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