See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/38021057

Cannabinoids and Parkinson's disease

Article in CNS & neurological disorders drug targets October 2009

Source: PubMed

CITATIONS READS

26 692

3 authors:

Moises Garcia-Arencibia Concepcin Garca

Universidad de Las Palmas de Gran Canaria Complutense University of Madrid
58 PUBLICATIONS 2,848 CITATIONS 17 PUBLICATIONS 441 CITATIONS

SEE PROFILE SEE PROFILE

Javier Fernndez-Ruiz
Complutense University of Madrid
320 PUBLICATIONS 12,410 CITATIONS

SEE PROFILE

All content following this page was uploaded by Moises Garcia-Arencibia on 23 June 2017.

The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document
and are linked to publications on ResearchGate, letting you access and read them immediately.
432 CNS & Neurological Disorders - Drug Targets, 2009, 8, 432-439

Cannabinoids and Parkinsons Disease

Moiss Garca-Arencibia, Concepcin Garca and Javier Fernndez-Ruiz*

Departamento de Bioqumica y Biologa Molecular and Centro de Investigacin Biomdica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain

Abstract: Cannabinoid-based medicines have been proposed as clinically promising therapies in Parkinsons disease
(PD), given the prominent modulatory function played by the cannabinoid signaling system in the basal ganglia.
Supporting this pharmacological potential, the cannabinoid signaling system experiences a biphasic pattern of changes
during the progression of PD. Thus, early and presymptomatic stages, characterized by neuronal malfunctioning but little
evidence of neuronal death, are associated with desensitization/downregulation of CB1 receptors. It was proposed that
these losses may be part of the pathogenesis itself, since they can aggravate different cytotoxic insults which are
controlled in part by cannabinoid signals, mainly excitotoxicity but also oxidative stress and glial activation. By contrast,
intermediate and, in particular, advanced stages of parkinsonism characterized by a profound nigral degeneration and
occurrence of major parkinsonian symptoms (e.g. bradykinesia), are associated with upregulatory responses of CB1
receptors, possibly CB2 receptors too, and the endocannabinoid ligands for both receptor types. This would explain the
motor inhibition typical of this disease and the potential proposed for CB1 receptor antagonists in attenuating the
bradykinesia typical of PD. In addition, certain cannabinoid agonists have been proposed to serve as neuroprotective
molecules in PD, given their well-demonstrated capability to reduce excitotoxicity, calcium influx, glial activation and, in
particular, oxidative injury that cooperatively contribute to the degeneration of nigral neurons. However, the potential of
cannabinoid-based medicines in PD have been still scarcely studied at the clinical level despite the existence of solid and
promising preclinical evidence. Considering the relevance of these preclinical data, the need for finding treatments for
motor symptoms that may be alternative to classic dopaminergic replacement therapy, and the lack of efficient
neuroprotective strategies in PD, we believe it is of major interest to develop further studies that allow the promising
expectations generated for these molecules to progress from the present preclinical evidence towards a real clinical
application.
Keywords: Cannabinoids, cannabinoid signaling system, CB1 receptors, CB2 receptors, basal ganglia, motor inhibition,
neurodegeneration, neuroprotection, Parkinsons disease.

OVERVIEW ON PARKINSONS DISEASE events, including abnormalities in proteolysis, protein

