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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 13, 2005 as doi:10.1096/fj.04-3010fje. |
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,1
,3
,4
* Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy;
Movement Disorders Clinic, Toronto Western Hospital, Toronto, Canada;
Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester UK; and
Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada
4 Correspondence: J.M.B., Toronto Western Research Institute, MC 11-419, Toronto Western Hospital, 399, Bathurst St, Toronto ON, Canada M5T 2S8. E-mail: Brotchie{at}uhnres.utoronto.ca; V.D.M., Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078, Pozzuoli (NA) Italy. E-mail: vdimarzo{at}icmib.na.cnr.it
SPECIFIC AIMS
The aim of the present study was to assess systematically in nonhuman primates the role of endocannabinoid stimulation of cannabinoid CB1 receptors in the generation of symptoms of parkinsonism and L-DOPA-induced dyskinesia (LID), the major complication of treatments for PD and the major factor limiting our ability to adequately control this condition with available therapeutics. Three hypotheses were addressed: 1) in untreated parkinsonism, enhanced endocannabinoids in the striatum may attempt to compensate for dopamine depletion; 2) endocannabinoids released in GPe may contribute to the mechanisms generating parkinsonian symptoms; thus, attenuation of CB1 transmission may have anti-parkinsonian actions; 3) after long-term L-DOPA therapy, enhanced endocannabinoid signaling at CB1 receptors may contribute to the pathophysiology of LID; thus, attenuation of CB1 transmission may have anti-dyskinetic properties.
In the first series of experiments, we assessed the effects of attenuating CB1 transmission with the selective CB1 antagonist rimonabant (SR141716) on parkinsonism and LID in the MPTP-lesioned marmoset. We then used ionization liquid chromatography/mass spectrometry to determine levels of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) levels throughout the basal ganglia in normal and three groups of MPTP-lesioned cynomolgus monkeys (untreated; acutely treated with L-DOPA, nondyskinetic; long-term treated, with levodopa-induced dyskinesia).
PRINCIPAL FINDINGS
In MPTP-lesioned primates, the CB1 cannabinoid receptor antagonist rimonabant can alleviate parkinsonian symptoms as monotherapy. These effects were equivalent to a 71% increase in motor activity at 3 mg/kg (Fig. 1
). Rimonabant monotherapy did not elicit dyskinesia. Rimonabant can reduce LID without compromising the ability of levodopa to alleviate parkinsonian symptoms. Endocannabinoids levels are altered after induction of parkinsonism and subsequent dopamine replacement therapy, either acutely or repeatedly, the latter inducing levodopa-induced dyskinesia (Fig. 2
). Anandamide and 2-AG are elevated (+88% and +49%, respectively) in the striatum of untreated parkinsonian monkeys. After treatment with levodopa acutely or repeatedly, endocannabinoid levels in this region were not significantly different from those measured in normal animals. Anandamide, but not 2-AG, is elevated (+34%) in the GPe of untreated parkinsonian monkeys, and this elevation is reversed by treatment of parkinsonian symptoms, acutely or repeatedly. There was no clear-cut alteration in endocannabinoid levels that correlated with the appearance of LID, although this pathological state was never accompanied by elevated endocannabinoid levels (Fig. 2)
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CONCLUSIONS AND SIGNIFICANCE
Results from the behavioral components of this study demonstrate for the first time in a nonhuman primate model of PD that it is extremely likely that the genesis of parkinsonian symptoms and LID involves enhanced endocannabinoid signaling at CB1 receptors in the basal ganglia circuit. These data are complemented by our biochemical data that define potential mechanisms by which this might occur and also highlight potential roles for endocannabinoids in processes attempting to compensate for loss of dopamine.
Compensatory changes
It has been suggested that elevation of endocannabinoids in the striatum of the 6-hydroxydopamine-lesioned rat model of PD may represent a mechanism attempting to compensate for loss of dopamine. The present study supports this hypothesis by demonstrating that anandamide and 2-AG are elevated in untreated parkinsonian monkeys and that acute treatment with levodopa, which reestablishes normal dopamine levels in the striatum, leads to endocannabinoid levels undistinguishable from those of control animals. That both endocannabinoids are elevated is in contrast to the rat, where only anandamide was found to be increased. These data highlight potential differences between the regulation of endocannabinoid metabolism in rodents compared with primates and/or in different models of the disease process. However, given the verisimilitude of the MPTP-lesioned nonhuman primate and the human condition, we can likely conclude that elevations in both striatal endocannabinoids accompany dopamine depletion in PD. It is speculated that these elevations represent compensatory mechanisms, as they would reduce glutamate transmission in the striatum. Indeed, there is an increasing body of evidence that reduction of glutamatergic transmission can have anti-parkinsonian actions. Enhancement of striatal endocannabinoid signaling by direct receptor activation, increasing synthesis or decreasing breakdown or removal, might represent a novel approach to extending the presymptomatic period of PD or reversing symptoms once expressed.
