Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Modi, Jigar; Menzie-Suderam, Janet; Xu, Hongyuan; Trujillo, Paola; Medley, Kristen; Marshall, Michael; Tao, Rui; Prentice, Howard; Wu, Jang‐Yen

doi:10.1186/s12929-019-0597-7

Cited by 42 publications

(42 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The protective effect of the single dose of hG-CSF gene therapy was significant at 4 days and 7 days after ischemia, evident from functional improvements determined by corner test and locomotor activity. This evidence is further supported by our previous study on the protective mechanism of the G-CSF protein [ 52 ] and provided added credence to the efficacy of hG-CSF gene therapy.…”

Section: Discussionsupporting

confidence: 75%

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Menzie-Suderam

Modi

et al. 2020

J Biomed Sci

Self Cite

View full text Add to dashboard Cite

Background Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection. Clinical application of human G-CSF (hG-CSF) is limited due to its plasma half-life of 4 h. Therefore, novel approaches need to be investigated that would (1) enable prolonged manifestation of hG-CSF and (2) demonstrate G-CSF efficacy from studying the underlying protective mechanisms of hG-CSF. In our previous work, we used the self-complementary adeno-associated virus (stereotype2: scAAV2) as a vector to transfect the hG-CSF gene into the global ischemic brain of a mouse. As an extension of that work, we now seek to elucidate the protective mechanisms of hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia. Method A single drop of either AAV-CMV-hG-CSF or AAV-CMV-GFP was dropped into the conjunctival sac of the Swiss Webster mouse’s left eye, 30–60 min after bilateral common artery occlusion (BCAO). The efficacy of the expressed hG-CSF gene product was analyzed by monitoring the expression levels of endoplasmic reticulum stress (ER), mitochondrial dynamics and autophagic proteins over 4- and 7-days post-BCAO in vulnerable brain regions including the striatum, overlying cortex (frontal brain regions) and the hippocampus (middle brain regions). Statistical analysis was performed using mostly One-Way Analysis of variance (ANOVA), except for behavioral analysis, which used Repeated Measures Two-Way ANOVA, post hoc analysis was performed using the Tukey test. Results Several biomarkers that facilitated cellular death, including CHOP and GRP78 (ER stress) DRP1 (mitochondrial dynamics) and Beclin 1, p62 and LC3-ll (autophagy) were significantly downregulated by hG-CSF gene transfer. hG-CSF gene therapy also significantly upregulated antiapoptotic Bcl2 while downregulating pro-apoptotic Bax. The beneficial effects of hG-CSF gene therapy resulted in an overall improvement in functional behavior. Conclusion Taken together, this study has substantiated the approach of sustaining the protein expression of hG-CSF by eye drop administration of the hG-CSF gene. In addition, the study has validated the efficacy of using hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia.

show abstract

Section: Discussionsupporting

confidence: 75%

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Menzie-Suderam

Modi

et al. 2020

J Biomed Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“…Activation of BAX and BAD also promote MOMP [ 88 ]. The BCL-2 family proteins are key regulators of MOMP and play critical role in the intrinsic apoptotic pathway, classified into anti-apoptotic (Bcl-2, Bcl-xl, Bcl-w) and pro-apoptotic (Bax, Bak, Bim, Bid, Bad) [ 45 ]. The increased expression of pro-apoptotic markers is also influenced by the hormones involved in the pituitary–adrenal response [ 89 ], while in the extrinsic pathway, binding ligands to death receptors (TNF-α, Fas, TRAIL, etc.)…”

Section: Regulation Of Cytokines and Apoptosis By G-csf In Neonatal Hmentioning

confidence: 99%

“…G-CSF administration downregulates GSK-3ß activity, resulting in reduced neuronal cell death, apoptosis, and infarct volume, as well as upregulating anti-apoptotic protein Bcl-2 expression levels [ 45 , 77 ]. Our previous study has demonstrated that increased Bax expression levels and cleaved caspase-3 (CC3) activation were attenuated significantly by G-CSF treatment and simultaneously increasing BCL-2 expression levels that were decreased following HI-induced injury.…”

