Recent studies have demonstrated that blockade of neuronal death in the hippocampus cannot prevent epileptogenesis in various epileptic models. These reports indicate that neurodegeneration alone is insufficient to cause epilepsy, and that the role of astrocytes in epileptogenesis should be reconsidered. Therefore, the present study was designed to elucidate whether altered morphological organization or the functionalities of astrocytes induced by status epilepticus (SE) is responsible for epileptogenesis. Glial responses (reactive microgliosis followed by astroglial death) in the dentate gyrus induced by pilocarpine-induced SE were found to precede neuronal damage and these alterations were closely related to abnormal neurotransmission related to altered vesicular glutamate and GABA transporter expressions, and mossy fiber sprouting in the dentate gyrus. In addition, newly generated astrocytes showed down-regulated expressions of glutamine synthase, glutamate dehydrogenase, and glial GABA transporter. Taken together, our findings suggest that glial responses after SE may contribute to epileptogenesis and the acquisition of the properties of the epileptic hippocampus. Thus, we believe that it is worth considering new therapeutic approaches to epileptogenesis involving targeting the inactivation of microglia and protecting against astroglial loss.

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Inflammation is a basic pathological mechanism leading to a variety of vascular diseases. The inflammatory reaction involves complex interactions between both circulating and resident leukocytes and the vascular endothelium. In this study, we report evidence for a novel action of TNF-related activation-induced cytokine (TRANCE) as an inflammatory mediator and its underlying signaling mechanism in the vascular wall. TRANCE significantly increased endothelial-leukocyte cell interactions, and this effect was associated with increased expression of the cell adhesion molecules, ICAM-1 and VCAM-1, on the endothelial cells. RT-PCR analysis and promoter assays revealed that expression of these cell adhesion molecules was transcriptionally regulated mainly by activation of the inflammatory transcription factor, NF-κB. TRANCE induced IκB-α phosphorylation and NF-κB activation via a cascade of reactions involving the TNFR-associated factors, phospholipase C, PI3K, and protein kinase C (PKC-α and PKC-ζ). It also led to the production of reactive oxygen species via PKC- and PI3K-dependent activation of NADPH oxidase in the endothelial cells, and antioxidants suppressed the responses to TRANCE. These results demonstrate that TRANCE has an inflammatory action and may play a role in the pathogenesis of inflammation-related diseases.

IntroductionPostnatal tissue neovascularization is an important adaptation for rescue from critical ischemia and is required for sufficient blood supply to growing tumors. This process was formerly attributed to the migration and proliferation of pre-existing, fully differentiated endothelial cells (ECs) in a process called angiogenesis. Recent studies have shown that circulating bone marrow (BM)-derived endothelial progenitor cells (EPCs) are recruited to the site of tissue regeneration and substantially contribute to neovascularization and re-endothelialization after acute vascular injury. 1,2 Intravenous infusion of EPCs after ischemia was shown to improve neovascularization and cardiac function in both animal models and pilot clinical studies. Conversely, BM-derived EPCs participate in the pathogenesis of various diseases, such as cancer, retinopathy, and atherosclerosis. 2,3 Impaired recruitment of BM-derived endothelial and hematopoietic precursor cells is known to block both tumor angiogenesis and growth. 4 Injection of BM cells promotes injuryassociated retinal angiogenesis. 5 BM-derived progenitors also contribute to the formation of the microvasculature in allograft arteriosclerotic lesions. 6 Therefore, EPCs have both physiologic and pathologic roles; thus, they have been widely considered for establishing new therapeutic strategies for the treatment of angiogenesis-related diseases.The number of circulating EPCs may limit the ultimate magnitude of angiogenesis therapies and, therefore, strategies that are based on the administration of ex vivo-expanded populations of EPCs harvested from the patient's circulating blood appear promising. 7 In addition, increased recruitment and specific lodging of EPCs in ischemic tissues may constitute another therapeutic target. Likewise, mechanisms to prevent EPC homing show promise as therapeutic strategies for the treatment of excessive neovascularization. Recently, stromal cell-derived factor-1 (SDF-1), a member of the chemokine CXC subfamily, was identified as an important factor for the trafficking of EPCs to ischemic tissues; it has also been recognized as a prominent target for increasing the engraftment of progenitor cells. 8,9 SDF-1 secreted from carcinomaassociated fibroblasts promotes angiogenesis by recruiting EPCs to tumor tissue. 3 Furthermore, ␤2-integrin expressed in EPCs was shown to mediate augmentation of the homing and neovascularization capacity of EPCs in vitro and in vivo. 10 CXCR2 also increased the homing of circulating EPCs to the sites of artery injury, possibly by enhancing adhesion of EPCs to extracellular matrix coimmobilized with chemokines. 11,12 Therefore, the identification of novel, endogenous factors that lead to both the mobilization and homing of EPCs in response to tissue hypoxia is important for the understanding of the functional contribution of EPCs to postnatal neovascularization and to the establishment of new strategies for the treatment of angiogenesis-related diseases. Here, we report a novel role and underlying signali...

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