aggregation, mitochondrial deficit, excitotoxicity, oxidative
The major clinical neuropathology in PD includes
stress and glial activation, which would act cooperatively to
bradykinesia (slowness of movement), rigidity and tremor,
produce the progressive death of nigrostriatal dopaminergic
symptoms that are the consequence of the progressive
neurons [6]. Therapy in PD covers exclusively the
degeneration of dopaminergic neurons of the substantia nigra alleviation of motor symptoms, particularly, the bradykinesia
pars compacta [1]. This progressive death of nigral neurons
and the rigidity. It is based on the activation of dopaminergic
produces a severe dopaminergic denervation of the striatum
receptors in striatal neurons by enhancing dopamine
with a subsequent loss of the regulatory effect exerted by this
generation from its precursor levodopa and/or by using
neurotransmitter on striatal neurons that culminates in
selective receptor agonists [7], which may transiently
adaptative changes in the basal ganglia circuitry, e.g.
normalize the imbalance between striatopallidal and
overactivity of the subthalamic nucleus, which explains the striatonigral inputs, thus improving motor control. However,
occurrence of tremor, and loss of striatal inhibitory inputs to
this remedy can be used only in early and intermediate
the substantia nigra/internal globus pallidus, which also
phases of the disease, is not effective in all parkinsonian
become hyperactive explaining the occurrence of
patients, and produces the appearance of irreversible
hypokinesia [2]. The exact etiology of PD is still uncertain,
dyskinetic stages after 5-10 years of medication [8], which
possibly because the disease is in fact heterogeneous and can
opens the possibility for novel symptomatic therapies. In
be elicited by different causes, including environmental addition, PD patients do not have an efficient therapy to
factors (e.g. pesticides, metals, antidopaminergic agents [3]),
arrest/delay the progression of nigral degeneration.
genetic vulnerabilities (e.g. mutation in different genes [4]),
or the combination of both types of factors [5]. These
CANNABINOIDS AND PARKINSONS DISEASE
primary factors would be followed by different cytotoxic
The need for novel therapies that may be alternatives to
levodopa in those conditions in which this therapy does not
*Address correspondence to this author at the Departamento de Bioqumica work (see above) or that may delay, arrest or repair the nigral
y Biologa Molecular III, Facultad de Medicina, Universidad Complutense, degeneration, opens the possibility for the use in PD of
Ciudad Universitaria s/n, 28040-Madrid, Spain; Tel: 34-91-3941450; Fax:
34-91-3941691; E-mails: jjfr@med.ucm.es, J.Fernandez-Ruiz@ciberned.es compounds active in the cannabinoid signaling system. This
hypothesis is supported by the observation that certain

1871-5273/09 $55.00+.00 2009 Bentham Science Publishers Ltd.

