Targeting Astrocytes for Stroke Therapy

Abstract

Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…It is generally acknowledged that astrocytes are substantially more ischemia‐resistant than neurons and survive in conditions of limited blood supply, characteristic for penumbra surrounding the core of the ischemic infarction (Swanson, Farrell, & Stein, 1997; Vangeison, Carr, Federoff, & Rempe, 2008). These surviving astrocytes undergo activation and are involved in neuroprotection and post‐ischemic regeneration (Takano, Oberheim, Cotrina, & Nedergaard, 2009; Zhao and Rempe 2010). Astroglia contributions to brain resilience could include clearance of glutamate, control over K + concentration, supply of lactate to the stressed neurons, secretion of neuroprotective factors, and scavenging reactive oxygen species by releasing GSH and ascorbic acid (Liu and Chopp 2015; Zhao and Rempe 2010).…”

“…These surviving astrocytes undergo activation and are involved in neuroprotection and post‐ischemic regeneration (Takano, Oberheim, Cotrina, & Nedergaard, 2009; Zhao and Rempe 2010). Astroglia contributions to brain resilience could include clearance of glutamate, control over K + concentration, supply of lactate to the stressed neurons, secretion of neuroprotective factors, and scavenging reactive oxygen species by releasing GSH and ascorbic acid (Liu and Chopp 2015; Zhao and Rempe 2010). Recently, using optogenetic control of H + pumps expressed on astrocytes, it was demonstrated that alkalinisation of astrocytes could reduce glutamate release and limit the ischemic brain damage in a cerebellar ischemia model.…”

“…Reactive astrocytes surrounding the ischemic core are the main contributors to the glial scar, along with oligodendrocytes and microglia, establishing a barrier between the damaged and surviving tissue. At the same time, astrocytes are involved in the pathology of stroke by production of neurotoxic substances, release of reactive oxygen species and by being a part of the brain edema mechanism (Liu and Chopp, 2015; Zhao and Rempe, 2010). After the stroke, scar formation and expression of proteoglycans might impede neurite outgrowth and inhibit structural and functional recovery (Cregg et al, 2014; Silver and Miller, 2004).…”

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…These can directly stimulate aspects of neural repair [27], and also induce an activated state in brain endothelial cells and astrocytes. Activated astrocytes and endothelial cells then further produce molecules that induce or alter the brain's reparative response [19,28]. Several cytokines from these cells influence a stem cell response to stroke.…”

P2Y1R-Initiated, IP3R-Dependent Stimulation of Astrocyte Mitochondrial Metabolism Reduces and Partially Reverses Ischemic Neuronal Damage in Mouse

“…Recent evidence points to astrocytes as an alternative candidate for the development of novel stroke therapies. 1 Astrocytes are the most abundant cell type in the human brain and they are more resistant to ischemia than neighboring neurons. They naturally support neuronal survival and modulate neuronal recovery by providing metabolic and trophic support, glutamate and K þ clearance, as well as antioxidant protection during ischemia.…”