3. Umbruch 4.4..2005 - Online Pot

80 J. Fernández-Ruiz et al.
other authors did not find this response [10]. For instance, Hansen and coworkers
described an increase in the levels of anandamide (N-arachidonoylethanolamine,
AEA) and its phospholipid precursor, but not of 2-arachidonoyl
glycerol (2-AG), during acute degeneration in the neonatal rat brain [11,
12]. Similar results, increases in AEA with no changes in 2-AG, were found by
Marsicano et al. [13] in a mouse model of kainate-induced excitotoxicity, and
by Gubellini et al. [14] in a rat model of PD. However, Panikashvili et al. [15]
showed that 2-AG is massively produced in the mouse brain after closed head
injury. In addition, they found that this endocannabinoid has neuroprotective
effects, as indicated by a reduction in edema and infarct volume and by
improved clinical recovery after being administered to animals. This endogenous
response has been also found in humans since elevated levels of AEA and
other fatty acid amides have been also measured around the site of damage in a
microdialysis study perfomed on a single stroke patient [16].
That the increases reported in endocannabinoid production during neurodegeneration
[11–16] are part of an endogenous response may be also concluded
from the observation that blockade of the endocannabinoid uptake with
UCM707 increased protection against kainate-induced seizures in mice,
where AEA levels were reported to be elevated [13]. However, this point is
also controversial since, although van der Stelt et al. [10] found protection
after exogenous administration of AEA in a neonatal model of secondary excitotoxicity,
they did not record any increases in AEA or 2-AG levels and, concomitantly,
they did not find any effect of another uptake inhibitor, VDM11,
on lesion volume [10].
Cannabinoid receptor subtypes are also induced in nerve cells in response
to injury and/or inflammation [12, 17–19]. Thus, Jin et al. [17] reported that
CB 1 receptors are induced in neuronal cells after experimental stroke, whereas
we described an increase of these receptors in response to excitotoxic stimuli
in neonatal rats [12]. As regards CB 2 receptors, a receptor subtype that is mostly
absent from the brain in healthy conditions (see below), recent reports have
shown induction of this receptor subtype in several pathologies [18, 19]. This
occurs in activated glial cells, mainly microglia surrounding senile plaques, in
human AD brain samples [18], which might indicate that CB 2 receptors play a
role in either reducing degenerative impact on neurons or, on the contrary, promoting
cytotoxic events. Induction of CB 2 receptors at lesioned sites has been
also documented in rat models of striatal degeneration replicating human HD
pathology [19].
In contrast with the protective properties of cannabinoids in non-transformed
nervous cells, these compounds are also able to elicit apoptosis in
transformed nerve cells (C6 glioma, human astrocytoma U373MG and mouse
neuroblastoma N18TG12 cells) in vitro [1, 20], and to promote the regression
of glioblastoma in vivo, through a mechanism that involves the activation of
mitogen-activated protein kinase and ceramide accumulation [21]. In addition,
cannabinoids have been recently reported to inhibit angiogenesis, which represents
a key process in tumorigenesis [22]. These anti-proliferative effects of