Cannabinoids and Parkinsons Disease
elements of the cannabinoid signaling, in particular the CB1
receptor type, are altered during the course of nigral
degeneration in PD (see [9] for review). In fact, a therapy
with cannabinoids in PD would imply the use of CB1
receptor antagonists for the alleviation of motor inhibition
(see [10, 11] for review), but also the use of different types
of cannabinoids, preferably antioxidant cannabinoids, for the
control of disease progression (see [9, 11] for review).
Following this, we will review all available literature that
demonstrates how the progression of PD is associated with
dual changes in cannabinoid signaling in the basal ganglia,
and the therapeutic options for cannabinoid-based medicines
differentiating the treatments addressed to alleviate certain
motor symptoms and those focused to provide
neuroprotection and/or neuroregeneration.
Changes in the Cannabinoid Signaling System in
Parkinsons Disease
Given the hypokinetic effect associated with the
activation of CB1 receptors located in different neuronal
subpopulations within the basal ganglia [11], it is reasonable
to expect that the cannabinoid signaling system, and
particularly this receptor type, would experience an up-
regulatory response in PD or other hypokinetic disorders. In
addition, if this were the case, an up-regulatory response
would explain the bradykinesia typical of parkinsonism.
Numerous studies conducted during recent years using
samples from patients or from experimental models of
parkinsonism have strongly demonstrated that the
cannabinoid system, in particular the number and function of
CB1 receptors, becomes overactive in this disease (see [9-11]
for recent reviews). However, these studies have also
indicated that this type of response is not the unique change
experienced by the cannabinoid signaling in PD (see Fig. (1)
for a schematic representation). For these authors, the
overactivity of the cannabinoid signaling was found in
conditions of evident nigral degeneration, but this would not
be the case in early phases of this disease when cell death
does not exist or its incidence is still too low to elicit motor
symptoms. This is particularly important in PD since, given
the adaptative properties of basal ganglia circuitry, the onset
of clinical symptoms occurs when nigral degeneration has
reached an important degree, i.e. more than 50% of neuronal
death [12]. Thus, we have recently demonstrated that CB1
receptors, rather than being increased, experienced a
reduction in different knockout mouse models of three
different genes linked to the development of parkinsonism
including PARK1 encoding for
-synuclein, PARK2
encoding for parkin, and PARK6 encoding for PINK1
protein [13]. This reduction was exclusively observed when
animals were analyzed at early and presymptomatic ages
[13]. However, when mice were analyzed at later and
symptomatic ages, we observed the same up-regulatory
responses of CB1 receptors [13] that were recorded in
patients or laboratory animals lesioned with neurotoxins (see
below). Therefore, we can conclude that down-
regulation/desensitization of CB1 receptors might be an early
event in PD, as also reported for other disorders [9], that
would occur in conditions of neuronal malfunctioning but in
the absence of cell death (see Fig. 1). This means that this
response might be used as an early biomarker of PD, which
is extremely important in a disease that, as has been
CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6 433
described above, shows the first neurological symptoms
when an important degree of neuronal damage has already
occurred [12]. In addition, it is reasonable to assume that
these early losses/malfunctioning of CB1 receptors might be
involved in the initiation or early progression of nigral
degeneration. They could render nigrostriatal neurons more
vulnerable to different cytotoxic stimuli that frequently
operate in PD, in particular excitotoxic stimuli that seem to
be under the influence of CB1 receptor-mediated signals (see
Fig. 1 and [9, 14, 15]).
As mentioned above, as soon as the disease progresses
and the major parkinsonian symptoms appear, the
cannabinoid signaling system becomes overactive rather than
hypoactive (see Fig. 1). This has been observed in patients
by analyzing the number and function of CB1 receptors in
post-mortem basal ganglia [16] or by measuring the levels of
endocannabinoids in cerebrospinal fluid samples [17], and
also in animal models of this disease by evaluating either
CB1 receptors [16, 18, 19] or endocannabinoids [20-22]. As
mentioned above, this type of up-regulatory response is
absolutely concordant with the hypokinetic profile that
characterizes the disease and also with the idea that the
blockade of CB1 receptors might be useful against
bradykinesia (see Fig. 1 and below). The fact that this type
of response was generally reversed by treatment with
levodopa [16, 22, 23] supports the idea that overactivity of
the cannabinoid signaling inversely correlates with the loss
of nigral neurons and with the dopaminergic denervation of
the striatum.
An additional aspect related to the changes experienced
by the cannabinoid signaling in PD that might represent an
important difference compared to the case of other
neurodegenerative diseases, is the lack of data that
demonstrate the type of response experienced by the other
major cannabinoid receptor type, CB2 receptor. In most
neurodegenerative disorders, including Alzheimers disease,
Huntingtons chorea, multiple sclerosis, amyotrophic lateral
sclerosis, HIV-associated dementia, neuropathic pain and
others, these receptors, that are generally scarcely present in
the healthy brain, have been reported to exhibit a significant
up-regulation in glial elements, e.g. astrocytes and, in
particular, reactive microglial cells (see [24, 25] for recent
reviews). Given the fact that astrocytosis and reactive
microgliosis occur to a great extent in the lesioned substantia
nigra, a fact demonstrated in PD patients and also in animal
models [26], it appears reasonable to expect that CB2
receptors are up-regulated in glial elements recruited at this
structure after the lesion. However, the issue has remained
elusive to date, possibly due to methodological problems
(see below), although the fact that CB2 receptor agonists
have demonstrated weak neuroprotection in parkinsonian
animals [27] has supported the idea that this disease might be
different depending on the response and the function of CB2
receptors [9].
Alleviation of Motor Symptoms by Cannabinoid-Based
Medicines in Parkinsons Disease
Despite some therapeutic properties that certain
cannabinoid agonists have exhibited in PD and that will be
addressed at the end of this section, two facts remain: (i) the
overactivity found in the cannabinoid signaling system in PD
434 CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6
Fig. (1). Pattern of changes in CB1 and CB2 receptors in the basal ganglia during the progression of Parkinsons disease.
[10, 11], and (ii) the hypokinetic action of most cannabinoid
agonists [10, 28], do not support that these compounds may
be recommended for alleviating bradykinesia, rigidity and
other hypokinetic symptoms typical of this disease. In fact,
the few clinical trials developed so far have failed to
demonstrate any beneficial effects with cannabinoid agonists
[29-31], despite some anecdotal data that indicated that PD
patients who self-medicated with cannabis obtained certain
subjective improvements in specific motor symptoms [31].
By contrast, recent studies have proposed that the type of
compounds that may be useful in PD against bradykinesia
should be CB1 receptor antagonists rather than agonists (see
Fig. 2), given that the cannabinoid signalling system
becomes overactive in the basal ganglia in PD [16-22]. This
has been evaluated in a series of preclinical [20, 32] and
clinical studies [33], although the first results were
controversial. Further studies have suggested that the
blockade of CB1 receptors might be effective only in certain
circumstances, for example, when low doses of CB1 receptor
antagonists are used, or when patients are in very advanced
phases of the disease or have a poor levodopa response [34-
36]. This represents an important advantage since it would
provide a novel anti-parkinsonian agent useful for conditions
in which classic dopaminergic replacement therapy generally
fails.
On the other hand, the beneficial effects of CB1 receptor
antagonists against parkinsonian bradykinesia might be
completed with the anti-hypokinetic properties exhibited by
the blockade of TRPV1 receptors (see Fig. 2), a cation
channel that, among others, is activated by certain
endocannabinoids. This proposal is based on recent data that
indicated that the activation of these receptors would inhibit
the synthesis and release of dopamine in striatal
dopaminergic terminals [37], therefore their blockade might
elicit the opposite effect than being useful against the
dopamine deficit and motor inhibition typical of PD. In this
respect, TRPV1 receptors have been identified in different
neuronal subpopulations in the basal ganglia, in particular, in
Garca-Arencibia et al.
nigrostriatal dopaminergic neurons [38] which enable these
receptors to directly control dopamine synthesis and release.
However, this might represent a disadvantage in terms of a
potential clinical exploitation of these receptors to alleviate
bradykinesia in PD, since the death of nigrostriatal
dopaminergic neurons during the progression of PD would
presumably be associated with progressive loss of TRPV 1
receptors, a fact recently demonstrated [39].
In addition to their suggested properties for the relief of
bradykinesia, CB1 receptor antagonists might be also useful
to delay and reduce the dyskinetic states caused by chronic
treatment with levodopa in PD (see [40] for review). This
has been studied both in patients [41, 42] and animal models
of PD [22, 43]. The problem is that this capability has also
been assigned to CB1 receptor agonists [44-47], which is
concordant with the idea that the presence of CB1 receptors
in multiple sites, both in excitatory and inhibitory synapses
within the basal ganglia circuitry, might facilitate the
occurrence of some paradoxical effects (reviewed in [11,
12]). This idea possibly also explains why CB1 receptor
agonists, and even the inhibitors of the endocannabinoid
inactivation, the so-called indirect agonists, may also provide
beneficial effects in PD in relation to certain parkinsonian
symptoms or under certain circumstances (see Fig. 2). This
would be the case of the demonstrated capability of CB1
receptor agonists to reduce tremor associated with the
overactivity of the subthalamic nucleus in animal models of
PD [48, 49], although the only clinical trial developed so far
to test the effects of cannabinoid agonists against the
parkinsonian tremor led to negative results [50]. CB1
receptor agonists have been reported to interact with
dopaminergic agonists too, given the co-localization of CB1
and D1 or D2 receptors in striatal projection neurons [51] and
the fact that they share common intracellular signals [52], so
that this interaction may enhance the positive effects of
dopaminergic agonists on certain motor impairments [53-
55]. Lastly, cannabinoid agonists have been demonstrated to
afford neuroprotection in PD by delaying and/or arresting the
Cannabinoids and Parkinsons Disease
Fig. (2). Diagram showing the different targets (CB1, CB2 and TRPV1 receptors) that might mediate the potential of cannabinoid-based
medicines to alleviate specific symptoms or to delay/arrest the progression of the disease in Parkinsons disease (DA = dopamine; GABA =

