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exerted preferentially through the activation of CB 1 receptors that, in this case,
would be postsynaptically located (on neurons containing NMDA glutamate
receptors) in contrast with those involved in the inhibition of glutamate release
which would be presynaptically located (see Fig. 1). Several types of calcium
channel (mainly N-, L- and P/Q-types) have been reported to be coupled to
CB 1 receptors and are inhibited by the activation of these receptors [43–46].
In addition, AEA has been also reported to directly interact with T-type Ca 2+
channels [47]. Cannabinoid agonists also affect K + currents by opening
inwardly rectifying K + channels [44, 48, 49], an effect that might be also part
of the neuroprotective action of cannabinoids.
This direct Ca 2+ -lowering effect of cannabinoid agonists would add to the
reduction of this ion produced indirectly as a consequence of the anti-glutamatergic
effects of cannabinoids, which, through reducing glutamate release or
blocking NMDA receptors (see above), would result in a reduction of glutamatergic
receptor-mediated Ca 2+ entry into the cells. As a consequence of this
direct and/or indirect inhibition of Ca 2+ influx produced by cannabinoid agonists,
they would reduce the activation of Ca 2+ -dependent cytotoxic cascades
thus preventing neuronal damage [4–6]. In support of this hypothesis, several
studies have demonstrated that the increase of Ca 2+ influx produced by different
neurotoxic stimuli, including NMDA and other excitotoxins, was reduced
by different plant-derived, synthetic or endogenous cannabinoids [13, 28, 38,
50, 51], and that most of these effects were counteracted by SR-141716, thus
suggesting involvement of CB 1 receptor activation [28, 38].
Antioxidant properties of cannabinoids
Brain injury in acute and chronic neurodegeneration triggers the accumulation
of harmful products, such as reactive oxygen intermediates (see [52] for
review), which, if not eliminated, damage DNA, proteins or membrane lipids,
leading oxidative cell death. These oxidative species are produced, in response
to excitotoxicity and/or mitochondrial dysfunction, from several sources,
including arachidonic acid metabolism, mitochondrial defects, and the action
of NO synthase and other enzymes (see [52, 53] for review). This process,
so-called oxidative stress, appears when the normal balance between oxidative
events and endogenous antioxidant mechanisms (i.e. antioxidative enzymes
such as superoxide dismutase, catalase and peroxidase, glutation and
small-molecule antioxidants such as vitamins A, C and E and ubiquinol) is disrupted,
being responsible for secondary damage in conditions of acute neurodegeneration
[54]. Certain classic cannabinoids, such as CBD, ∆ 9 -tetrahydrocannabinol
(∆ 9 -THC), cannabinol, nabilone, levonantradol, dexanabinol
and others, that contain phenolic groups in their chemical structure, are able to
reduce oxidative stress [55]. These cannabinoids are potent antioxidant compounds
against reactive oxygen species formed during the ischemic metabolism
or in several chronic brain injuries where oxidative stress represents a crit-