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.

Fig. (1)

Expression of different astrocytic proteins following stroke. Increased expression of GFAP is a hallmark of astrocytes activation, as is induction/re-expression of vimentin. Astrocytes normally express glutamine synthetase (GS) and S100β, genes that are widely expressed in both reactive and non-reactive astrocytes. The GFAP and S100β labelling are for the same cell, while the Vim and GS staining labels are for of other cells. Scale bar, 50µm.

Fig. (2)

Mechanisms of astrocyte support of neurons important in stroke. Antioxidant defense includes release of glutathione and ascorbate. Regulation of extracellular levels of ions and neuro-transmitters, especially K⁺ and glutamate, strongly influences neuronal excitability. Elevated extracellular K⁺ triggers astrocyte glycolysis and enhances lactate and pyruvate release which support neuronal metabolism. Sodium dependent glutamate uptake by astrocytes activates the Na⁺/K⁺ ATPase, stimulating glycolytic activity and production of lactate. Astrocytes and neurons are also coupled by the glutamate-glutamine cycle. Astrocytes take up glutamate, convert it to glutamine, and release glutamine to the extracellular space where it is taken up by neurons and used to synthesize glutamate to replenish the neurotransmitter pool.

Fig. (3)

Targeted over-expression of Hsp72 in astrocytes reduces the vulnerability of CA1 neurons to forebrain ischemia. Selective overexpression of Hsp72 in astrocytes by expressing it from the astrocyte specific GFAP promoter was achieved by unilateral stereotaxic injection of the expression plasmid just above the CA1 region of the hippocampus (black arrows for microinjection tracks) 2 days before rats were subjected to 15 min forebrain ischemia. Selective loss of CA1 hippocampal neurons (between white arrows in middle panel) was observed at 7 days reperfusion by cresyl violet staining. The loss of CA1 hippocampal neurons was significantly reduced with astrocytic Hsp72 overex-pression (right panel) compared to the neuronal loss seen with injection of control DNA (middle panel). Modified from [16].