3. Umbruch 4.4..2005 - Online Pot

92 J. Fernández-Ruiz et al.
rats with striatal atrophy caused by injection of mitochondrial toxins exhibited
profound changes in G-protein activation by CB 1 receptor agonists, several
days before overt striatal degeneration and appearance of severe motor symptoms,
and in the absence of significant modifications of binding sites and
mRNA levels for this receptor [65]. All these observations, collectively, support
the notion that early functional changes in CB 1 receptors might be involved in
the pathogenesis of HD but, more importantly, they might play an instrumental
role in striatal neurodegeneration [65]. In other words, (1) these defects in
CB 1 receptor signaling [65] could render neurons more vulnerable to the
degenerative process associated with HD and (2) the stimulation of these receptors
might reduce/delay the progression of striatal degeneration. This hypothesis
has been also considered by van der Stelt et al. [9], who, considering the
data obtained in HD and also in other pathologies, proposed that the malfunctioning
of the endocannabinoid system (i.e. AEA or 2-AG synthesis is inhibited,
CB 1 receptors are inactive or their expression is lost) might be a signal to
trigger an unbalance in glutamate homeostasis and initiate excitotoxicity.
The neuroprotective potential of cannabinoids in HD would be based on one
or more of the above-described mechanisms by which cannabinoids may
reduce neuronal injury (i.e. acting as chemical antioxidants, inhibiting glutamate
release, reducing Ca 2+ influx and/or producing anti-inflammatory effects;
for review, see [4, 5]). This is possible in HD because it is a neurodegenerative
disorder where mitochondrial dysfunction, excitotoxicity, inflammation and
oxidative stress have been proposed as cooperative events in the pathogenesis
[116]. In a recent study [65] we have found a promising action of the
non-selective plant-derived cannabinoid, ∆ 9 -THC, by protecting striatal neurons
against the in vivo toxicity of 3-nitropropionic acid, a mitochondrial toxin
that replicates the complex II deficiency characteristic of HD patients [146].
Striatal injury in this animal model progresses by mechanisms that mainly
involve non-apoptotic death, since it is caspase 3-independent and produced
via the Ca 2+ -regulated protein calpain and activation of non-NMDA receptors
[147, 148]. However, it remains to be demonstrated whether the neuroprotective
effect of ∆ 9 -THC in this animal model of HD is caused by the activation
of CB 1,CB 2 or the combined action of both receptors, as well as through other
mechanisms available to ∆ 9 -THC. The involvement of CB 2 receptors, but not
CB 1 receptors, has been demonstrated in other rat models of striatal injury generated
by unilateral injections of malonate, another complex II inhibitor.
Malonate produces cell death that progresses mainly through the activation of
apoptotic machinery (it activates NMDA receptors and caspase 3 [149]). Thus,
we found that activation of CB 2 (using HU-308) but not CB 1 (using ACEA)
receptors provided neuroprotection, and that this effect was reversed by
SR-144528, a selective CB 2 receptor antagonist [19]. This indicates a crucial
role for this receptor subtype in neuroprotective effects of cannabinoids in this
model. An important aspect of these observations is that CB 2 receptors are
induced in response to malonate application in glial cells, possibly in reactive
microglia [19]. As this receptor subtype is usually absent in the brain in