3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 95
However, we have also found evidence that glial-mediated effects are also
involved in the neuroprotection provided by cannabinoids in PD. In this sense,
although the cause of dopaminergic cell death in PD is still unknown, it has
been postulated that alterations in glial cell function (i.e. microglial activation)
may also play an important role in the initiation and/or early progression of the
neurodegenerative process [165], especially in a region like the substantia
nigra which is particularly enriched in microglia and other glial cells [166]. In
fact, several glial-derived cytotoxic factors, such as TNF-α, IL-1β, NO and
others, have been reported to be elevated in the substantia nigra and the caudate
putamen of PD patients [167]. Based on this previous evidence, we
recently performed an in vitro study to evaluate the effects of cannabinoid agonists
on the neuronal toxicity of 6-hydroxydopamine. We found a marked
increase in neuronal survival when cells were incubated with conditioned
media generated by exposing glial cells to the non-selective cannabinoid
HU-210, compared with the poor increase in neuronal survival produced by
direct exposure of neuronal cells to HU-210 [64]. This supports the hypothesis
that neuroprotection by cannabinoids in PD might be significantly dependent,
not only on the antioxidant potential of certain cannabinoids, but also on
the anti-inflammatory and glial cell-mediated effects reported for most of
cannabinoids [24, 68]. Because of the role suggested for CB 2 receptors in
glial-mediated effects of cannabinoids [68], it is possible that this receptor subtype
may be involved in part of the effects observed in PD, as found in HD
[19], although this question must be explored in further studies.
AD
AD is the leading cause of dementia in the elderly, affecting to more than 4
million people in the United States alone. The pathological hallmarks of AD
are currently well known and include neuritic plaques (enriched in β-amyloid
peptide, Aβ) and fibrillary tangles (enriched in hyperphosphorylated tau protein),
neuronal loss, synaptic dysfunction and gliosis (see [94, 118, 168] for
review). The cellular and molecular events involved in the pathogenesis of AD
have been partially unveiled. Briefly, it is currently thought that aberrant processing
of the β-amyloid precursor protein leads to the formation of Aβ
deposits which, in conjuction with other factors, stresses nearby neurons,
resulting in tau hyperphosphorylation and inducing the formation of neurofibrillary
tangles [168]. Additionally, this process initiates an inflammatory
response in which astrocytes and microglia play a critical role [118], as
described for other neurodegenerative diseases (see above). The current therapies
for AD are (1) acetylcholinesterase inhibitors that serve to improve memory
deficits caused by depleted levels of acetylcholine resulting from neuronal
loss [169] and (2) NMDA receptor blockers, such as the uncompetitive antagonist
memantine that has provided efficacy against β-amyloid-induced neurodegeneration
in rats and shown great promise in clinical trials [170].