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Neurobiol Dis. 2014 Sep;69:192-9. doi: 10.1016/j.nbd.2014.05.024. Epub 2014 May 27.

Anti-neutrophil antibody enhances the neuroprotective effects of G-CSF by decreasing number of neutrophils in hypoxic ischemic neonatal rat model.

Author information

1
Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
2
Department of Anaesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
3
Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, USA.
4
Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: jtang@llu.edu.

Abstract

OBJECTIVES:

Neonatal hypoxia ischemia (HI) is an injury that can lead to neurological impairments such as behavioral and learning disabilities. Granulocyte-colony stimulating factor (G-CSF) has been demonstrated to be neuroprotective in ischemic stroke however it has also been shown to induce neutrophilia, ultimately exacerbating neuronal injury. Our hypothesis is that coadministration of anti-neutrophil antibody (Ab) with G-CSF will decrease blood neutrophil counts thereby reducing infarct volume and improving neurological function post HI brain injury.

METHODS:

Rat pups were subjected to unilateral carotid artery ligation followed by 2.5h of hypoxia. Animals were randomly assigned to five groups: Sham (n=15), vehicle (HI, n=15), HI with G-CSF treatment (n=15), HI with G-CSF+Ab treatment (n=15), and HI with Ab treatment (n=15). Ab (325μg/kg) was administered intraperitoneally while G-CSF (50μg/kg) was administered subcutaneously 1h post HI followed by daily injections for 3 consecutive days. Animals were euthanized at 96h post HI for blood neutrophil counts and brain infarct volume measurements as well as at 5weeks for neurological function testing and brain weight measurements. Lung and spleen weights at both time points were further analyzed.

RESULTS:

The G-CSF treatment group showed tendencies to reduce infarct volume and improve neurological function while significantly increasing neutrophil counts. On the other hand, the G-CSF+Ab group significantly reduced infarct volume, improved neurological function and decreased neutrophil counts. The Ab alone group showed reversal of the neuroprotective effects of the G-CSF+Ab group. No significant differences were found in peripheral organ weights between groups.

CONCLUSION:

Our data suggest that coadministration of G-CSF with Ab not only prevented brain atrophy but also significantly improved neurological function by decreasing blood neutrophil counts. Hence the neuroprotective effects of G-CSF may be further enhanced if neutrophilia is avoided.

KEYWORDS:

Anti-neutrophil antibody (Ab); Granulocyte-colony stimulating factor (G-CSF); Hypoxia–ischemia (HI); Neonatal; Neurological function; Neutrophil

PMID:
24874543
PMCID:
PMC4109395
DOI:
10.1016/j.nbd.2014.05.024
[Indexed for MEDLINE]
Free PMC Article

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