Granulocyte Colony-Stimulating Factor Does Not Promote Neurogenesis after Experimental Intracerebral Haemorrhage

Abstract

Background

Hematopoietic growth factors have been suggested to induce neuroprotective and regenerative effects in various animal models of cerebral injury. However, the pathways involved remain widely unexplored.

Aims

This study aimed to investigate effects of local and systemic administration of granulocyte colony-stimulating factor on brain damage, functional recovery, and cerebral neurogenesis in an intracerebral haemorrhage whole blood injection model in rats.

Methods

Eight-week-old male Wistar rats (n = 100) underwent induction of striatal intracerebral haemorrhage by autologous whole blood injection or sham procedure and were randomly assigned to either (a) systemic treatment with granulocyte colony-stimulating factor (60 μg/kg) for five-days; (b) single intracerebral injection of granulocyte colony-stimulating factor (60 μg/kg) into the cavity; or (c) application of vehicle for five-days. Bromodeoxyuridine-labelling and immunohistochemistry were used to analyze proliferation and survival of newly born cells in the sub-ventricular zone and the hippocampal dentate gyrus. Moreover, functional deficits and lesion volume were assessed until day 42 after intracerebral haemorrhage.

Results

Differences in lesion size or hemispheric atrophy between granulocyte colony-stimulating factor-treated and control groups did not reach statistical significance. Neither systemic, nor local granulocyte colony-stimulating factor administration induced neurogenesis within the dentate gyrus or the sub-ventricular zone. The survival of newborn cells in these regions was prevented by intracerebral granulocyte colony-stimulating factor application. A subtle benefit in functional recovery at day 14 after intracerebral haemorrhage induction was observed after granulocyte colony-stimulating factor treatment.

Conclusion

There was a lack of neuroprotective or neuroregenerative effects of granulocyte colony-stimulating factor in the present rodent model of intracerebral haemorrhage. Conflicting results from functional outcome assessment require further research.

Keywords

acute stroke therapy brain bleed cerebral haemorrhage neuroprotection stem cells stroke

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References

Morgenstern

Hemphill

3rd Anderson

. Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010; 41: 2108–29.

Hwang

Appelboom

Ayer

. Advances in neuroprotective strategies: Potential therapies for intracerebral hemorrhage. Cerebrovasc Dis 2011; 31: 211–22.

Schneider

Kruger

Steigleder

. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005; 115: 2083–98.

Park

Chu

Lee

. Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 2005; 1041: 125–31.

Zhang

Shu

Zhou

. Protective effect of granulocyte colony-stimulating factor on intracerebral hemorrhage in rat. Neurochem Res 2009; 34: 1317–23.

Shyu

Lin

Yang

. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 2004; 110: 1847–54.

Kawada

Takizawa

Takanashi

. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation 2006; 113: 701–10.

Bullock

Mendelow

Teasdale

Graham

. Intracranial haemorrhage induced at arterial pressure in the rat. Part 1: Description of technique, ICP changes and neuropathological findings. Neurol Res 1984; 6: 184–8.

MacLellan

Langdon

Churchill

Granter-Button

Corbett

. Assessing cognitive function after intracerebral hemorrhage in rats. Behav Brain Res 2009; 198: 321–8.

10.

MacLellan

Davies

Fingas

Colbourne

. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke 2006; 37: 1266–70.

11.

Keep

Hoff

. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 2006; 5: 53–63.

12.

Kirkman

Allan

Parry-Jones

. Experimental intracerebral hemorrhage: Avoiding pitfalls in translational research. J Cereb Blood Flow Metab 2011; 31: 2135–51.

13.

MacLellan

Plummer

Silasi

Auriat

Colbourne

. Rehabilitation promotes recovery after whole blood-induced intracerebral hemorrhage in rats. Neurorehabil Neural Repair 2011; 25: 477–83.

14.

Kirschenbaum

Doetsch

Lois

Alvarez-Buylla

. Adult subventricular zone neuronal precursors continue to proliferate and migrate in the absence of the olfactory bulb. J Neurosci 1999; 19: 2171–80.

15.

Arvidsson

Collin

Kirik

Kokaia

Lindvall

. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002; 8: 963–70.

16.

Frank

Klinker

Falkenburger

. Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson's disease. Brain 2012; 135(Pt 6):1914–25.

17.

Tsai

Shen

. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med 2007; 204: 1273–80.

18.

Pollari

Savchenko

Jaronen

. Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 2011; 8: 74.

19.

Dittgen

Pitzer

Plaas

. Granulocyte-colony stimulating factor (G-CSF) improves motor recovery in the rat impactor model for spinal cord injury. PLoS ONE 2012; 7: e29880.

20.

Frank

Schlachetzki

Goricke

. Both systemic and local application of granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy. BMC Neurosci 2009; 10: 49.

21.

Ringelstein

Thijs

Norrving

. Granulocyte colony-stimulating factor in patients with acute ischemic stroke: Results of the AX200 for ischemic stroke trial. Stroke 2013; 44: 2681–7.