Abstract
Purpose: :
Haematopoietic growth factors are circulating cytokines that regulate the bone marrow production of red cells, white cells and platelets. These cytokines can exhibit actions that extend beyond their haematopoietic properties. For example, erythropoietin (EPO) provides neuroprotection and promotes neurogenesis and angiogenesis following stroke and retinal ischemia. Thrombopoietin (TPO) is the primary haematopoietic factor that regulates megakaryocytes and platelet production. Compared with EPO, TPO might be beneficial but with fewer side effects if used for clinical intervention (i.e., TPO might provide protection on CNS ischemia independent of its platelet production and be efficacious within a longer time window for intervention). Since TPO’s CNS protection is unknown, here we studied TPO at low doses in two CNS models (focal stroke and retinal ischemia).
Methods: :
For focal ischemic stroke, male Sprague Dawley rats underwent 2 hr middle carotid artery occlusion (MCAO) then 22 hr reperfusion,followed by sectioning and TTC staining to evaluate infarct size. For retinal ischemia, male Sprague Dawley rats was were subjected to high intraocular pressure (HIOP) in the right eye for 45 minutes and then reperfused for 7 days.Electroretinograms (ERG) a- and b- waves were measured in each eye before and after retinal ischemia and again at 7 days.PBS (vehicle) or TPO at different doses were administered intravenously immediately after reperfusion in both models.
Results: :
Following PBS administration, MCAO-reperfusion induced a large infarct. TPO exhibited a "U" shaped dose response on infarct size and swelling. The optimum dose was 0.1 µg/kg. Following retinal ischemia, the ERG a-wave did not differ between groups, however, the ERG b-wave was preserved by TPO. TPO protection also exhibited a "U" shaped dose response. The optimum dose was also 0.1 µg/kg. This dose improved ERG responses by 312 %. TPO was more potent in the retina.
Conclusions: :
These data demonstrate post-ischemic TPO protects the CNS from morphological and functional injury.TPO provides new opportunities for intervention and can further our knowledge of growth factors, CNS protection and recovery
Keywords: retina • ischemia • neuroprotection