Therapeutic Usefulness of Cannabinoids

Medicines used for the treatment of HD include mainly antidopaminergic drugs to reduce the hyperkinesia characteristic of the first phases of the disease (Factor and Firedman 1997) and antiglutamatergic agents to reduce excitotoxicity (Kieburtz 1999). However, the outcome of both strategies has been poor in terms of improving quality of life for HD patients, despite the progress in the elucidation of molecular events involved in the pathogenesis of HD (Cattaneo et al. 2001). In this context, cannabinoid agonists might be a reasonable alternative, since they combine both antihyperkinetic and neuroprotective effects (for review see Fernandez-Ruiz et al. 2002; Lastres-Becker et al. 2003b). As mentioned above, we will not address here the neuroprotective potential of cannabinoids in HD, because this has been addressed in the chapter by Guzman (this volume), but we will address the potential antihyperkinetic action of substances that can elevate endocannabinoid activity in

Table 2. Potential therapeutic effects of cannabinoid-related compounds in basal ganglia disorders (continuedonnextpage)

Compound

Disease

Therapeutic application

Plant-derived cannabinoids

A9-THC Huntington's disease

Parkinson's disease

Cannabidiol

Tourette's syndrome Huntington's disease

Parkinson's disease

Synthetic cannabinoids

CP 55,940 Huntington's disease

Parkinson's disease

Nabilone

WIN 55,212-2 HU308

Huntington's disease Parkinson's disease Dystonia

Parkinson's disease Dystonia

Huntington's disease

Endogenous cannabinoids

Anandamide Huntington's disease

Reduction of striatal injury in 3NP rat model (Lastres-Becker et al. 2004b)

Divergent effects on striatal injury in the malonate rat model (Lastres-Becker et al. 2003c; Aroyo et al. 2005)

Reduction of dopaminergic injury in the 6-hydroxydopamine rat model (Lastres-Becker et al. 2004a)

Failure to alleviate symptoms in PD patients (reviewed byConsroe 1998)

Reduction of tics and obsessive-compulsive behaviors (reviewed by Müller-Vahl 2003)

Failure to reduce hyperkinetic movements in HD patients (reviewed byConsroe 1998)

Poor neuroprotective action in the malonate rat model (Aroyo et al. 2005)

Reduction of dopaminergic injury in the 6-hydroxydopamine rat model (Lastres-Becker et al. 2004a)

Certain antihyperkinetic activity in 3NP-lesioned rats (Lastres-Becker et al. 2003a)

Potential reduction of tremor by reducing the overactivity of the subthalamic nucleus in the 6-hydroxydopamine rat model (Sanudo-Pena et al. 1998)

Increase of hyperkinesia (choreic movements) in HD patients (Müller-Vahl etal. 1999b)

Reduction of L-dopa-induced dyskinesia in PD patients (Sieradzan et al. 2001)

No effects in patients with generalized and segmental primary dystonia (Fox et al. 2002b)

Reduction of L-dopa-induced dyskinesia in rat models of PD (Segovia et al. 2003; Ferrer et al. 2003)

Antidystonic effects in mutant dystonic hamsters (Richter and Löscher 1994,2002)

Reduction of GABAergic injury in the malonate rat model; reversed by SR144528 (Aroyo et al. 2005)

Certain antihyperkinetic activity in 3NP-lesioned rats (possibly VR1-mediated effect) (Lastres-Becker et al. 2002a)

Compound

Disease

Therapeutic application

Inhibitors of endocannabinoid inactivation

AM404 Huntington's disease

VDM11

UCM707

AM374

Parkinson's disease Huntington's disease Huntington's disease Huntington's disease

Receptor antagonists

SR141716 (CB1) Huntington's disease

Parkinson's disease

SR144528 (CB2) Huntington's disease Capsazepine (VR1) Huntington's disease

Antihyperkinetic activity and recovery from neurochemical deficits in 3NP-lesioned rats (involvement of VR1 receptors) (Lastres-Becker et al. 2002a, 2003a)

