3. Umbruch 4.4..2005 - Online Pot

96 J. Fernández-Ruiz et al.
Cannabinoids have been recently proposed as candidates for both symptom
relief and slowing of degeneration (see [171] for review).
The evidence relating cannabinoids to AD is relatively recent and has been
obtained from either biochemical or pharmacological studies. Thus, Westlake
et al. [172] reported a decrease of CB 1 receptor gene expression in AD postmortem
tissues, in particular in the basal ganglia, but which could not be attributable
to the pathologic process. Thus, while CB 1 receptor protein levels
remained unchanged, CB 1 mRNA exhibited a reduction that, as the authors
argued in their study, was probably parallel to the neuronal loss that accompanies
the progression of the disease. Studies conducted in aged rats have provided
similar findings [173]. More recently, Benito et al. [18] reported that
CB 1 receptor levels were unaltered in brain regions affected by Aβ deposits. In
this immunohistochemical study, a slight decrease in the staining intensity of
the samples was observed, but CB 1 receptor protein distribution was basically
the same as in control cases.
In contrast with the lack of changes in CB 1 receptors, the analysis in postmortem
tissues from AD patients revealed that CB 2 receptors are selectively
overexpressed in the microglial cells that are associated with Aβ-enriched neuritic
plaques [18]. This selectivity is especially striking, as parenquimal (silent)
microglia seem not to express CB 2 receptors. Recent data [90] indicate that
CB 2 receptors may be also expressed by a limited population of microglial cells
in the healthy brain, i.e. perivascular microglial cells, which play a pivotal role
in infectious processes affecting the CNS [174]. It may be hypothesized that
the induction of CB 2 receptors in microglial cells surrounding neuritic plaques
in AD may be part of an anti-inflammatory response of the CNS in order to
protect neurons from degeneration. In addition, FAAH expression and enzymatic
activity are increased in neuritic plaques from AD tissue samples; in particular,
FAAH seems to be abundantly expressed by plaque-associated astroglia
[18]. These results suggest that FAAH may participate in the important role
that astrocytes play in the gliotic response to Aβ deposition [118].
Despite the observation of changes in specific elements of the endocannabinoid
system, in particular CB 2 receptors, during the pathogenesis in
AD, only few preclinical or clinical data exist regarding the potential therapeutic
usefulness of cannabinoids in this disease. A part of these studies deals
with the treatment of specific symptoms, as revealed by the clinical study of
Volicer et al. [126], who demonstrated a beneficial effect of dronabinol
(∆ 9 -THC in oil solution for oral administration) by stimulating appetite and
improving disturbed behavior in AD patients. In addition, the abundance of
CB 1 receptors in the hippocampus and the parahippocampal and enthorinal
cortices, as well as their involvement in the control of cholinergic activity, suggests
an additional usefulness of cannabinoid-based compounds in memory
deficits typical of these patients. In this sense, cannabinoid receptor agonists
impair memory processing and cognition [175], whereas CB 1 receptor blockade
with SR-141716 improves memory deficits in mice administered with Aβ,
presumably by an increase in hippocampal acetylcholine levels [133].