-aminobutiric acid; GLU = glutamate).
progression of nigral degeneration (see [9] for review).
However, this effect does not appear to be dependent, at least
significantly, on the capability of these agonists to activate
CB1 receptors but instead is dependent on other additional
cannabinoid properties, as will be described in the following
section.
Neuroprotective/Neuroregenerative Potential of
Cannabinoids in Parkinsons Disease
Cannabinoid agonists have been proposed as potentially
useful neuroprotective substances in PD, although the issue
has been explored only very recently and, at the moment,
remains almost exclusively at the preclinical level [9, 56].
An important obstacle for this development has been the
hypokinetic profile of most cannabinoid agonists that, rather
than reduce, can acutely enhance motor disability, as has
been demonstrated in a few clinical experiments [29, 30].
Recently, we have conducted a series of preclinical studies
CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6 435
using rats with hemiparkinsonism generated by the unilateral
application of 6-hydroxydopamine, a classic experimental
model of PD frequently used to test neuroprotective
strategies, where we have evaluated the neuroprotective
effects of various types of cannabinoid agonists [27, 39]. Our
results have proved strong evidence that the key mechanism
that enables cannabinoids to serve as neuroprotectants in this
parkinsonian model would be their capability to reduce
oxidative injury through a receptor-independent effect (see
Fig. (3) and [9] for review). Thus, selective CB1 receptor
agonists, such as arachidonoyl-chloro-ethanolamide, or non-
selective CB1 /CB2 receptor agonists, such as WIN55,212-2,
did not protect nigral neurons from 6-hydroxydopamine-
induced damage [27], whereas selective CB2 receptor
agonists, such as HU-308, only produced very poor
neuroprotection [27]. These data strongly indicated that, at
least in rats lesioned with 6-hydroxydopamine, neither CB1
receptors nor CB2 receptors appear to play a fundamental
role in the neuroprotection afforded by cannabinoids. Of
436 CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6
Fig. (3). Mechanisms proposed to explain the neuroprotective action of antioxidant cannabinoids in Parkinsons disease (ROS = reactive
oxygen species; SOD = superoxide dismutase).
course, this does not exclude that agonists for both receptor
types might be effective in another parkinsonian model or
that they might play secondary roles in 6-hydroxydopamine-
lesioned animals (see Fig. 2). In our studies [27, 39], three
compounds provided neuroprotection:
9-tetrahydrocanna-
binol (
9-THC) [39], cannabidiol (CBD) [39] and AM404
[27].
9-THC is a phytocannabinoid with affinity for both
CB1 and CB2 receptors, although their capability to protect
dopaminergic neurons from death seems to be more related
to their antioxidant properties rather than to the capability to
activate these receptor types. This conclusion is also
supported by the fact that equivalent neuroprotection was
also attained with CBD [39], an antioxidant phytocanna-
binoid with negligible activity at both receptor types. Lastly,
AM404 is an inhibitor of endocannabinoid inactivation but
its neuroprotective potential in this model derives from its
antioxidant profile [27], since other inhibitors of the
endocannabinoid inactivation are devoid of this effect, such
as UCM707 [57]. The case of AM404 is particularly
interesting since it is possible that it might be involved in the
neuroprotective effect of acetaminophen (paracetamol) in PD
[58], given the recent description of a metabolic pathway
capable to convert acetaminophen in AM404 in the brain
[59].
Therefore, these data taken together clearly support the
notion that the key mechanism for a neuroprotective effect
with cannabinoid agonists in PD is the control of the toxic
influence exerted by reactive oxygen intermediates, as has
been outlined in Fig. (3). Further studies that used
invertebrate models of parkinsonism and another antioxidant
cannabinoid agonist CP55,940 [60] led to similar findings,
and the same happens when our data are compared with
previous studies conducted with antioxidant cannabinoids in
different in vitro or in vivo models of neurodegeneration [61,
62]. In the case of PD, this is of special relevance because
Garca-Arencibia et al.
oxidative stress is a major hallmark in the pathogenesis of
this neurodegenerative disorder [6]. Reactive oxygen species
are produced from several sources, including mitochondria,
metabolism of arachidonic acid, nitric oxide synthase and
other enzymes and, in the case of PD, from the metabolism
of dopamine itself [6]. Compounds such as CBD,
9-THC
and AM404, which contain phenolic groups in their
chemical structure, are antioxidant because they can act as
scavengers of reactive oxygen species and, subsequently,
they can improve the function of endogenous antioxidant
mechanisms, e.g. superoxide dismutase (see Fig. 3).
However, it has been also suggested that the antioxidant
effect of these compounds in PD might be exerted by
regulating some intracellular signals that have been linked to
the expression and/or function of superoxide dismutase or
other antioxidant enzymes, which might be then the
responsible of the reduction in the levels of reactive oxygen
species [9,11] (see Fig. 3). If this were case, it would
possibly imply the participation of a novel cannabinoid
receptor type, an aspect needing further experimentation.
On the other hand, another aspect pending further
exploration is the question of CB2 receptors in PD. As
mentioned above, selective agonists of these receptors are
poorly effective [27], in concordance with the fact that PD is
the only neurodegenerative disorder where it has not yet
been demonstrated whether CB2 receptors are up-regulated
in glial elements in response to neuronal damage (see [24,
25] for review). However, the absence of evidence is not
evidence of absence, so more studies are needed, with more
selective tools, e.g. better antibodies, in vivo ligands, etc.,
that allow to completely clarify whether CB2 receptors might
be important neuroprotective players in this disease.
Possibly, this question represents one of the major
challenges for research on the neuroprotective potential of
cannabinoids in PD, together with the need to conduct
Cannabinoids and Parkinsons Disease CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6 437