Symptoms of parkinsonism
We previously suggested that enhanced endocannabinoids in the GPe may contribute to the processes responsible for the generation of parkinsonian symptoms in a rodent model. This is supported by the present finding that anandamide levels are increased in GPe of untreated parkinsonian monkeys and normal in parkinsonian monkeys in which parkinsonism is reversed by levodopa. However, the detailed nature of the endocannabinoid abnormality involved in the generation of parkinsonian symptoms in primates may differ from that in rodents, as was the case (discussed above) for potential compensatory mechanisms. Thus, in the reserpine-treated rat model of parkinsonism, an elevation in 2-AG, and not anandamide, accompanies parkinsonian symptoms. We further support the involvement of endogenous cannabinoids in the generation of parkinsonian symptoms by demonstrating that rimonabant, as monotherapy, alleviates parkinsonian symptoms in the MPTP-lesioned primate. This finding is remarkable as it is one of only a small number of nondopaminergic therapies that have been shown to alleviate parkinsonian symptoms as monotherapy, the others being NMDA receptor antagonism, adenosine A2A antagonism, delta opioid agonists, and subthalamic nucleus inactivation. All these approaches are thought to exert their actions via the striato-GPe-subthalamic-GPi/substantia nigra circuit, the indirect pathway, and highlight the potential importance of endocannabinoids in controlling this circuit.
Levodopa-induced dyskinesia
We previously proposed that enhanced CB1 transmission in the output regions of the basal ganglia might contribute to the expression of LID. However, in the present study we found no elevation above untreated or acutely treated parkinsonian animals in endocannabinoid, GPi, or substantia, nigra that would correlate with the expression of LID. However, our finding that rimonabant decreased the severity of LID in MPTP-lesioned primates, without reducing anti-parkinsonian efficacy of levodopa, certainly points to a role for enhanced CB1 signaling in LID. One possibility is that enhanced endocannabinoid signaling outside the output regions of the basal ganglia may contribute to the mechanisms of LID.
On the other hand, CB1 signaling in LID may be enhanced even in the presence of normal levels of endocannabinoids. Several mechanisms for such an enhancement might be speculated. For instance, the coupling of CB1 receptors to G-proteins may be aberrant. However, although CB1-G-protein coupling is enhanced in untreated MPTP-lesioned marmosets, it appears to be normal in dyskinetic animals. Additional mechanisms of enhanced CB1 signaling must be considered and investigated; for instance, the CB1 receptor may change its properties with respect to constitutive activity.
CONCLUSIONS AND SIGNIFICANCE
While our studies are unable to provide a complete understanding of the role of endocannabinoids in parkinsonism and LID, we significantly strengthen the concept that these key neuromodulators play a role in movement disorders. By using primate models of disease processes, we highlight not only the value, but also the limitations, of studies in rodents. In considering the relevance of changes in endocannabinoid levels to behavioral effects of attenuation of CB1 signaling, we have remained cognizant of the fact that anandamide has been reported to act as a partial agonist at the vanilloid TRPV1 receptor. To date, few data are available to illuminate the role of TRPV1 in parkinsonism or LID. Investigation of such effects will be an important path resulting from our identification of abnormalities in anandamide levels in PD and LID. Overall, the data presented here add weight to the concept that manipulation of endocannabinoid signaling represents an exciting and viable therapeutic opportunity in Parkinson’s disease.
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FOOTNOTES
1 These authors contributed equally to this work. 
2 Current address: NV Organon, Molenstraat 110, PO Box 20, 5340 BH, Oss, The Netherlands.
3 Current address: Motac Neuroscience Ltd, Williams House, Lloyd, Manchester, UK.
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-3010fje; doi: 10.1096/fj.04-3010fje
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0.05, **P<0.01).