Desislava M Doycheva1, Tiffany Hadley2, Li Li1, Richard L Applegate2, John H Zhang3, Jiping Tang4. 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.
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.
Authors: W-R Schäbitz; R Kollmar; M Schwaninger; E Juettler; J Bardutzky; M N Schölzke; C Sommer; S Schwab Journal: Stroke Date: 2003-02-13 Impact factor: 7.914
Authors: Erik R Swenson; Marco Maggiorini; Stephen Mongovin; J Simon R Gibbs; Ilona Greve; Heimo Mairbäurl; Peter Bärtsch Journal: JAMA Date: 2002-05-01 Impact factor: 56.272
Authors: A A Kocher; M D Schuster; M J Szabolcs; S Takuma; D Burkhoff; J Wang; S Homma; N M Edwards; S Itescu Journal: Nat Med Date: 2001-04 Impact factor: 53.440
Authors: David A Hess; Krysta D Levac; Francis N Karanu; Michael Rosu-Myles; Martin J White; Lisa Gallacher; Barbara Murdoch; Michael Keeney; Pamela Ottowski; Ronan Foley; Ian Chin-Yee; Mickie Bhatia Journal: Blood Date: 2002-08-01 Impact factor: 22.113
Authors: Bram J van Raam; Agata Drewniak; Vincent Groenewold; Timo K van den Berg; Taco W Kuijpers Journal: Blood Date: 2008-06-04 Impact factor: 22.113