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the progression of this lethal disease whose duration averages approximately
2–3 years after diagnosis [122, 123]. Recent evidence has provided support to
the possibility that cannabinoids may also function in ALS as neuroprotectant
agents. This evidence has been obtained by Raman and coworkers [192] in a
mouse genetic model of ALS (HSOD G93A transgenic mice) that overexpresses
a mutated form of the enzyme copper/zinc superoxide dismutase 1 (SOD-1),
which is linked to approximately 20% of familial cases of ALS [193, 194].
This enzyme plays a critical role as the endogenous scavenger of the superoxide
anion, thus reducing the occurrence of oxidative stress. The mutation of
SOD-1 increases the formation of superoxide anions and the oxidative tissue
damage, and this is the key process that elicits all symptomatology characteristic
of this ALS genetic mouse model. Raman and coworkers found that
∆ 9 -THC was effective in delaying motor impairment and prolonging survival
if administered before or after the onset of signs in the ALS mouse model
[192]. In addition, ∆ 9 -THC was also effective at reducing oxidative damage
and excitotoxicity in spinal cord cultures [192]. No data exist on possible
changes in specific elements of the endocannabinoid system in humans affected
by this disease, but very recently Witting et al. [195] have published the first
paper demonstrating endocannabinoid accumulation in the spinal cord of
HSOD G93A transgenic mice, which was interpreted by these authors as part of
an endogenous defense mechanism against the oxidative damage characteristic
of this disease.
Concluding remarks and future perspectives
Among a variety of pharmacological effects, cannabinoids have been demonstrated
as potentially useful and clinically promising neuroprotective molecules.
In this chapter we have reviewed the cellular and molecular mechanisms
that might be involved in these neuroprotective effects, paying emphasis in
their potential (1) to reduce excitotoxicity exerted by either inhibiting glutamate
release or, in some specific cases, blocking glutamatergic receptors, (2)
to block NMDA receptor-induced calcium influx exerted directly, as a consequence
of the antagonism of these receptors, or indirectly, through the inhibition
of selective channels for this ion, (3) to decrease oxidative injury by acting
as scavengers of reactive oxygen species, a property independent of
cannabinoid receptor and restricted to specific classic cannabinoids, (4) to
reduce inflammation by acting predominantly through the activation of CB 2
receptors on the glial processes that regulate neuronal survival and (5) finally,
to restore blood supply to injured areas by reducing the vasocontriction produced
by several endothelium-derived factors such as ET-1 or NO. Through
one or more of these processes cannabinoids may provide neuroprotection in
conditions of acute or accidental neurodegeneration, such as that occurring in
traumatic injury or ischemic episodes. In fact, dexanabinol is already in a
phase III clinical trial for therapeutic intervention in these pathologies.