Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids

Abstract

Cannabinoids induce apoptosis on glioma cells via stimulation of ceramide synthesis de novo, whereas they do not affect viability of primary astrocytes. In the present study, we show that incubation with Delta9-tetrahydrocannabinol did not induce accumulation of ceramide on astrocytes, although incubation of these cells in a serum-free medium (with or without cannabinoids) led to stimulation of ceramide synthesis de novo and sensitization to oxidative stress. Thus treatment with H2O2 induced apoptosis of 5-day-serum-deprived astrocytes and this effect was abrogated by pharmacological blockade of ceramide synthesis de novo. The sensitizing effect of ceramide accumulation may depend on p38 mitogen-activated protein kinase activation rather than on other ceramide targets. Finally, a protective role of cannabinoids on astrocytes is shown as a long-term incubation with cannabinoids prevented H2O2-induced loss of viability in a CB1 receptor-dependent manner. In summary, our results show that whereas challenge of glioma cells with cannabinoids induces accumulation of de novo -synthesized ceramide and apoptosis, long-term treatment of astrocytes with these compounds does not stimulate this pathway and also abrogates the sensitizing effects of ceramide accumulation.

The cannabinoid δ9‐tetrahydrocannabinol inhibits RAS‐MAPK and PI3K‐AKT survival signalling and induces BAD‐mediated apoptosis in colorectal cancer cells

“…53 Previously, cannabinoids have been reported to cause heterogeneous changes to the growth and survival of tumour cells. These changes include alterations to the cell cycle, resulting in growth arrest, 54,55 the induction of apoptosis, 16,56 nonapoptotic cell death, 19 necrosis, 57 and in some instances the promotion of cell proliferation. 53 Interestingly, we found that relatively low concentrations of THC were required to cause a considerable reduction in colorectal cancer cell survival (i.e., 7.5-12.5 lM), which is comparable with the concentrations of THC required to elicit antitumoral responses in other epithelial cells, such as breast cancer cell lines.…”

The endocannabinoid system in normal and pathological brain ageing

“…The protective effect of cannabinoids against oxidative stress in vitro in neurons is dependent on their anti-oxidant properties as cannabinoid receptors are not involved in this process [157,158]. However, in astrocytes, the CB1 receptor mediates the protective effect of cannabinoids, because cannabinoids prevented H 2 O 2 -induced loss of viability of astrocytes in cell culture in a CB1-receptor-dependent manner [159]. For the neuroprotective effect of cannabinoids both their anti-oxidant and receptor binding properties contribute, as was shown in a rodent model of Parkinson's disease [160,161].…”

Suppression of sphingomyelin synthase 1 by small interference RNA is associated with enhanced ceramide production and apoptosis after photodamage

“…However, de novo ceramide can be associated with apoptotic sensitization after oxidative stress [11]. The oxidative stress inducer photodynamic therapy uses a photosensitizer, visible light and oxygen to generate reactive oxygen species that can destroy malignant cells by apoptosis [12,13].…”