3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 93
healthy conditions, its induction in this model of striatal injury might be interpreted
as part of an endogenous response against the degeneration caused by
the inhibition of the mitochondrial complex II. In addition, CBD was not effective
in this HD model, thus indicating that neuroprotection exerted by cannabinoids
is not due to their antioxidant properties [19].
Another aspect that remains to be elucidated concerns the mechanism(s)
(i.e. reduction of excitotoxicity, antioxidant effects or anti-inflammatory
action) that underlies the neuroprotective properties of cannabinoids in HD. In
this sense, using an in vitro design to test 3-nitropropionic acid toxicity, we
recently found a dose-dependent increase in the survival of cultured cerebellar
granule cells when these cells were incubated in the presence of another
non-selective cannabinoid agonist, HU-210 (I Lastres-Becker, F
Molina-Holgado, JA Ramos and JJ Fernández-Ruiz, unpublished observations).
Interestingly, this neuroprotective effect is slightly enhanced if the
exposure to HU-210 is indirect, by incubating glial cells with the cannabinoid
and the resulting conditioned medium being exposed to neurons (I
Lastres-Becker, F Molina-Holgado, JA Ramos and JJ Fernández-Ruiz, unpublished
observations). This would indicate that the neuroprotective effect of
cannabinoids might be produced in part through modulating glial influence to
neurons (i.e. by increasing prosurvival factors such as glial anti-inflammatory
molecules, and/or by reducing cytotoxic ones such as NO, TNF-α or proinflammatory
cytokines; see [24, 68] for review). Two specific observations support
this hypothesis. First, it has been largely demonstrated that activation of
glial cells (astrocytes, oligodendroglia or microglia) occurs in HD [73, 150] as
in other neurodegenerative pathologies. Second, neuronal survival in these in
vitro experiments was extremely enhanced if the conditioned media were generated
after exposure to HU-210 of glial cells obtained from IL-1β-deficient
mice (I Lastres-Becker, F Molina-Holgado, JA Ramos and JJ Fernández-Ruiz,
unpublished observations).
PD
The major clinical neuropathology in PD includes bradykinesia (slowness of
movement), rigidity and tremor caused by the progressive degeneration of
dopaminergic neurons of the substantia nigra pars compacta that leads to a
severe dopaminergic denervation of the striatum (see a recent review in [117]).
Although the etiology of PD is presently unknown, major pathogenic processes
that trigger the progressive loss of nigral dopaminergic neurons are oxidative
stress, mitochondrial dysfunction and inflammatory stimuli [72, 151,
152]. Dopaminergic-replacement therapy with L-dopa represents a useful remedy
to release rigidity and bradikynesia in PD patients [153], at least in the
early and middle phases of this disease. Later on, the chronic use of this therapy
loses efficiency and elicits the appearance of an irreversible dyskinetic
state characterized by involuntary movements. On the other hand, PD is in the