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2-AG was administered to mice subjected to closed head injury and significant
reduction of brain edema and infart volume, better clinical recovery and
reduced hippocampal cell death were documented [15]. Interestingly, the
effects of 2-AG as a neuroprotective agent were enhanced by several 2-acylglycerols,
which are present in the brain but that do not bind cannabinoid
receptors. It was assumed that this effect, called the entourage effect, might be
produced by partially blocking the mechanisms involved in 2-AG inactivation
(uptake and hydrolysis) [25, 112].
Except in a few cases [30, 111], most of the neuroprotectant effects of several
cannabinoid agonists were attenuated by SR-141716, thus supporting a
mediation of CB 1 receptors, which can be also concluded from the studies of
Parmentier-Batteur et al. [113]. These authors reported a greater brain injury
(increased infart size and neurological deficits) in CB 1 receptor-deficient mice
subjected to transient focal cerebral ischemia [113]. Similar results were
recently reported by Marsicano et al. [13] in the same knockout mouse model
but subjected to kainate injections. Conversely, in an in vivo neonatal model of
NMDA-induced excitotoxicity, CB 1 receptor blockade reduced infart size and
number of degenerating cortical neurons [33]. By contrast, other authors used
a different in vivo neonatal model that, by blocking the Na + /K + -ATPase with
ouabain, replicates the changes produced in ionic homeostasis during energy
deprivation and/or mitochondrial dysfunction characteristic of acute (and also
chronic) neurodegenerative diseases. They found a reduction of neuronal
injury in neonatal rats by ∆ 9 -THC [50] or AEA [10], an effect that was prevented
by SR-141716, mainly in the case of ∆ 9 -THC [50], thus indicating CB 1
receptor mediation. Lastly, it is important to note that, in all these examples,
the neuroprotective capability of cannabinoid agonists is likely the consequence
of their capability to reduce excitotoxicity, oxidative stress and/or
inflammation, which are key events involved, to different extents, in the neurodegeneration
occurring in these acute pathologies.
Despite the neuroprotectant properties that cannabinoids display in acute
degeneration, the clinical development with cannabinoid-based compounds is
still poor and only dexanabinol (HU-211) is presently being tested in a phase
III clinical trial to reduce brain damage caused by head trauma or cerebrovascular
injuries [34, 114] (see also www.pharmoscorp.com/product/dexanabinol.htm).
This clinical trial has already demonstrated that HU-211 significantly
improves the neurological outcome of head injured patients.
Cannabinoids in chronic neurodegeneration
Cannabinoids, based again on their anti-glutamatergic, antioxidant and/or
anti-inflammatory properties, might be useful to delay/arrest the progression of
neuronal degeneration also in chronic diseases, where processes such as excitotoxicity,
mitocondrial dysfunction, energy failure, oxidative stress and
inflammation are cooperative events in the pathogenesis (see [115–123] for