Effects on Cell Viability 6353.3.1
Mechanism of Action
—It has been shown that cannabinoids activate two pivotal survival pathways in
glial cells: the PI-3-K/Akt pathway (Gómez del Pulgar et al. 2002a; Molina-Holgado
et al. 2002) and the ERK pathway (Sánchez et al. 1998b; Gómez del Pulgar 2002a)
(Table 1). Both signalling pathways appear to act in concert upon CB 1 receptor acti-
vationandGiproteindissociation,asPI-3-Kactivationisrequiredforcannabinoid-
induced ERK activation, which occurs in a Ras-independent and tyrosine kinase
receptor-independent manner (Galve-Roperh et al. 2002). Additionally, adenylyl
cyclase inhibition via the CB 1 receptor might supress cAMP-dependent Raf-1 in-
hibition and cooperate in neural cell ERK activation (Derkinderen et al. 2003).
Altogether, these observations show that, most likely, cannabinoids regulate cell
survival and cell death pathways differently in transformed and non-transformed
neural cells (Fig. 1).
Fig.1.Dual effect of cannabinoids on the viability of transformed versus non-transformed glial cells. In glioma
cells, cannabinoids activate CB 1 and CB 2 receptors, inducing sustained ceramide accumulation and inhibition
of the pro-survival kinase Akt, leading in turn to apoptosis. In normal astrocytes, cannabinoids activate CB 1
receptors, preventing ceramide-induced Akt inhibition and leading in turn to cell survival
4
Immune Cells
4.1
Cell Death/Survival Effect
Many in vitro and in vivo studies have shown that cannabinoids are immunosup-
pressive agents (Roth et al. 2002; Klein et al. 2003). In this context, cannabinoids
induce apoptosis of human peripheral blood mononuclear cells (Schwarz et al.
1994) as well as of mouse macrophages and lymphocytes (Zhu et al. 1998). THC
also inhibits the proliferation and induces apoptosis of mouse thymocytes and
splenocytes in culture and in mice (McKallip et al. 2002b). Moreover, various