Using the rat spinal ischemia model, we have shown that specific intervals of transient spinal ischemia lead to a selective degeneration of small and medium-sized inhibitory neurons in lumbosacral segments and the development of prominent spastic paraplegia. Comparable neurological deficit in patients undergoing thoracoabdominal aortic aneurysm repair has been described. While the extent of neuronal degeneration can partially be manipulated by peri-ischemic temperature and/or pharmacological treatment once a significant population of spinal neurons is lost, the resulting neurological deficit is permanent and irreversible. Importantly, in contrast to spinal mechanical injury-induced paraplegia, which is characterized by a partial or complete loss of descending tracts integrity after ischemia-induced paraplegia, descending systems show long-term survival. These characteristics point into a simple disinhibitory mechanism accounting for the presence of spastic paraplegia. In recent years a significant attention has been focused on a potential role of neuronal stem cells or cultured differentiated neurons and their therapeutic potentials in ameliorating neurological dysfunction after brain or spinal neuronal neurodegeneration/injury. These initial studies clearly show that intraspinal or intracerebral grafting of neuronal progenitors or neurons have a beneficial effect on recovery of function after a variety of pathological insults including trauma or ischemia. In the present studies, using a rat model of aortic occlusion, we will examine a possible therapeutic potential of spinally implanted neuronal progenitors or differentiated neurons as assessed by the recovery of motor function in animals with spastic paraplegia. In addition, these experiments serve to shed light upon: i) the fate and differentiation of spinally implanted stem cells or neurons after transient ischemia, and, ii) characterization of growth factors (neurotrophin-3 [NT-3], brain-derived neurotrophic factor [BDNF], glial cell line-derived neurotrophic factor [GDNF]) that may modulate survivability of implanted cells as well as local synaptogenesis between implanted cells and host neurons. From a practical standpoint, these studies will systematically address issues which we believe have both basic and clinical importance. Thus, the ability to replace neuronal pools selectively that were lost after spinal ischemia and modulate their functional incorporation in the host tissue may prove to be of particular significance in developing novel therapeutic modalities for managing spinal-ischemia-induced paraplegia.
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