TISSUE-CULTURE MODEL OF KRABBES-DISEASE - PSYCHOSINE CYTOTOXICITY IN RAT OLIGODENDROCYTE CULTURE

Krabbe's disease (globoid cell leukodystrophy) is a progressive cerebr al degenerative disease of infancy characterized by severe myelin loss and the presence of globoid bodies in the white matter. Previous stud ies have suggested that psychosine is the causative agent for the path ogenesis of Krabbe's disease. In the present study, we investigated ps ychosine-induced injury and cell death of oligodendrocytes in enriched cultures of oligodendrocytes prepared from 3-week-old rat brain. The psychosine concentration sufficient to induce 50% cell death in oligod endrocytes was 30 mu g/ml in the medium containing serum and 10 mu g/m l in the serum-free medium. When oligodendrocytes were exposed to psyc hosine in the presence of phorbol esters? insulin, insulin-like growth factor I (IGF-I), demethylsulfoxide, or serum albumin, the survival o f oligodendrocytes was greatly increased. These results indicate that psychosine cytotoxicity against oligodendrocytes is blocked by phorbol esters, insulin, and IGF-I through activation of protein kinase-C, by dimethylsulfoxide through activation of P-galactosidase, and by album in through its binding to psychosine.