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Table 1 An Overview of G-CSF application in Hypoxia-schaemia Brain Injury Models

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

Model Adult/Neonate Dosage (μg/kg) Application/Duration Outcome Ref
Acute ischaemic cerebral injury (MCAO) Adult SD rats 100 s.c. injected immediately after injury for 7d Reduced infarct volume & necrotic cells [29]
Increased Egr-1 & VEGF expression levels
Stroke (BCAO) adult male Swiss Webster mice 50 s.c. injected 30min afterocclusion for 4 to 7 consecutive days Increased expression of G-CSF receptor [36]
Decreased GRP78 expression & decreased ATF6 cleavage levels
Decreased apoptotic protein signalling (DRI1 & P53) & increased pro-survival signalling (OPAI)
Upregulated anti-apoptotic protein Bcle-2 and downregulated pro-apoptotic proteins Bax & Bak
Increased locomotor sensitisation
Cerebral ischaemia reperfusion (tMCAO) Adult SD rats 50 s.c. injected 1h after restoring CBF for 5 consecutive days Reduced infarct volume & oedema [37]
Improved neurological function & reduced apoptotic neurons
Downregulated the activation of the JNK apoptosis pathway
Ischaemic brain injury (DHCA) Newborn piglets 34 iv. 2h prior to inintiation of bypass Reduced neuronal injury in the hippocampus [38]
Focal cerebral ischaemia (MCAO) Adult male SD rats 50 s.c. injected at the onset of reperfusion; 2nd injected at onset of reperfusion for 2d Attenuated infarct volume & early neurological deficits [39]
Elevated STAT3 phosphorylation & nuclear Pim-1 expression
Increased expression of cIAP2 & Bcl-2 & decreased caspase-3 & Bax levels
Hypoxia-ischaemia (RCCA ligation) Neonatal SD rats 50 s.c. injected 1h after HI for 56 Less vacuolization, neuron loss & tissue breakqown [33]
Increased brain weight & G-CSF receptor expression
Reduced cleaved caspase-3 activity
Increased expression of anti-apoptotic pathway mediators
Hypoxic-ischaemic brain damage (RCCA ligation) Neonatal SD rats 50 s.c. injected 1h after HI for 6 days & 11 days Promoted physical development & improved functional deficits [40]
Reduced brain atrophy & increased systemic organ weight
Increased exploratory behaviour & shorm-term memory
Hypoxia- ischaemia (RCCA ligation) Neonatal SD rat pups 50 s.c. injected 1h after HI Reduced infarct volume & corticosterone levels [41]
Decreased cleaved caspase-3 level & lowered Bax/Bcl-2 ratio
G-CSF did not influence ACTH response
Hypoxia- ischaemia (RCCA ligation) Neonatal SD rat pups 50 s.c. or i.p. 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]
Increased expression of G-CSF receptor in neurons
(MCAO)   60 iv 2h after onset of occlusion for 5d Increased protein level of STAT3 & increased AKt phosphorylation
Improved long-term behaviour
Hypoxic-ischaemic brain injury (MCAO) Neonatal mice pups 200 s.c. injected 1h after injury & 60h after injury for 5d Did not improved neurobehavioural outcomes & brain injuries [48]
Perinatal hypoxia Neonatal rat pups 30 i.p. 1d after HI induction for 6d Enhanced neurogenesis & improved long-term cognitive function [49]
Hypoxia- ischaemia (RCCA ligation) Neonatal SD rat pups 50 i.p. 2.5h after HI induction Decreased expression levels of TNF-α and IL-1β & increased IL-10 levelsDecreased expression levels of TNF-α and IL-1β & increased IL-10 levels [50]
Increased Bcl-2 expression levels & decreased CC3 and Bax expression levels
Upregulated p-mTOR and p-P70S6K protein expression levels
Hypoxia-ischaemia (RCCA ligation) Neonatal SD rat pups 50 s.c. injected 1h after HI Showed localisation of G-CSF receptor in enthothial cells [51]
Decreased β-catenin and p120-catenin phosphorylationDecreased β-catenin and p120-catenin phosphorylation
Attenuated PICs (IKKβ, NF-κB, TNF-α, IL-1β) & enhanced IL-10 levelsAttenuated PICs (IKKβ, NF-κB, TNF-α, IL-1β) & enhanced IL-10 levels
Decreased adheren proteins & increased tight junction proteins expression
Hypoxia-ischaemia (RCCA ligation) Neonatal SD rat pups 50 s.c. injected 1h after hypoxia Inhibited corticosterone synthesis by activating its receptor in cortical cells [52]
Increased expression of JAK2, PI3K, AKt and PDE3B proteins
Inhibited cAMP elevation induced by cholera toxin
Decreased infarct volume and increased body weight
  1. Abbreviations: G-CSF Granulocyte-colony stimulating factor, MCAO Middle cerebral artery occlusion, BCAO Bilateral cerebral artery occlusion, tMCAO transient middle cerebral artery occlusion, DHCA Deep hypothermic circulation arrest, RCCA Right common carotid artery, VEGF Vascular endothelial growth factor, HI Hypoxia-ischaemia, Egr-1 Early growth response-1, s.c subcutaneous, iv intravenous, i.p intraperitoneal, GRP78 Glucose regulated protein 78, ATF6 Activating transcription factor 6, DRP1 Dynamin-related protein 1, OPA1 Optic atrophy protein 1, JNK c-Jun N-terminal kinase, Bcl-2 B-cell lymphoma 2, cIAP2 cellular inhibitor of apoptosis protein 2, ACTH Adrenocorticotropic hormone, p-GSK-3β phosphorylated glycogen synthase kinase-3 beta, p-AKt phosphorylated protein kinase B, PSD-95 Postsynaptic density protein-95, pCREB phosphorylated cAMP-responsive element binding protein, pERK phosphorylated exracellular signal-regulated kinase, pRaf phosphorylated mitogen-activated protein-kinase-kinase-kinase, SVZ Subventricular zone, CC3 Cleaved caspase-3, STAT3 Signal transducer and activated protein kinase 3, p-P70S6K Phosphorylated p70 ribosomal s6 protein kinase, p-mTOR Phosphorylated mammalian target of rapamycin, IL-10 Interleukin 10, IL-1β Interleukin 1 beta, TNF-α Tumour necrosis factor-alpha, NF-κB Nuclear factor-kappa B, IKKB Inhibitor of kappa B kinase, PICs Pro-inflammatory cytokines, PDE3B Phosphodiesterase 3B, AKt Protein kinase B, PI3K Phosphatidylinositol 3-kinase, JAK2 Janus kinase 2, cAMP cyclic adenosine monophosphate, CBF Cerebral blood flow