3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 83
interesting option because HU-211 has a cannabinoid structure, but does not
bind cannabinoid receptors [4, 34]. Its neuroprotective activity originates from
its capability to directly act on the glutamate system, by blocking the NMDA
receptor at a site close to, but distinct from, that of non-competitive antagonists,
such as MK-801 and phencyclidine, and from the recognition site for
glutamate or glycine [4, 35]. Based on this antagonistic capability, HU-211
directly reduces NMDA receptor-mediated Ca 2+ influx into neurons ([4, 36];
see more details below). However, it also provides neuroprotection because it
is antioxidant [4, 37] and reduces the levels of tumor necrosis factor-α
(TNF-α) [4, 34]. The result of these neuroprotective mechanisms activated by
HU-211 is an improvement of motor and memory functions in association with
reduced edema and blood–brain-barrier breakdown in rats subjected to closed
head injury (see [4, 34] for review). AEA was also shown to directly interact
with NMDA receptors in cortical, cerebellar and hippocampal slices, thereby
producing a potentiation of NMDA-induced calcium responses [38]. However,
this occurs only in the presence of SR-141716 [38]. This effect would be independent
of its neuroprotective effects mediated by the activation of cannabinoid
receptors (i.e. cannabinoid receptor-mediated reduction in Ca 2+ influx,
and anti-inflammatory and vascular effects; see details below).
Finally, it is interesting to also consider the recent evidence suggesting that
one of the mechanisms of neuroprotection elicited by NMDA receptor blockade
would imply the enhancement of GABA transmission [39]. Cannabinoids
are able to increase inhibitory transmission mediated by GABA in some
regions such as the basal ganglia [40, 41]. This would speak in favour of the
critical importance of the imbalance between inhibitory and stimulatory innervations
during processes of transneuronal delayed death. Cannabinoid agonists,
by inhibiting glutamate release [4, 31] and/or increasing GABA presence
at synapses – presumably by blocking GABA reuptake [40, 41] – might rectify
this imbalance, thus delaying/arresting transneuronal death occurring in
specific regions such as the substantia nigra pars reticulata [42].
Reduction of calcium influx by cannabinoids
As mentioned above, excitotoxicity causes hyperactivation of glutamate receptors
that results in intracellular accumulation of cytotoxic levels of Ca 2+ , which
activate numerous destructive pathways involving calpains, caspases and other
proteases, protein kinases, lypases, endonucleases, NO synthase, reactive oxygen
species, etc. (for review, see [26]). In addition, voltage-sensitive ion channels
are activated in response to the depolarization associated with
NMDA-induced Ca 2+ influx, and elevate intracellular levels of this and other
ions. Cannabinoid agonists are able to close these voltage-sensitive ion channels,
then reducing the overall Ca 2+ current and the overactivation of destructive
pathways which decrease the degree of neuronal death providing neuroprotection
(see Fig. 1, and [4–6, 9, 25] for review). These effects would be