specific clinical trials with some of the available during the last years by the Ministerio de Ciencia e
cannabinoid-based medicines, for example the combination Innovacin, Plan Nacional de Biomedicina (SAF2006-
of
9-THC and CBD in the oromucosal spray Sativex [63], 11333 and SAF2009-11847), CIBERNED (CB06/05/0089)
that would allow preclinical evidence to be validated in and Comunidad de Madrid (S-SAL-0261/2006). The
patients. Another key aspect pending of further authors are indebted to all colleagues who contributed in this
experimentation would be to elucidate in PD whether experimental work.
cannabinoid agonists might also serve to repair the injured
tissue, given the recent identification of a cannabinoid- ABBREVIATIONS
sensitive mechanism that participates in the control of adult
CB1 = Cannabinoid Receptor Type 1
neurogenic structures, including the subventricular zone and
the hippocampal dentate gyrus [64-66]. This capability CB2 = Cannabinoid Receptor Type 2
would complete the above-described potential of these
CBD = Cannabidiol
molecules to preserve nigral neurons from death, allowing
the replacement of injured neurons in the case where D1 = Dopamine Receptor Type 1
treatments were initiated after degeneration had already D2 = Dopamine Receptor Type 2
begun or in the case that the treatments were effective only
in delaying, but not to arresting, the progression of the HIV = Human Immunodeficiency Virus
disease. The idea would be to use cannabinoid compounds to PD = Parkinsons Disease
activate the neurogenic structures, for example, the
subventricular zone, then allowing the proliferation of cell PINK1 = PTEN-Induced Putative Kinase 1
progenitors, their differentiation to neurons and/or their
-THC =
9-Tetrahydrocannabinol
9

