Ischemia‐induced programmed cell death in astrocytes

Abstract

Astrocytes are essential for neuronal survival and function, neurogenesis, and neural repair. Although astrocytes are more resistant than neurons to most stress conditions in vitro, certain astrocyte subtypes, such as the glial fibrillary acidic protein (GFAP)-negative protoplasmic astrocytes that predominate in gray matter structures, may be equally or more sensitive than neurons to ischemia in vivo. Programmed cell death differs from passive, necrotic death in that cell constituents actively participate in cell demise. Like neurons, astrocytes undergo programmed cell death during normal development. Cell culture studies have shown that astrocytes can be induced to undergo apoptosis and other forms of programmed cell death by many factors relevant to ischemia, including acidosis, oxidative stress, substrate deprivation, and cytokines. Animal models of cerebral ischemia have confirmed nuclear condensation and upregulation of Bax and caspases in a subset of astrocytes exposed to ischemia, especially in immature brain. A causal role for these events in astrocyte death is supported by improved astrocyte survival after inhibition of caspase-dependent cell death pathways. Astrocyte survival is also improved by blocking the poly(ADP-ribose)-1 cell death pathway. Markers of programmed cell death are generally less evident and less widespread in astrocytes than in neighboring neurons. However, most studies to date have relied only on markers of classical apoptosis. In addition, these studies have relied almost exclusively on GFAP to identify astrocytes. Since most protoplasmic astrocytes are poorly immunoreactive for GFAP, the extent of ischemia-induced programmed cell death in this cell type remains uncertain.

Caspase‐3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation

“…Astroglial cells can undergo cell death in vitro in a variety of situations such as calcium overload, oxidative stress, mitochondrial dysfunction, and treatment with apoptotic inducers like staurosporine and ceramide (Giffard and Swanson, 2005;Takuma et al, 2004), although it has been established that they are more resistant than neuronal cells (Xu et al, 2004). In this regard, studies of astroglial cell death after different types of acute injuries such as traumatic brain injury (Beer et al, 2000;Newcomb et al, 1999) and ischemia/ excitotoxicity (Biran et al, 2006;Dihne et al, 2001), have shown that apoptosis occurs only in few astrocytes, in agreement with our findings in the injured neonatal brain.…”

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

“…Although its neurotrophic properties were known (Morrison et al, 1987;Hanson et al, 1998;Boillee et al, 2001;Kerr et al, 2003), a survival effect on glial cells remained to be demonstrated. In mammals, astrocyte death contributes to various pathological events (Takuma et al, 2004;Giffard and Swanson, 2005), and regulation of astrocytes numbers through developmental death has been documented (Soriano et al, 1993;Krueger et al, 1995). Nevertheless, only scarce studies have been devoted to the identification of growth factors capable of promoting the survival of these glial cells (Yokoyama et al, 1993;Bakhiet et al, 2001;Saas et al, 2002).…”

“…Patients suffering from Alexander disease bear GFAP mutations, which directly affect astrocytes, and result in profound fatal cerebral alterations (Rodriguez et al, 2001). In addition, astrocytes death participates in several neuropathological diseases ranging from HIVassociated dementia to ischemic and traumatic brain injury (Thomas et al, 1995;Thompson et al, 2001;Takuma et al, 2004;Giffard and Swanson, 2005). The identification of molecules capable of promoting the survival of astrocytes is therefore essential.…”

Targeting Astrocytes for Stroke Therapy

“…Several expert reviews discuss these numerous aspects of astrocyte function and death during stroke. 4,[7][8][9][10][11][12][13][14][15] Here, we will briefly review mechanisms of astrocyte cell death during stroke, but focus most of the discussion on the adaptive and pathological roles of astrocytes during ischemia. Where applicable, we will discuss the potential for targeting astrocyte function to reduce cell death during stroke and so improve functional recovery.…”

“…Nonetheless, caspase activation and apoptosis of astrocytes could contribute to delayed astrocyte death. 11 The relative vulnerability in vivo of astrocytes and neurons during stroke is still an open question. Some in vivo studies of focal cerebral ischemia suggest that astrocytes may be more vulnerable than neurons, 22,23 and indeed certain subtypes of astrocytes, such as protoplasmic astrocytes, may be particularly vulnerable during stroke.…”