Background and Purpose-The physiological function of cellular prion protein (PrP c ) is not yet understood. Recent findings suggest that PrP c may have neuroprotective properties, and its absence increases susceptibility to neuronal injury. The purpose of this study was to elucidate the role of PrP c in ischemic brain injury in vivo. Methods-PrP knockout (Prnp 0/0 ) and Prnp ϩ/ϩ wild-type (WT) mice were subjected to 60-minute transient or permanent focal cerebral ischemia followed by infarct volume analysis 24 hours after lesion. To identify effects of PrP c deletion on mechanisms regulating ischemic cell death, expression analysis of several proapoptotic and antiapoptotic proteins was performed at 6 and 24 hours after transient ischemia and in nonischemic controls using Western blot or immunohistochemistry. Results-Prnp0/0 mice displayed significantly increased infarct volumes after both transient or permanent ischemia when compared with WT animals (70.2Ϯ23 versus 13.3Ϯ4 mm

Background and Purpose-Systemic injection of hematopoietic stem cells after ischemic cardiac or neural lesions is one approach to promote tissue repair. However, mechanisms of possible protective or reparative effects are poorly understood. In this study we analyzed the effect of lineage-negative bone marrow-derived hematopoietic stem and precursor cells (Lin Ϫ -HSCs) on ischemic brain injury in mice. Methods-LinϪ -HSCs were injected intravenously at 24 hours after onset of a 45-minute transient cerebral ischemia. Effects of Lin Ϫ -HSCs injection on infarct size, apoptotic cell death, postischemic inflammation and cytokine gene transcription were analyzed. Results-Green fluorescent protein (GFP)-marked LinϪ -HSCs were detected at 24 hours after injection in the spleen and later in ischemic brain parenchyma, expressing microglial but no neural marker proteins. Tissue injury assessment showed significantly smaller infarct volumes and less apoptotic neuronal cell death in peri-infarct areas of Lin Ϫ -HSC-treated animals. Analysis of immune cell infiltration in ischemic hemispheres revealed a reduction of invading T cells and macrophages in treated mice. Moreover, Lin Ϫ -HSC therapy counter-regulated proinflammatory cytokine and chemokine receptor gene transcription within the spleen.Conclusions-Our data demonstrate that systemically applied Lin Ϫ -HSCs reduce cerebral postischemic inflammation, attenuate peripheral immune activation and mediate neuroprotection after ischemic stroke.

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Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection.

Summary: Basic fibroblast growth factor (bFGF) is a polypeptide that supports the survival of brain cells (in cluding neurons, glia, and endothelia) and protects neu rons against a number qf toxins and insults in vitro. This factor is also a potent dilator of cerebral pial arterioles in vivo. In previous studies, we found that intraventricularly administered bFGF reduced infarct volume in a model of focal cerebral ischemia in rats. In the current study, bFGF (45 I-lg/kg/h) in vehicle, or vehicle alone, was in fused intravenously for 3 h, beginning at }O min after permanent middle cerebral artery occlusion by intralumi nal suture in mature Sprague-Dawley rats. After 24 h, neurological deficit (as assessed by a 0-to 5-point scale, with 5 = most severe) was 2.6 ± 1.0 in vehicle-treated "Neurotrophic" growth factors are polypeptides that, acting through specific receptors, initiate cas cades of signal transduction resulting in increased neuronal survival. Recently, it has been appreciated that these factors also protect neurons against var ious insults and toxins. In particular, basic fibro blast growth factor (bFGF) is a 154-amino acid, 18-kD polypeptide that supports the survival of a wide

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