Functional alterations of astroglia on brain pathologies and their intracellular mechanisms

Abstract

A phenotypic alteration of astroglia, "astroglial activation", is a common phenomenon observed on brain pathologies. The hypertrophy/hyperplasia of activated astroglia causes a glial scar, which prevents synaptic re-generation. In contrast, many neurotrophic substances are produced by the activated astroglia. Thus, the functional alteration of astroglia is important in tissue repair processes of the damaged CNS. Endothelins (ETs) are involved in the pathophysiological responses of the CNS. We found that injection of ETs into rat brain induced activated astroglia. A selective ETB-receptor antagonist attenuated the induction of activated astroglia. In cultured astroglia, ETs reproduce the functional alterations characterizing activated astroglia; i.e., increases in proliferation, morphological changes and stimulation of several gene transcriptions. ETs re-organized astroglial cytoskeletal actin through a small GTP-binding protein, rho, which may underlie the astroglial hypertrophy. Analysis of gene expression showed that transcriptions of neurotrophic factors (GDNF and BDNF) were stimulated by ETs. ETs stimulated astroglial proliferation by both adhesion-dependent and -independent mechanisms, where FAK and ERK plays key roles, respectively. These findings suggest important roles of ETs in the regulation of astroglial functions.