Ceramide-mediated and isoquinolinesulfonamide-sensitive pathways of neuronal death: anything in common?

ABSTRACT

In neurons, apoptosis can be triggered by a variety of exogenous stimuli. In spite of a significant diversity in the nature of apoptotic signals, it is possible to identify points of convergence common to neuronal 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 kinases (SAPK) are activated in response to a variety of cellular stresses that lead to apoptosis. The SAPK-mediated apoptosis is also a ceramide-dependent processes. Recently, we reported that stress-induced neuronal apoptosis is prevented by the isoquinolinesulfonamides (IQS) H7, H8, 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 C2-ceramide induced morphological signs of apoptosis (assayed by propidium iodide staining) and cell death. We treated cultures with C2-ceramide in the presence or absence of IQS and assessed cell death. The IQS provided neuroprotection, suggesting that ceramide-activated SAPK might play a role in IQS-sensitive neuronal death. Similarities between the ceramide-dependent and IQS-sensitive pathways indicate that they may utilize a common principle.