Granulocyte colony‐stimulating factor has a negative effect on stroke outcome in a murine model

Abstract

The administration of CD34-positive cells after stroke has been shown to have a beneficial effect on functional recovery by accelerating angiogenesis and neurogenesis in rodent models. Granulocyte colony-stimulating factor (G-CSF) is known to mobilize CD34-positive cells from bone marrow and has displayed neuroprotective properties after transient ischemic stress. This led us to investigate the effects of G-CSF administration after stroke in mouse. We utilized permanent ligation of the M1 distal portion of the left middle cerebral artery to develop a reproducible focal cerebral ischemia model in CB-17 mice. Animals treated with G-CSF displayed cortical atrophy and impaired behavioral function compared with controls. The negative effect of G-CSF on outcome was associated with G-CSF induction of an exaggerated inflammatory response, based on infiltration of the peri-infarction area with CD11b-positive and F4/80-positive cells. Although clinical trials with G-CSF have been started for the treatment of myocardial and limb ischemia, our results indicate that caution should be exercised in applying these results to cerebral ischemia.

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

“…In brief, the left MCA was isolated, electrocauterized, and disconnected just distal to its crossing of the olfactory tract (distal M1 portion) under halothane inhalation. The infarct area in mice of this background has been shown to be highly reproducible and limited to the ipsilateral cerebral cortex [8,15,33,34].…”

“…Permanent focal cerebral ischemia was produced by ligation and disconnection of the distal portion of the left middle cerebral artery (MCA) [8,15,33,34]. In brief, the left MCA was isolated, electrocauterized, and disconnected just distal to its crossing of the olfactory tract (distal M1 portion) under halothane inhalation.…”

“…Functional recovery of mice subjected to stroke and then treated with BMMCs was investigated by behavioral testing using a modification of the open field task [44] as described [15,33,34]. Because dysfunction of the cortex is closely linked to disinhibition of behavior in the presence of light [15,33], we investigated locomotion during the light phase 30 days after stroke.…”

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: A systematic review

“…Once pre-specified exclusion criteria were applied, a total of 19 publications were chosen for analysis (table 1); these came from 12 laboratories in 8 countries (China, France, Germany, Japan, South Korea, Taiwan, UK and USA). Only one negative study was identified in which G-CSF had a detrimental effect on behavioural function, caused brain atrophy and exaggerated the inflammatory response in the infarcted area (Taguchi et al, 2007). Studies excluded (table 2) were those administering G-CSF in combination with other agents such as stem cell factor (SCF) and those assessing chronic (i.e.…”

“…G-CSF significantly reduced neurological deficit (SMD -1.37, 95% CI -2.13 to -0.61, p=0.0004) in 11 studies (Komine-Kobayashi et al, 2006;Sehara et al, 2007a;Sevimli et al, 2009;Solaroglu et al, 2009;Taguchi et al, 2007;Yanqing et al, 2006). Impairment was measured at various time points post stroke (1, 2, 3, 7, 14, 21 and 35 days); beneficial effects of G-CSF were seen at all times but there was no correlation between reduction in impairment and time to measurement (r s = 0.37, p=0.47).…”