutaneous NRG1 or saline to assess dentate gyrus proliferation and neurogenesis, as well as cell fate determination. Mice also underwent behavioral testing. Expression of ErbB3 and ErbB4 NRG1 receptors in newborn dentate gyrus cells was assessed at various time points between birth and maturity. The phenotype of ErbB-expressing progenitor cells was also characterized with cell type-specific markers.
The current study shows that subchronic peripheral NRG1β administration selectively increased cell proliferation (by 71%) and neurogenesis (by 50%) in the caudal dentate gyrus within the ventral hippocampus. This pro-proliferative effect did not alter neuronal fate, and may have been mediated by ErbB3 receptors, which were expressed by newborn dentate gyrus cells from cell division to maturity and colocalized with SOX2 in the subgranular zone. Furthermore, four weeks after cessation of subchronic treatment, animals displayed robust antidepressant-like behavior in the absence of changes in locomotor activity, whereas acute treatment did not produce antidepressant effects.
These results show that neuregulin-1β has pro-proliferative, neurogenic and antidepressant properties, further highlight the importance of peripheral neurotrophic factors in neurogenesis and mood, and support the role of hippocampal neurogenesis in mediating antidepressant effects.
... We believe that this endogenous anti-inflammatory response may hold clues for the development of antiinflammatory treatments for TBI and other acute brain injuries. Inflammation resulting from many different types of acute brain injuries, including TBI and ischemic stroke, has been linked to subsequent neuronal cell death [13][14][15][16] . By extension, we believe that understanding the post-TBI expression of genes involved in acute cell death will provide clues for the development of neuroprotective strategies. ...
BACKGROUND:
Delayed or secondary cell death that is caused by a cascade of cellular and molecular processes initiated by traumatic brain injury (TBI) may be reduced or prevented if an effective neuroprotective strategy is employed. Microarray and subsequent bioinformatic analyses were used to determine which genes, pathways and networks were significantly altered 24 h after unilateral TBI in the rat. Ipsilateral hemi-brain, the corresponding contralateral hemi-brain, and naïve (control) brain tissue were used for microarray analysis.
RESULTS:
Ingenuity Pathway Analysis showed cell death and survival (CD) to be a top molecular and cellular function associated with TBI on both sides of the brain. One major finding was that the overall gene expression pattern suggested an increase in CD genes in ipsilateral brain tissue and suppression of CD genes contralateral to the injury which may indicate an endogenous protective mechanism. We created networks of genes of interest (GOI) and ranked the genes by the number of direct connections each had in the GOI networks, creating gene interaction hierarchies (GIHs). Cell cycle was determined from the resultant GIHs to be a significant molecular and cellular function in post-TBI CD gene response.
CONCLUSIONS:
Cell cycle and apoptosis signalling genes that were highly ranked in the GIHs and exhibited either the inverse ipsilateral/contralateral expression pattern or contralateral suppression were identified and included STAT3, CCND1, CCND2, and BAX. Additional exploration into the remote suppression of CD genes may provide insight into neuroprotective mechanisms that could be used to develop therapies to prevent cell death following TBI.
... Our findings indicated that the inflammatory response and its associated genes and pathways are significant in the post-TBI molecular response. This is consistent with our published studies indicating that inflammation is involved with delayed , secondary neuronal injury following other acute brain injuries (ABI's) including stroke and neurotoxin exposure17181920. Activated microglia, astrocytes and macrophages have been shown to be the source of several of the inflammatory molecules identified in this study [10,212223. ...
Background
Traumatic brain injury (TBI) results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury in the surrounding tissue. We used microarray analysis to determine which genes, pathways and networks were significantly altered using a rat model of TBI. Adult rats received a unilateral controlled cortical impact (CCI) and were sacrificed 24 h post-injury. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naïve (control) brain tissue were used for microarray analysis. Ingenuity Pathway Analysis (IPA) software was used to identify molecular pathways and networks that were associated with the altered gene expression in brain tissues following TBI.
