634 M. Guzmán
3.2
Neurotoxic Effect
In contrast to the aforementioned cannabinoid neuroprotection, some studies
have reported a neurotoxic effect of THC. Thus, morphological changes in the
hippocampus,decreasesinthemeanvolume,synapticdensityanddendriticlength
of CA3 pyramidal neurons, and reduced neuronal density in rat hippocampus
associated with chronic THC oral administration have been described (Scallet et
al.1987).However,otherscouldnotfindanysignificanthistopathologicalalteration
in the brains of rats and mice treated orally with very high doses of THC for 2 years
(Chan et al. 1996). Likewise, direct intracranial administration of THC or WIN
55,212-2 to rats for 1 week did not induce neural cell apoptosis (Galve-Roperh et
al. 2000).
In vitro studies have also shown that THC induces apoptosis of primary hip-
pocampal (Chan et al. 1998) and cortical (Downer et al. 2003) neurons. In contrast,
in another report the viability of cortical neurons in culture did not decrease after
prolonged exposure to THC (Sánchez et al. 1998a).
3.2.1
Mechanism of Action
CB 1 -dependent apoptosis of primary neurons may involve phospholipase A 2 -
induced release of arachidonic acid, which promotes the activation of cyclooxy-
genases and lipoxygenases (Chan et al. 2003). This may generate free radicals and
lead to lipid peroxidation and cell death. Activation of the JNK cascade may also
contribute to this neurotoxic process (Downer et al. 2003) (Table 1).
3.3
Glioprotective Effect
Cannabinoids protect glial cells from death. Thus, cannabinoids prevent astrocyte
apoptosis as induced by ceramide both in vivo and in vitro (Gómez del Pulgar et
al. 2002a). Moreover, cannabinoids protect oligodendrocytes from growth factor
deprivation-induced cell death (Molina-Holgado et al. 2002), and furthermore
they prevent demyelination in vivo in a virus-induced model of multiple sclerosis
(Arévalo-Martín et al. 2003). The finding that cannabinoid-induced prevention of
neural cell death is not restricted to neurons may be relevant, as protection of
more than one type of cell within the brain could result in a synergistic action by
increasing the efficiency of the injured-brain response.