Enhancement in cognitive function recovery by granulocyte-colony stimulating factor in a rodent model of traumatic brain injury

Sikoglu, Elif; Heffernan, Meghan E.; Tam, Kelly; Sicard, Kenneth M.; Bratane, Bernt T.; Quan, Meina; Fisher, Marc; King, Jean A.

doi:10.1016/j.bbr.2013.11.008

Cited by 15 publications

(9 citation statements)

References 16 publications

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“…Granulocyte colony-stimulating factor (G-CSF) is a target of NF-kB and has been shown to be neuroprotective in stroke by inducing anti-apoptotic pathways [50–53]. The NF-kB inducible cytokine IL-9 has also been reported to prevent apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…G-CSF has been shown to be neuroprotective in ischemic stroke models by inducing anti-apoptotic pathways, and IL-9 is known to promote cell proliferation and inhibit apoptosis [53, 58]. It has been reported that G-CSF significantly reduced the expression of microglial p65, reduced pro-inflammatory mediators, and promoted anti-inflammatory responses in models of multiple sclerosis [59, 60].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Simmons

Surles-Zeigler

et al. 2016

J Neuroinflammation

110

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BackgroundWe previously demonstrated that neuregulin-1 (NRG-1) was neuroprotective in rats following ischemic stroke. Neuroprotection by NRG-1 was associated with the suppression of pro-inflammatory gene expression in brain tissues. Over-activation of brain microglia can induce pro-inflammatory gene expression by activation of transcriptional regulators following stroke. Here, we examined how NRG-1 transcriptionally regulates inflammatory gene expression by computational bioinformatics and in vitro using microglial cells.MethodsTo identify transcriptional regulators involved in ischemia-induced inflammatory gene expression, rats were sacrificed 24 h after middle cerebral artery occlusion (MCAO) and NRG-1 treatment. Gene expression profiles of brain tissues following ischemia and NRG-1 treatment were examined by microarray technology. The Conserved Transcription Factor-Binding Site Finder (CONFAC) bioinformatics software package was used to predict transcription factors associated with inflammatory genes induced following stroke and suppressed by NRG-1 treatment. NF-kappa B (NF-kB) was identified as a potential transcriptional regulator of NRG-1-suppressed genes following ischemia. The involvement of specific NF-kB subunits in NRG-1-mediated inflammatory responses was examined using N9 microglial cells pre-treated with NRG-1 (100 ng/ml) followed by lipopolysaccharide (LPS; 10 μg/ml) stimulation. The effects of NRG-1 on cytokine production were investigated using Luminex technology. The levels of the p65, p52, and RelB subunits of NF-kB and IkB-α were determined by western blot analysis and ELISA. Phosphorylation of IkB-α was investigated by ELISA.ResultsCONFAC identified 12 statistically over-represented transcription factor-binding sites (TFBS) in our dataset, including NF-kBP65. Using N9 microglial cells, we observed that NRG-1 significantly inhibited LPS-induced TNFα and IL-6 release. LPS increased the phosphorylation and degradation of IkB-α which was blocked by NRG-1. NRG-1 also prevented the nuclear translocation of the NF-kB p65 subunit following LPS administration. However, NRG-1 increased production of the neuroprotective cytokine granulocyte colony-stimulating factor (G-CSF) and the nuclear translocation of the NF-kB p52 subunit, which is associated with the induction of anti-apoptotic and suppression of pro-inflammatory gene expression.ConclusionsNeuroprotective and anti-inflammatory effects of NRG-1 are associated with the differential regulation of NF-kB signaling pathways in microglia. Taken together, these findings suggest that NRG-1 may be a potential therapeutic treatment for treating stroke and other neuroinflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Simmons

Surles-Zeigler

et al. 2016

J Neuroinflammation

110

View full text Add to dashboard Cite

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“…Currently under investigation for treating multiple sclerosis, 118 therapies such as glatiramer acetate, interferon-β, or dimethyl fumarate may promote the beneficial aspects of neuroinflammation-neurogenesis and repair-while reducing cytotoxic mediators. A similar approach is being adapted from spinal cord injury research with the use of "pro-inflammatory" therapy: G-CSF alone 119 or in combination with mesenchymal stem cells. 120 These therapies may also be useful late in the course of the disease to mitigate CTE.…”

Section: Promoting Inflammation-mediated Regenerationmentioning

confidence: 99%

Emerging Therapies in Traumatic Brain Injury

et al. 2015

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Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discuss TBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field.

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“…Hematopoietic growth factors have been extensively studied and used in neonates for hematologic indications for several years [15]. In addition to their hematopoietic effects, they may have other potential benefits, including neuroprotection, neural tissue repair, and neurovasculogenesis [15–17]. The effects of these agents on neuronal death or survival, however, seem to be context-specific [12], conveying neuroprotection in some neonatal brain injury models [18–28], while having no effect or even exacerbating damage in others [29, 30].…”

Section: Introductionmentioning

confidence: 99%

Short-, Mid-, and Long-Term Effect of Granulocyte Colony-Stimulating Factor/Stem Cell Factor and Fms-Related Tyrosine Kinase 3 Ligand Evaluated in an In Vivo Model of Hypoxic-Hyperoxic Ischemic Neonatal Brain Injury

Posod

Wegleiter

Neubauer

et al. 2019

BioMed Research International

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Hematopoietic growth factors are considered to bear neuroprotective potential. We have previously shown that delayed treatment with granulocyte colony-stimulating factor (G-CSF)/stem cell factor (SCF) and Fms-related tyrosine kinase 3 ligand (FL) ameliorates excitotoxic neonatal brain injury. The effect of these substances in combined-stressor neonatal brain injury models more closely mimicking clinical conditions has not been investigated. The aim of this study was to assess the short-, mid-, and long-term neuroprotective potential of G-CSF/SCF and FL in a neonatal model of hypoxic-hyperoxic ischemic brain injury. Five-day-old (P5) CD-1 mice were subjected to unilateral common carotid artery ligation and subsequent alternating periods of hypoxia and hyperoxia for 65 minutes. Sixty hours after injury, pups were randomly assigned to intraperitoneal treatment with (i) G-CSF (200 μg/kg)/SCF (50 μg/kg), (ii) FL (100 μg/kg), or (iii) vehicle every 24 hours for three or five consecutive days. Histopathological and functional outcomes were evaluated on P10, P18, and P90. Baseline outcome parameters were established in sham-treated and healthy control animals. Gross brain injury did not significantly differ between treatment groups at any time point. On P10, caspase-3 activation and caspase-independent apoptosis were similar between treatment groups; cell proliferation and the number of BrdU-positive vessels did not differ on P18 or P90. Neurobehavioral assessment did not reveal significant differences between treatment groups in accelerod performance, open field behavior, or novel object recognition capacity on P90. Turning behavior was more frequently observed in G-CSF/SCF- and FL-treated animals. No sex-specific differences were detected in any outcome parameter evaluated. In hypoxic-hyperoxic ischemic neonatal brain injury, G-CSF/SCF and FL treatment does not convey neuroprotection. Prior to potential clinical use, meticulous assessment of these hematopoietic growth factors is mandated.

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Enhancement in cognitive function recovery by granulocyte-colony stimulating factor in a rodent model of traumatic brain injury

Cited by 15 publications

References 16 publications

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway

Emerging Therapies in Traumatic Brain Injury

Short-, Mid-, and Long-Term Effect of Granulocyte Colony-Stimulating Factor/Stem Cell Factor and Fms-Related Tyrosine Kinase 3 Ligand Evaluated in an In Vivo Model of Hypoxic-Hyperoxic Ischemic Neonatal Brain Injury

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