632 M. Guzmán
de novo abrogates the antitumoural effect of cannabinoids in vivo as well as the
cannabinoid-induced inhibition of VEGF production by glioma cells in vitro and
by gliomas in vivo (C. Blázquez and M. Guzmán, unpublished results), indicating
that ceramide may play a general role in cannabinoid antitumoural action. In addi-
tion, activation of cannabinoid receptors in vascular endothelial cells inhibits cell
migration and survival, which might contribute as well to the impaired tumour
vascularisation observed in cannabinoid-treated gliomas (Blázquez et al. 2003).
Cannabinoids have been recently shown to reduce the number of metastatic
nodes produced by paw injection of Lewis lung carcinoma cells in rats (Portella et
al. 2003). Moreover, cannabinoid administration to glioma-bearing mice also de-
creases the activity and expression of matrix metalloproteinase-2 (MMP2), a prote-
olytic enzyme that allows tissue breakdown and remodelling during angiogenesis
and metastasis (Blázquez et al. 2003). Hence it is conceivable that cannabinoids
may also control tumour invasiveness.
3
Neural Cells
3.1
Neuroprotective Effect
One of the most exciting aspects of current cannabinoid research is the possibility
that cannabinoids play a role as neuroprotective agents, both pharmacologically
and physiologically via the endocannabinoid system (Mechoulam et al. 2002; van
der Stelt et al. 2002). Thus, most of the experimental evidence indicates that
cannabinoids may protect neurons from insults such as ischaemia, glutamater-
gic excitotoxicity, mechanical trauma and oxidative damage. The neuroprotective
action of cannabinoids has been shown in vivo. The neurotoxicity induced by
global cerebral ischaemia in vivo following cerebral artery occlusion is reduced in
the CA1 region of the hippocampus by WIN 55,212-2 administration via the CB 1
receptor (Nagayama et al. 1999). Cannabinoid treatment also reduces the infarct
volume caused by focal cerebral ischaemia, leading to enhanced neuronal survival
of penumbral cortical tissue (Nagayama et al. 1999). Likewise, THC exerts a CB 1 -
mediated reduction of the infarct volume in an in vivo model of ouabain-induced
excitotoxicity (van der Stelt et al. 2001). Moreover, the harmful consequences of
traumatic brain injury such as edema and neuronal cell death are blunted as a con-
sequence of increased 2-arachidonoylglycerol levels (Panikashvili et al. 2001). The
involvement of the CB 1 receptor in endocannabinoid-mediated neuroprotection is
further supported by results from experiments with knock-out animals, as CB 1 -
defective mice are more susceptible to stroke-induced neuronal death (Parmentier-
Batteur et al. 2002) and kainate-induced excitotoxicity (Marsicano et al. 2003). The
use of CB 1 knock-out mice in which receptor expression is abolished exclusively in
principal forebrain neurons, but not in GABAergic interneurons, indicate a direct
action of the CB 1 receptor within the same neuronal cells susceptible for primary
excitotoxicity damage (Marsicano et al. 2003).