Astrocyte Influences on Ischemic Neuronal Death

Abstract

Glutamate excitotoxicity, oxidative stress, and acidosis are primary mediators of neuronal death during ischemia and reperfusion. Astrocytes influence these processes in several ways. Glutamate uptake by astrocytes normally prevents excitotoxic glutamate elevations in brain extracellular space, and this process appears to be a critical determinant of neuronal survival in the ischemic penumbra. Conversely, glutamate efflux from astrocytes by reversal of glutamate uptake, volume sensitive organic ion channels, and other routes may contribute to extracellular glutamate elevations. Glutamate activation of neuronal N-methyl-D-aspartate (NMDA) receptors is modulated by glycine and D-serine: both of these neuromodulators are transported by astrocytes, and D-serine production is localized exclusively to astrocytes. Astrocytes influence neuronal antioxidant status through release of ascorbate and uptake of its oxidized form, dehydroascorbate, and by indirectly supporting neuronal glutathione metabolism. In addition, glutathione in astrocytes can serve as a sink for nitric oxide and thereby reduce neuronal oxidant stress during ischemia. Astrocytes probably also influence neuronal survival in the post-ischemic period. Reactive astrocytes secrete nitric oxide, TNFalpha, matrix metalloproteinases, and other factors that can contribute to delayed neuronal death, and facilitate brain edema via aquaporin-4 channels localized to the astrocyte endfoot-endothelial interface. On the other hand erythropoietin, a paracrine messenger in brain, is produced by astrocytes and upregulated after ischemia. Erythropoietin stimulates the Janus kinase-2 (JAK-2) and nuclear factor-kappaB (NF-kB) signaling pathways in neurons to prevent programmed cell death after ischemic or excitotoxic stress. Astrocytes also secrete several angiogenic and neurotrophic factors that are important for vascular and neuronal regeneration after stroke.

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

“…Slit's ability to protect against neuronal injury in this model, the first demonstration of its kind that we are aware of, must result from Slit-mediated signaling of cytoprotective pathways in glia and/or neurons independent of any reduction in leukocyte chemotaxis. Although further studies are required to elucidate the mechanistic basis for the observed protective effect, a direct effect of Slit that improves the glial response to ischemia is possible, since the ability of glial cells to promote neuronal viability in the setting of ischemia is well established (Lee et al, 2004;Rosenberg et al, 1989;Heidinger et al, 1999;Trendelenburg et al, 2005;Swanson et al, 2004). In Drosophila, glial Slit receptors play an important role in neuron-glia interactions by influencing the survival and migration of both cell types; moreover, interfering with these interactions alters their responsiveness to Slit-Robo signaling (Kinrade et al, 2001).…”

Epidermal Growth Factor Receptor Activation: An Upstream Signal for Transition of Quiescent Astrocytes into Reactive Astrocytes after Neural Injury

“…Astrocytes are the major glial subtype and are important effectors that participate in the pathogenesis of numerous neural disorders (Miller, 2005), including trauma (Norton, 1999), stroke (Swanson et al, 2004), aging (Luo and Roth, 2000), and developmental, genetic, idiopathic or acquired neurodegenerative diseases (Abraham, 2001;Teismann et al, 2003;Barbeito et al, 2004) Modulating the behaviors of reactive astrocytes is increasingly thought to be a therapeutic strategy for the treatment of CNS disorders (Tacconi, 1998;Neufeld et al, 1999;Mrak and Griffin, 2001;Wyss-Coray and Mucke, 2002;Neufeld and Liu, 2003b).…”

Cyclosporin a Increases Mitochondrial Calcium Uptake Capacity in Cortical Astrocytes but not Cerebellar Granule Neurons

“…Most studies of ischemic brain damage have focused on neurons, but in recent years it has become clear that astrocytes are also damaged in ischemia (Petito et al, 1998;Liu et al, 1999;Dugan and KimHan, 2004;Swanson et al, 2004). There is evidence in vitro that oxidative stress can induce an MPT in astrocytes (Muyderman et al, 2004), however the role of Ca 2+ in MPT in astrocytes is less clear.…”