Section: Regulation Of Cytokines and Apoptosis By G-csf In Neonatal Hmentioning

confidence: 99%

“…1h after HI for 4d Reduced infarct volume & lung injury [ 30 ] Increased neutrophil count & less brain tissue atrophy Improved physical development & neurological function Hypoxia-ischaemia (RCCA ligation) Neonatal SD rat pups 50 s.c. injected 1h after HI Reduced infarct volume & increased expression of G-CSF receptor in neurons [ 42 ] Increased p-AKt expression & decreased p-GSK-3β/GSK-3β ratio Decreased aopototic markers & TUNEL positice cells in neuron Perinatal hypoxia Neonatal SD rat pups 10, 30, 50 s.c. injected 1d after HI Attenuated PSD-95 protein expression levels & improved long-term deficits [ 43 ] Increased phosphorylated activity of pRaf-pERK1/2-PCREB pathway Enhanced increase expression of neurogenesis in hippocampal neuron Stroke (MCA ligation) Adult male SD rats 15 s.c. injected 1h after restoring CBF for 15d Decreased mortality rate & less effect in reducing infarct volume [ 44 ] Improved functional recovery of motor function Increased number of proliferating cells & new neurons in the SVZ Hypoxia-ischaemia (RCCA ligation) Neonatal SD rats 50 i.p. immediately after HI induction Attenuated cerebral infarction & improved body weight [ 45 ] Inhibited apoptosis by decreasing apoptotic cells & increased brain volume Focal cerebral ischaemia (MCAO) Male Wistar rats 60 iv 30min after occlusion Reduced infarct volume & mortality rate [ 46 ] Increased STAT3 expression & anti-excitotoxic effect Stroke (MCAO/CCA) 50 iv 60min after induction Elevated neutrophil count & reduced infarct volume [ 47 ...…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

Dumbuya

Chen

et al. 2021

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

Hypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to central nervous system (CNS) that may result in neonatal death or manifest later as mental retardation, epilepsy, cerebral palsy, or developmental delay. The primary cause of this condition is systemic hypoxemia and/or reduced cerebral blood flow with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. About 20 to 25% of infants with HIE die in the neonatal period, and 25-30% of survivors are left with permanent neurodevelopmental abnormalities. The mechanisms of hypoxia-ischemia (HI) include activation and/or stimulation of myriad of cascades such as increased excitotoxicity, oxidative stress, N-methyl-d-aspartic acid (NMDA) receptor hyperexcitability, mitochondrial collapse, inflammation, cell swelling, impaired maturation, and loss of trophic support. Different therapeutic modalities have been implicated in managing neonatal HIE, though translation of most of these regimens into clinical practices is still limited. Therapeutic hypothermia, for instance, is the most widely used standard treatment in neonates with HIE as studies have shown that it can inhibit many steps in the excito-oxidative cascade including secondary energy failure, increases in brain lactic acid, glutamate, and nitric oxide concentration. Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein that has been implicated in stimulation of cell survival, proliferation, and function of neutrophil precursors and mature neutrophils. Extensive studies both in vivo and ex vivo have shown the neuroprotective effect of G-CSF in neurodegenerative diseases and neonatal brain damage via inhibition of apoptosis and inflammation. Yet, there are still few experimentation models of neonatal HIE and G-CSF’s effectiveness, and extrapolation of adult stroke models is challenging because of the evolving brain. Here, we review current studies and/or researches of G-CSF’s crucial role in regulating these cytokines and apoptotic mediators triggered following neonatal brain injury, as well as driving neurogenesis and angiogenesis post-HI insults.

show abstract

“…G-CSF (granulocyte-colony stimulating factor) is an endogenous ligand in the CNS that displays several important functions including anti-apoptotic activity, immunomodulatory action, stimulates neurogenesis, and angiogenic capabilities. G-CSF treatment exerts neuroprotective effects on damaged neurons by decreasing pro-apoptotic proteins and increasing of antiapoptotic proteins, both reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia [ 88 , 89 ]. Balseanu et al, demonstrated in a stroke rat model that daily intravenous injection of G-CSF led to robust and consistent improvement of neurological functions, which in a combination with a single intravenous administration of mesenchymal stromal cells (MSC) increased the neurogenesis in the subventricular zone and improved microvessel density in the formerly infarct core and perilesional area of treated aged rats, but had no beneficial effect on the infarct volume or mortality [ 90 ].…”

Section: Gene Therapy For Strokementioning

confidence: 99%

Genetic Aspects of Inflammation and Immune Response in Stroke

Nikolić

Janković

Petrović³

et al. 2020

IJMS

View full text Add to dashboard Cite

Genetic determinants play important role in the complex processes of inflammation and immune response in stroke and could be studied in different ways. Inflammation and immunomodulation are associated with repair processes in ischemic stroke, and together with the concept of preconditioning are promising modes of stroke treatment. One of the important aspects to be considered in the recovery of patients after the stroke is a genetic predisposition, which has been studied extensively. Polymorphisms in a number of candidate genes, such as IL-6, BDNF, COX2, CYPC19, and GPIIIa could be associated with stroke outcome and recovery. Recent GWAS studies pointed to the variant in genesPATJ and LOC as new genetic markers of long term outcome. Epigenetic regulation of immune response in stroke is also important, with mechanisms of histone modifications, DNA methylation, and activity of non-coding RNAs. These complex processes are changing from acute phase over the repair to establishing homeostasis or to provoke exaggerated reaction and death. Pharmacogenetics and pharmacogenomics of stroke cures might also be evaluated in the context of immuno-inflammation and brain plasticity. Potential novel genetic treatment modalities are challenged but still in the early phase of the investigation.

show abstract

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

Cited by 42 publications

References 59 publications

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

Genetic Aspects of Inflammation and Immune Response in Stroke

Contact Info

Product

Resources

About