Results
Inspection of the top fifteen biological functions in IPA associated with TBI in the ipsilateral tissues revealed that all had an inflammatory component. IPA analysis also indicated that inflammatory genes were altered on the contralateral side, but many of the genes were inversely expressed compared to the ipsilateral side. The contralateral gene expression pattern suggests a remote anti-inflammatory molecular response. We created a network of the inversely expressed common (i.e., same gene changed on both sides of the brain) inflammatory response (IR) genes and those IR genes included in pathways and networks identified by IPA that changed on only one side. We ranked the genes by the number of direct connections each had in the network, creating a gene interaction hierarchy (GIH). Two well characterized signaling pathways, toll-like receptor/NF-kappaB signaling and JAK/STAT signaling, were prominent in our GIH.
Conclusions
Bioinformatic analysis of microarray data following TBI identified key molecular pathways and networks associated with neural injury following TBI. The GIH created here provides a starting point for investigating therapeutic targets in a ranked order that is somewhat different than what has been presented previously. In addition to being a vehicle for identifying potential targets for post-TBI therapeutic strategies, our findings can also provide a context for evaluating the potential of therapeutic agents currently in development.
... Two proofof-concept studies for NRG1 treatment have been published by two independent laboratories, confirming that peripherally administered NRG1 can pass the blood– brain barrier, most likely via a receptor-mediated transport mechanism (Kastin et al. 2004; Rösler et al. 2011). The rapid uptake of peripheral NRG1 enables time-sensitive treatment schedules, making NRG1 available both for acute and long-term treatment schemes, as shown by neuroprotective effects following intravascular administration in acute stroke models (Xu et al. 2004Xu et al. , 2006). Animal studies have highlighted the time-sensitive effect of NRG1 administration on neurodevelopment and behaviours. ...
Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.
... A role for NRG1 in SZ has also been supported by animal studies using NRG1 and ErbB4 mutant mice (Gerlai et al., 2000; Stefansson et al., 2002; Bao et al., 2003; Corfas et al., 2004; Steinthorsdottir et al., 2004; Gu et al., 2005; Rimer et al., 2005), which exhibit behaviors similar to those of established rodent models of SZ (Lipska, 2004). NRG1 polymorphisms have been proposed as risk factors for several other common disorders, including Alzheimer's disease (Chaudhury et al., 2003; Go et al., 2005); epilepsy (early myoclonic encephalopathy; Backx et al., 2009), stroke (Shyu et al., 2004; Xu et al., 2004) breast cancer (Raj et al., 2001), multiple sclerosis (Cannella et al., 1999; Viehover et al., 2001), bipolar disorder (Thomson et al., 2007; Goes et al., 2008; Prata et al., 2009; Walker et al., 2010; Moon et al., 2011) and Hirschsprung Disease (Garcia-Barcelo et al., 2009; Tang et al., 2011). In sum, NRG1 likely plays a key role in brain development and neurotransmitter function. ...
... In particular, the degree of leukocyte infiltration following focal stroke correlates with the severity of neuronal injury and neurological deficits in animals ( Clark et al., 1994; del Zoppo et al., 1991) and humans (Akopov et al., 1996). Moreover, in focal ischemia models, anti-leukocyte interventions decrease cerebral edema (Strachan et al., 1992), improve cerebral blood flow (Grogaard et al., 1989; Connolly et al., 1996; Ishikawa et al., 2004), and reduce infarct size (Connolly et al., 1996; Chopp et al., 1994; Beech et al., 2001; Xu et al., 2004; Zheng et al., 2004). Finally, adhesion molecule knockout mice consistently exhibit smaller lesion volumes following focal stroke than their wild-type counterparts (Prestigiacomo et al., 1999; Soriano et al., 1996). ...
Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFalpha application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFalpha and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFalpha. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.
Perinatal brain damage is one of the leading causes of life long disability. This damage could be hypoxic-ischemic, inflammatory, or both. This mini-review discusses different interventions aiming at minimizing inflammatory processes in the neonatal brain, both before and after insult. Current options of anti-inflammatory measures for neonates remain quite limited. We describe current anti-inflammatory intervention strategies such as avoiding perinatal infection and inflammation, and reducing exposure to inflammatory processes. We describe the known effects of anti-inflammatory drugs such as steroids, antibiotics, and indomethacin, and the possible anti-inflammatory role of other substances such as IL-1 receptor antagonists, erythropoietin, caffeine, estradiol, insulin-like growth factor, and melatonin as well as endogenous protectors, and genetic regulation of inflammation. If successful, these may decrease mortality and long-term morbidity among term and pre-term infants.
Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease.
Neuregulin 1 (NGR1) and survivin have been shown to be neuroprotective. However, the link between their expression and aspirin in the treatment of cerebral ischemia remains unclear. Here, we investigated the effect of aspirin on NGR1 and survivin expression after focal cerebral ischemia/reperfusion in rats. Sprague Dawley rats were randomly divided into an aspirin treatment group (n=40) and a control group (n=40). Each group was further divided into five subgroups according to the time after reperfusion. A middle cerebral artery model was established by an occlusion suture. At 24 h, 3, 5 and 7 days after reperfusion, the Bederson neurological deficit scores were 1.47±0.11, 1.22±0.08, 0.85±0.15 and 0.59±0.12 in the treatment group, and 1.87±0.18, 1.45±0.14, 1.05±0.08 and 0.75±0.15 in the control group, respectively, indicating a significant difference at each time point (P<0.05). In the infarct center, the number of NGR1- and survivin-positive cells reached the maximum at 6 h and decreased gradually to a minimum at 7 days, while in the peri-infarct area, the number was few at 6 h, peaked at 3 days and then was reduced gradually with significant differences between the two time points (P<0.05). There were more NGR1- and survivin-positive cells in the treatment group compared to the control group (P<0.05). In conclusion, the neuroprotective effect of aspirin is at least partly mediated by the upregulation of NGR1 and survivin expression after ischemia.
The Neuregulin-1 gene encodes a family of ligands that act through the ErbB family of receptor tyrosine kinases to regulate morphogenesis of many tissues. Work in isolated cardiac cells as well as genetically altered mice demonstrates that neuregulin-1/ErbB signaling is a paracrine signaling system that functions in endocardial-endothelial/cardiomyocyte interactions to regulate tissue organization during development as well as maintain cardiac function throughout life. Treatment of animals with cardiac dysfunction with recombinant neuregulin-1beta improves cardiac function. This has led to ongoing early phase clinical studies examining neuregulin-1beta as a potential novel therapeutic for heart failure. In this review we synthesize the literature behind this rapidly evolving area of translational research. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
Neuregulin 1 (NRG1) is a trophic factor that has been implicated in neural development, neurotransmission, and synaptic plasticity. NRG1 has multiple isoforms that are generated by usage of different promoters and alternative splicing of a single gene. However, little is known about NRG1 isoform composition profile, whether it changes during development, or the underlying mechanisms. We found that each of the six types of NRG1 has a distinct expression pattern in the brain at different ages, resulting in a change in NRG1 isoform composition. In both human and rat, the most dominant are types III and II, followed by either type I or type V, while types IV and VI are the least abundant. The expression of NRG1 isoforms is higher in rat brains at ages of E13 and P5 (in particular type V), suggesting roles in early neural development and in the neonatal critical period. At the cellular level, the majority of NRG1 isoforms (types I, II, and III) are expressed in excitatory neurons, although they are also present in GABAergic neurons and astrocytes. Finally, the expression of each NRG1 isoform is distinctly regulated by neuronal activity, which causes significant increase in type I and IV NRG1 levels. Neuronal activity regulation of type IV expression requires a CRE cis-element in the 5' untranslated region (UTR) that binds to CREB. These results indicate that expression of NRG1 isoforms is regulated by distinct mechanisms, which may contribute to versatile functions of NRG1 and pathologic mechanisms of brain disorders such as schizophrenia.
Perinatal brain damage has been implicated in the pathogenesis of neurodevelopmental impairments and psychiatric illnesses. This article reviews evidence that infection outside of the brain can damage the brain, and discusses specific cytokines and pathomechanisms that probably mediate the putative effect of remote infection on the developing brain. Events associated with increased circulating inflammatory cytokines, chemokines, and immune cells are described. Finally, studies of genetic variation in susceptibility to cytokine-related brain damage are reviewed.
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