Inhibition of complement as a therapeutic approach in inflammatory central nervous system (CNS) disease.

In recent years it has become clear that inflammation and tissue destruction in central nervous system (CNS) disease is due, at least in part, to the activation of complement. Although often implicated in contributing to the pathology of diseases such as multiple sclerosis (MS), Alzhei-mer's disease, and many others, how central the role of complement is to the pathology of these diseases remains controversial. Interestingly, studies in the last few years have demonstrated endogenous synthesis of complement system proteins by most CNS cell types (including complement anaphylatoxin receptors that mediate most of the inflammatory effects of the complement system) (1-4). This information, combined with a number of animal model studies in which inhibition of complement activation leads to a favorable disease outcome (both in and out of the CNS), now make it evident that the development of complement therapeutics for CNS disease merits more attention than received in recent years. As will be discussed below, the difficulty of targeting the complement system for therapeutic intervention lies with the large number of proteins , several pathways, and numerous receptors that mediate complement host defense functions (see Fig. 1). Targeting the appropriate complement protein or proteins is further complicated by the fact that the details of the roles each activation peptide and receptor plays in CNS disease are largely unknown. However, insight Address correspondence and reprint requests to: of Alabama at from the success of complement inhibition studies outside the CNS, as well as a few studies in CNS disease models, will prove useful as rational starting points in designing new therapeutic agents and applying those therapeutics currently in use (5,6). This review will focus on how complement contributes to inflammation in the brain, where intervention in the complement system may prove useful, and the currently available repertoire of inhibitors that hold therapeutic potential. The reader is also referred to several excellent recent reviews on therapeutic inhibition of complement outside the CNS (5-10). Potential Although still largely untested, complement therapeutics in CNS disease could have a major impact on the health and quality of life for individuals with a number of different diseases. For example, complement activation has been strongly implicated in the inflammation associated with Alzheimer's disease (reviewed in refs. 1,1 1). It is estimated that over 4 million persons in North America alone are affected by Alzhei-mer's disease (Table 1) (12). Worldwide this number may be as large as 20 …