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anti-glutamatergic substances since they are able to reduce excitotoxicity
[4–6, 9, 27]. This has been demonstrated both in vitro (i.e. using cultures of
hippocampal neurons [28] or spinal cord neurons [29]) and in vivo (i.e. rodent
models of ischemic damage [30]).
These anti-glutamatergic effects of cannabinoid agonists are mainly exerted
by inhibiting glutamate release, a fact that has been largely demonstrated using
cultured neurons from numerous brain regions (see [4, 9] for recent reviews)
and also in vivo, through the activation of CB 1 receptors located presynaptically
in glutamatergic terminals (see Fig. 1, and [31] for review). This inhibitory
effect of cannabinoid agonists on glutamate release is reversed by selective
CB 1 receptor antagonists, such as SR-141716 [4, 9]. In addition, the antagonist
by itself potentiated excitotoxicity in kainate-injected mice [13] and increased
lesion volume in a rat model of HD generated by local injections of the complex
II inhibitor malonate [32]. However, other authors, using neonatal models
of excitotoxicity, reported no effects of SR-141716 by itself [10] or a neuroprotective
effect that was counteracted by co-administration of cannabinoid
agonists [33].
On the other hand, some specific cannabinoids, such as dexanabinol
(HU-211) and AEA, are also able to directly act on NMDA glutamatergic
receptors (see [4–6] for review). The case of HU-211 represents, together with
cannabidiol (CBD) whose neuroprotective effects will be discussed below, an
Figure 1. Cellular and molecular mechanisms involved in neuroprotective actions of cannabinoids.