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Erythropoietin (EPO) promotes neuronal survival after cerebral ischemia in vivo and after hypoxia in vitro. However, the mechanisms underlying the protective effects of EPO on ischemic/hypoxic neurons are not fully understood. The present in vitro experiments showed that EPO attenuated neuronal damage caused by chemical hypoxia at lower extracellular concentrations (10(- 4)-10(-2) U/ml) than were previously considered. Moreover, EPO at a concentration of 10(-3) U/ml up-regulated Bcl-xL mRNA and protein expressions in cultured neurons. Subsequent in vivo study focused on whether EPO rescued hippocampal CA1 neurons from lethal ischemic damage and up-regulated the expressions of Bcl-xL mRNA and protein in the hippocampal CA1 field of ischemic gerbils. EPO was infused into the cerebroventricles of gerbils immediately after 3 min of ischemia for 28 days. Infusion of EPO at a dose of 5 U/day prevented the occurrence of ischemia-induced learning disability. Subsequent light microscopic examinations showed that pyramidal neurons in the hippocampal CA1 field were significantly more numerous in ischemic gerbils infused with EPO (5 U/day) than in those receiving vehicle infusion. The same dose of EPO infusion caused significantly more intense expressions of Bcl-xL mRNA and protein in the hippocampal CA1 field of ischemic gerbils than did vehicle infusion. These findings suggest that EPO prevents delayed neuronal death in the hippocampal CA1 field, possibly through up-regulation of Bcl-xL, which is known to facilitate neuron survival.

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NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

Resident quiescent microglia have been thought to respond rapidly to various pathologic events in the brain by proliferating and producing many bioactive substances, including proinflammatory cytokines and nitric oxide (NO). In this study, we investigated the reaction of microglia in traumatic and ischemic lesions caused by stab wounds and the transient 90-min occlusion of middle cerebral artery in a mature rat brain. Although many Iba1(+) resident microglia underwent apoptotic degeneration in the lesion core within 24 hr after the onset of the brain insult as revealed by TUNEL staining, numerous small, round, isolectin B4(+)/CD11b(+)/CD68(+) cells were localized in the lesion core. These small, round cells with diameters of 7-9 mum and polymorph nuclei expressed neutrophil-specific elastase, alkaline phosphatase, and platelet-activating factor receptor. Accordingly, they were not activated microglia but neutrophils. Immunohistochemical staining with antibodies to inducible NO synthase (iNOS) showed that most iNOS(+) cells were neutrophils. The results from spatial and kinetic analyses using RT-PCR and immunoblotting were consistent with the immunohistochemical observations. These results suggest the necessity of reevaluating the traditional view on the roles of activated microglia in severe neuropathologic events. Note that the traditional microglial markers isolectin B4, CD11b, and CD68 are not specific for microglia, particularly in a pathologic brain.

Reactive oxygen and nitrogen species (RO/NS) such as nitric oxide (NO), hydroxyl radical (OH·), and superoxide anion (O2−) are generated in a variety of neuropathological processes and damage neurons. In the present study, we investigated the neuroprotective effects of rat astrocytes against RO/NS‐induced damage using neuron–glia cocultures, and the effects were compared to those of microglial cells. Sodium nitroprusside (SNP), 3‐morpholinosydnonimine (SIN‐1), and FeSO4 were used to generate NO, O2− and NO, and OH·, respectively. Solely cultured neurons, which were transiently exposed to these agents, degenerated, possibly through apoptotic mechanisms as revealed by in situ detection of DNA fragmentation, whereas neurons cocultured with either astrocytes or microglial cells were viable even after exposure to RO/NS. In contrast, most neurons cocultured with meningeal fibroblasts degenerated. Astrocyte‐conditioned medium partially attenuated RO/NS‐induced neuronal damage. When neurons were cultured on astrocyte‐derived extracellular matrix (AsECM), neuronal death induced by SNP and FeSO4 was almost completely inhibited. AsECM contained significant amounts of laminin and fibronectin, and pure fibronectin and laminin also protected neurons against RO/NS‐induced damage in the same manner as AsECM. These results suggest that astrocytes can protect neurons against RO/NS‐induced damage by secreting soluble and insoluble factors. GLIA 28:85–96, 1999. © 1999 Wiley‐Liss, Inc.