The neuregulins are a complex family of factors that perform many functions during neural development. Recent experiments have shown that neuregulins promote neuronal migration and differentiation, and regulate the selective expression of neurotransmitter receptors in neurons and at the neuromuscular junction. They also regulate glial commitment, proliferation, survival and differentiation. At interneuronal synapses, neuregulin ErbB receptors associate with PDZ-domain proteins at postsynaptic densities where they can modulate synaptic plasticity. How this combinatorial network - comprising many neuregulin ligands that signal through distinct combinations of dimeric ErbB receptors - elicits its multitude of biological effects is beginning to be resolved.
"It is possible that the link between genetic variation in neuregulin (NRG) and the increased risk of developing schizophrenia could be established through the influence NRG has on the regulation of distributed cerebral activity. NRGs are a family of signalling proteins containing an epidermal growth factor (EGF)-like domain that activates ErbB receptor-tyrosine kinases, which orchestrate a broad range of cellular responses [1-3]. Among them, Neuregulin 1 (NRG1) has a significant impact upon differentiation, migration and maturation of gamma-Aminobutyric acid (GABA) interneurons . "
[Show abstract][Hide abstract] ABSTRACT: Background
Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1–4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance.
We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype.
Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia.
Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia.
Annals of General Psychiatry 06/2014; 13(18). DOI:10.1186/1744-859X-13-18 · 1.40 Impact Factor
"Neuregulin-1 (NRG-1) is a member of the neuregulin family of growth factors that promotes survival and function of neuronal cells
[28-31]. 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 poisoning
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neuroinflammation 01/2014; 11(1):9. DOI:10.1186/1742-2094-11-9 · 5.41 Impact Factor
"In muscle, functional homodimerization of ErbB4 upon binding of NRG can regulate the transcription of acetylcholine receptors . We investigated NRG1 function on α7nAChR expression in microglial and macrophage cell lines to determine if NRG1 has a similar inductive effect on the expression of α7nAChRs. "
[Show abstract][Hide abstract] ABSTRACT: Neuregulin, previously known as ARIA, is a signaling protein involved in cell survival, synaptic plasticity, cell communication and differentiation. Neuregulin has also been described as a potent inducer of acetylcholine receptor transcription in muscle and although both neuregulin and acetylcholine have been individually described to have neuroprotective roles, their relationship in the cholinergic anti-inflammatory pathway of the brain has not been examined.
Using three cell lines, BV-2, EOC-20 and RAW 264.7, we investigated the role that neuregulin signaling through the Erb family of tyrosine kinases may play in the anti-inflammatory process mediated by the α7 nicotinic acetylcholine receptors. Here we show that ErbB4 is expressed in all of our cell lines and is phosphorylated upon treatment with neuregulin. Neuregulin treatment further increases the expression of α7 nicotinic acetylcholine receptors in the microglial lines tested. Given the central role of α7 nicotinic acetylcholine receptors in regulating system inflammation we analyzed the expression of several pro-inflammatory cytokines in our system. Using ELISAs for TNF-α and IL-6 we show that treatment with NRG can produce a nearly a 33% decrease in the levels of tumor necrosis factor-α secreted by activated microglia and a nearly 88% decrease in IL-6.
Given these results we propose a neuroprotective role for neuregulin wherein it modulates the expression of TNF-α and thus inflammation in the CNS via the upregulation of α7 nicotinic acetylcholine receptor expression in microglia in vitro. We suggest that the disregulation of neuregulin expression may be pivotal in neurological disorders characterized by inflammation.
PLoS ONE 07/2013; 8(7):e70338. DOI:10.1371/journal.pone.0070338 · 3.23 Impact Factor
Brenna C Beckelman, Xueyan Zhou, C Dirk Keene, Tao Ma
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