3. Umbruch 4.4..2005 - Online Pot

Cannabinoids in neurodegeneration and neuroprotection 91
review). This would include diseases such as AD, ALS, HD, PD, MS and other
pathologies (see Tab. 1 for an overview, and [4–7, 24, 25, 68, 76] for review).
This adds to other benefits reported for cannabinoid-based compounds by alleviating
specific clinical signs, such as the anti-hyperkinetic effect in HD [124,
125], the orexigenic action in AD [126] or the antispastic effects in MS
[127–130] produced by direct or indirect agonists of cannabinoid receptors. By
contrast, CB 1 receptor blockade has been reported to be effective to improve
motor inhibition in PD [131, 132] and memory deficits in AD [133]. However,
these effects on symptom relief will be addressed here only marginally.
HD
HD is an inherited neurodegenerative disorder characterized by motor abnormalities,
cognitive dysfunction and psychiatric symptoms, which presents in
mid life and is ultimately fatal (for review, see [115, 116]). The most striking
neuropathological change in HD patients is the preferential and progressive
degeneration of the striatum due to the selective death of striatal projection
neurons (these neurons contain CB 1 receptors [134]), which is accompanied
by a biphasic pattern of motor deterioration that evolves from an early hyperkinetic
phase (choreic movements) to a late akinetic and more disabling phase
[115, 116]). Although it has been demonstrated that HD is a disease of genetic
origin (it is caused by an expansion of a polyglutamine tract in the N-terminal
portion of the huntingtin protein [116]), mechanisms underlying striatal
degeneration are still unknown. In addition, the therapeutic outcome for HD
patients has been scarce and includes mainly (1) anti-dopaminergic drugs to
reduce the excessive movement characteristic of first phases of the disease
[135] and (2) anti-glutamatergic agents to reduce excitotoxicity [136].
However, both treatments have resulted to be poor in terms of improving quality
of life for HD patients. In this context, cannabinoid agonists might provide
therapeutic benefits in both aspects since they produce hypokinesia [7, 137]
and also provide neuroprotection [4–6, 27, 137].
As mentioned above, recent studies have addressed the anti-hyperkinetic
effects of direct or indirect cannabinoid agonists in animal models of HD [124,
125], based on the demonstration, in humans and laboratory animals, that the
endocannabinoid transmission becomes hypofunctional in the basal ganglia in
HD [138–145]. More recently, the neuroprotective potential of cannabinoids
has been also tested in this disease [19, 32, 65], and, although the matter is still
far from being clarified, some results have provided promising expectatives.
The rationale for these studies is based on the idea that the losses and/or dysfunction
of CB 1 receptors in the basal ganglia is a very early event that takes
place before the appearance of major neuropathological signs and when cell
death has not occurred or is minimal. This has been found in both humans and
different models of transgenic mice that express mutated forms of huntingtin
like the human pathology [140–142]. In addition, we have recently found that