Mechanisms of Glial Death and Protection

Introduction

Cerebrovascular diseases cause tissue damage to both gray and white matter, which contribute about half of the CNS volume and differ in structure and cellular composition. White matter exclusively contains axons and their glial cell partners including fibrous astrocytes, oligodendrocytes (myelinating and nonmyelinating), and microglia. Gray matter harbors neurons and is rich in protoplasmic astrocytes, which shape synaptic transmission as they partner with nerve endings and postsynaptic elements to form the tripartite synapse.

Pharmacological developments of potential treatments for stroke have failed in clinical trials because they typically aimed at protecting neurons from postischemic damage and neglected glial cells, especially oligodendrocytes, which are highly vulnerable to shortage of oxygen and nutrients. Oligodendrocytes are most abundant in white matter whose damage is a major cause of functional disability in cerebrovascular disease and the majority of ischemic strokes.

Early animal studies indicated that oligodendrocytes can be damaged by even brief focal ischemia , preceding by several hours the appearance of necrotic neurons in ischemic regions. In addition, pathological changes after ischemic insults include segmental swelling of myelinated axons and the formation of spaces or vacuoles between the myelin sheath and axolemma . These observations confirm that oligodendrocytes and myelin are vulnerable to ischemia and that their damage proceeds independently from neuronal injury.

Stroke, therefore, produces disability not only as a result of dysfunction of neurons and synapses, but also by primary or secondary damage to oligodendrocytes and other glial cells. This chapter summarizes current knowledge of the molecular mechanisms of ischemic injury to glia and discusses its translational implications for the treatment of stroke ( Table 44.1 ).

Glia Metabolism

Glucose is the primary energy source in the adult brain. Glucose transporter proteins on endothelial cells, glial cells, neurons, and axons are necessary for glucose uptake from the circulation and into cells. Astrocytes take up glucose in their end feet surrounding the capillaries and store glucose residues as glycogen. In addition to glucose, lactate can also support brain energy metabolism and function. Thus astrocyte glycogen is quickly mobilized to produce lactate that can be delivered to neurons and axons ensuring function during high activity or when glucose supply is limited. Lactate is impermeable and is transported across cell membranes by monocarboxylate transporters present in neurons and glia. Lactate enters neurons and sustains their function by producing ATP via oxidative phosphorylation. Lactate is also taken up by oligodendrocytes and their myelin sheath via MCT1 transporters, and utilized for lipid metabolism and myelin synthesis. In vitro evidence suggests that oligodendrocytes consume lactate at a higher rate than neurons or astrocytes, apparently to support the high lipid demand associated with myelin manufacture, and myelination is rescued during hypoglycemia when exogenous lactate is supplied.

During partial ischemia, when glucose would still be present, although reduced, increased glycolysis in astrocytes, and possibly in oligodendrocytes, can contribute usable energy substrate to neurons and axons, although the mechanism(s) that signals axon metabolic need and mediates glial substrate production is still unknown. An attractive possibility is that neurotransmitters (i.e., glutamate and ATP) released from discharging axons signal surrounding astrocytes, and possibly oligodendrocytes, to release fuel in the form of lactate, delivered via cytoplasmic compartments within the myelin sheath , which can be quickly used by the axons.