Unable to reduce L-dopa-induced dyskinesia in the reserpine rat model (Segovia et al. 2003) Not effective in 3NP-lesioned rats (Lastres-Becker et al. 2003a) Certain antihyperkinetic activity in 3NP-lesioned rats (de Lago et al. 2004c) Not effective in 3NP-lesioned rats (Lastres-Becker et al. 2003a)

Increased striatal damage in the malonate rat model (Lastres-Becker et al. 2003c)

Unable to reverse antihyperkinetic effects of AM404 in 3NP-lesioned rats (Lastres-Becker et al. 2003a)

Unable to reduce late akinesia in 3NP-lesioned rats (Lastres-Becker et al. 2002b)

Effective to reduce L-dopa-induced dyskinesia in MPTP-treated marmosets and the reserpine rat model

(Brotchie 1998,2000; Segovia etal. 2003)

Unable to reverse bradykinesia and rigidity in MPTP-treated primates (Meschler etal. 2001) Able to restore locomotion in the reserpine model of PD (Di Marzo et al. 2000a) Able to reverse neuroprotective effect of HU308 in the malonate rat model (Aroyo et al. 2005) Able to reverse antihyperkinetic effects of AM404 in 3NP-lesioned rats (Lastres-Becker et al. 2003a)

3NP, 3-nitropropionic acid; HD, Huntington's disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson's disease.

the basal ganglia. Thus, we have recently demonstrated that the endocannabinoid transporter inhibitor AM404 was able to reduce hyperkinesia and induce recovery from GABAergic and dopaminergic deficits in rats with striatal lesions caused by local application of 3-nitropropionic acid (Lastres-Becker et al. 2002a, 2003a), while direct agonists of CB1 receptors, such as CP 55,940, only produced very modest effects (Lastres-Becker et al. 2003a). AM404 was also able to normalize motor activity in genetically hyperactive rats without causing overt cannabimimetic effects (Beltramo et al. 2000). However, in view of the fact that a progressive decrease of CB1 receptors has been recorded in this disease, the efficacy of this compound might a priori be extended only to the early or intermediate hyperkinetic phases, when cell death is still moderate, but not to the late akinetic stages of the disease characterized by high neuronal death (see Lastres-Becker et al. 2003b for a review). These results, however, contrast with some clinical data that indicate that the administration of plant-derived cannabinoids (Consroe 1998), or some of their synthetic analogs (Muller-Vahl et al. 1999b), increased choreic movements in HD patients. It is possible that this is related to the lack of VR1 receptor activity of these cannabinoid agonists, since recent studies carried out in our laboratory (see details in Table 2) in rats with striatal lesions have revealed that only those cannabinoid-based compounds having an additional profile as VR1 receptor agonists were really effective in alleviating hyperkinetic signs (Lastres-Becker et al. 2003a). This was so for AM404, which, in addition to its ability to block the en-docannabinoid transporter, also exhibits affinity for the VR1 receptor (Zygmunt et al. 2000). Interestingly, inhibitors of endocannabinoid inactivation that are not active at the VR1 receptor, such as VDM11 or AM374, did not have any antihy-perkinetic action in HD rats (Lastres-Becker et al. 2003a), whereas UCM707, the most potent inhibitor to date, only produced modest effects (de Lago et al. 2004c) (see Table 2). Therefore, our data suggest that VR1 receptors alone, or better in combination with CB1 receptors, might represent novel targets through which the hyperkinetic symptoms of HD could be alleviated. Possibly, the best option might be to develop "hybrid" compounds with the dual capability of activating both VR1 and CB1 receptors, although the relative contribution made by each ofthese targets is likely to change during the course of the disease due to a progressive loss of CB1 receptors without any concomitant loss of VR1 receptors (see Lastres-Becker et al. 2003b for a review).

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