An extended window of opportunity for G-CSF treatment in cerebral ischemia

Here, we have further delayed treatment and studied effects of G-CSF on infarct volume in the middle cerebral artery occlusion (MCAO) model and functional outcome in the cortical photothrombotic model. In the MCAO model, we applied a single dose of 60 μg/kg bodyweight G-CSF in rats 4 h after onset of ischemia. Infarct volume was determined 24 h after onset of ischemia. In the rat photothrombotic model, we applied 10 μg/kg bodyweight G-CSF daily for a period of 10 days starting either 24 or 72 h after induction of ischemia. G-CSF both decreased acute infarct volume in the MCAO model, and improved recovery in the photothrombotic model at delayed timepoints.These data further strengthen G-CSF's profile as a unique candidate stroke drug, and provide an experimental basis for application of G-CSF in the post-stroke recovery phase.Granulocyte-colony stimulating factor (G-CSF) is a cytokine that stimulates generation of neutrophilic granulocytes, and has been in clinical use for more than 10 years in indications related to counteracting neutropenia, or for bone-marrow transplantations [1-3]. Recently, a surprising activity of G-CSF in protecting against experimental cerebral ischemia has been shown by a large number of laboratories [4-12]. The explanations for the effects of G-CSF on the CNS appear as a combination of direct anti-apoptotic activity on neurons [5,6,13] mediated by the presence of the cognate G-CSF receptor in a broad array of brain regions [14], stimulation of endogenous neurogenesis [14], regeneration of vascularisation [8], potential mobilisation of bone-marrow derived cells that migrate to the brain [11,12], and possible systemic anti-inflammatory effects ([15], discussed in [14]).Characterised by this multimodal array, G-CSF appears beneficial for short-term damage parameters such as infarct size, and long-term effects on functional outcome (for example, see [6]). Based on this broad pre-clinical basis for efficacy, G-CSF is now undergoing testing in cl