Reactive astrocytes as therapeutic targets for CNS disorders

Reactive astrogliosis has long been recognized as a ubiquitous feature of CNS pathologies. Although its roles in CNS pathology are only beginning to be defined, genetic tools are enabling molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. It is now clear that reactive astrogliosis is not simply an all-or-nothing phenomenon but, rather, is a finely gradated continuum of molecular, cellular, and functional changes that range from subtle alterations in gene expression to scar formation. These changes can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Dysfunction of either astrocytes or the process of reactive astrogliosis is emerging as an important potential source of mechanisms that might contribute to, or play primary roles in, a host of CNS disorders via loss of normal or gain of abnormal astrocyte activities. A rapidly growing understanding of the mechanisms underlying astrocyte signaling and reactive astrogliosis has the potential to open doors to identifying many molecules that might serve as novel therapeutic targets for a wide range of neurological disorders. This review considers general principles and examines selected examples regarding the potential of targeting specific molecular aspects of reactive astrogliosis for therapeutic manipulations, including regulation of glutamate, reactive oxygen species, and cytokines.