CERAMIDE-MEDIATED AND ISOQUINOLINESULFONAMIDE-SENSITIVE PATHWAYS OF NEURONAL DEATH - ANYTHING IN COMMON

In neurons, apoptosis can be triggered by a variety of exogenous stimu li. In spite of a significant diversity in the nature of apoptotic sig nals, it is possible to identify points of convergence common to neuro nal apoptotic processes irrespective of the nature of the signal that has initiated apoptosis. These points of convergence can be defined as a common mechanism that is activated prior to neuronal death and, if inhibited, it can prevent apoptosis. The stress-activated protein kina ses (SAPK) are activated in response to a variety of cellular stresses that lead io apoptosis. The SAPK-mediated apoptosis is also a ceramid e-dependent processes. Recently, we reported that stress-induced neuro nal apoptosis is prevented by the isoquinolinesulfonamides (IQS) H7, H 8, and H9, which are known protein kinase inhibitors. We hypothesized that IQS will prevent ceramide-induced neuronal death. We observed in primary cultures of rat cerebellar granule neurons that C-2-ceramide i nduced morphological signs of apoptosis (assayed by propidium iodide s taining) and cell death. We treated cultures with C-2-ceramide in the presence or absence of IQS and assessed cell death. The IQS provided n europrotection, suggesting that ceramide-activated SAPK might play a r ole in IQS-sensitive neuronal death. Similarities between the ceramide -dependent and IQS-sensitive pathways indicate that they may utilize a common principle. (C) 1997 Elsevier Science Ltd.