Astrocytes: Targets for Neuroprotection in Stroke

Abstract

In the past two decades, over 1000 clinical trials have failed to demonstrate a benefit in treating stroke, with the exception of thrombolytics. Although many targets have been pursued, including antioxidants, calcium channel blockers, glutamate receptor blockers, and neurotrophic factors, often the focus has been on neuronal mechanisms of injury. Broader attention to loss and dysfunction of non-neuronal cell types is now required to increase the chance of success. Of the several glial cell types, this review will focus on astrocytes. Astrocytes are the most abundant cell type in the higher mammalian nervous system, and they play key roles in normal CNS physiology and in central nervous system injury and pathology. In the setting of ischemia astrocytes perform multiple functions, some beneficial and some potentially detrimental, making them excellent candidates as therapeutic targets to improve outcome following stroke and in other central nervous system injuries. The older neurocentric view of the central nervous system has changed radically with the growing understanding of the many essential functions of astrocytes. These include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and modulation of neuronal excitability. In this review, we will focus on those functions of astrocytes that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcome following cerebral ischemia.

HAMI 3379, a CysLT2 Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation

“…In neuron-astrocyte cocultures, OGD/R induced relatively severe neuronal necrosis, which might result from both direct ischemic injury and astrocyte-mediated injury. In general, astrocytes play protective roles in the ischemic injury of the neurons by releasing protective molecules like neurotrophic factors and removing toxic substances (Takano et al, 2009;Barreto et al, 2011a). On the other hand, proliferating or activated astrocytes may also be associated with neuronal injury (Katayama et al, 2010;Sullivan et al, 2010;Qu et al, 2011), which may explain our OGD/R results.…”

Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model

“…Astrocyte activation plays a crucial role in maintaining the stability of the internal environment and the survival of neurons in ischemic brain injury [22]. GFAP, the major intermediate filament of astrocytes, is thought to mainly participate in the regulation of neuron construction, amino acid transport and myelinogenesis [23,24].…”

Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo

“…Neurons may undergo damage that is more severe when astrocytes are injured by ischemia [18,19] . TLR3 is expressed throughout the CNS and is most prominent in astrocytes [8] .…”