The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis
Armin Schneider, … , Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz
Armin Schneider, … , Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2083-2098. https://doi.org/10.1172/JCI23559.
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Research Article Neuroscience

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis

Abstract

G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong antiapoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.

Authors

Armin Schneider, Carola Krüger, Tobias Steigleder, Daniela Weber, Claudia Pitzer, Rico Laage, Jaroslaw Aronowski, Martin H. Maurer, Nikolaus Gassler, Walter Mier, Martin Hasselblatt, Rainer Kollmar, Stefan Schwab, Clemens Sommer, Alfred Bach, Hans-Georg Kuhn, Wolf-Rüdiger Schäbitz

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G-CSF has stable neuroprotective activity in focal cerebral ischemia and...
G-CSF has stable neuroprotective activity in focal cerebral ischemia and passes the intact BBB. (A) G-CSF has efficacy in the transient MCAO stroke model when given 2 hours after onset of ischemia, as shown by reduction in infarct volume (dose: 60 μg/kg i.v.; vehicle, n = 7; G-CSF, n = 10; **P < 0.01 by 2-sided t test). (B) G-CSF reduces infarct volume in the rat cortical combined CCA/distal MCA occlusion model when given 1 hour after onset of ischemia (dose: 50 μg/kg i.v.; n = 5 each; *P < 0.05). (C) Behavioral measurements in the cortical combined CCA/distal MCA occlusion model. G-CSF–treated animals have a better composite neurological deficit score (NDS) (*P < 0.05). (D) Comparison of the brain/serum ratios of i.v. injected iodinated G-CSF and albumin at 1, 4, and 24 hours following injection. Albumin does not pass the BBB. Radiolabeled proteins (G-CSF and BSA) were injected via the tail vein of healthy female Sprague-Dawley rats. The relative amount of radiolabeled G-CSF and BSA in serum and brain was measured, and the ratio of brain/serum was plotted against the time. The brain/serum ratio of G-CSF was significantly greater than that of albumin, which indicated passage of the intact BBB in non-ischemic animals.