migration to the damaged substantia nigra, where they would

acquire the phenotype corresponding to nigrostriatal neurons
that are lost in PD. Unhappily, the experimental evidence
accumulated so far on a possible neurorepair action of
cannabinoids in PD is still minimal.
CONCLUDING REMARKS AND FUTURES
PERSPECTIVES
The studies reviewed here support the view that the
cannabinoid signaling system becomes impaired in PD, as
demonstrated in both patients and animal models, which
supports the idea that the pharmacological management of this
system with compounds that selectively target its different
elements, might serve to alleviate certain motor symptoms (e.g.
bradykinesia) and also to delay/arrest the disease progression
and, even, to repair the damaged structures. The selective
blockade of CB1 receptors and, possibly, TRPV1 antagonists
too, might serve for the first of these two capabilities, whereas
cannabinoid receptor-independent antioxidant cannabinoids
might serve for the purpose to control the disease progression.
However, the issue is pending some important novel
developments including first the evaluation in patients of the
therapeutic benefits already demonstrated in animal models.
The already available combination of antioxidant cannabinoids
might be a reasonable choice for clinical examination as a novel
neuroprotectant therapy, whereas CB1 and TRPV1 receptor
antagonists would deserve examination for their capability to
alleviate bradykinesia in patients that can not receive benefits
from the classic therapy with levodopa. A second aspect
deserving additional experimentation would be to clarify the
function and eventual therapeutic potential of CB2 receptors in
PD, although this would require the development of novel
methodological tools, such as more selective anti-CB2
antibodies and selective ligands useful for in vivo analysis, to
allow determination of whether this receptor is up-regulated in
this disease.
ACKNOWLEDGEMENTS
The experimental work carried out by our group and that
has been mentioned in this review article, has been supported
TRPV1 = Transient Receptor Potential Vanilloid Type 1.
REFERENCES
[1] Sethi, K.D. Clinical aspects of Parkinson disease. Curr. Opin.
Neurol., 2002, 15, 457-460.
[2] Blandini, F.; Nappi, G.; Tassorelli, C.; Martignoni, E. Functional
changes of the basal ganglia circuitry in Parkinson's disease. Prog.
Neurobiol., 2000, 62, 63-88.
[3] Di Monte, D.A. The environment and Parkinson's disease: is the
nigrostriatal system preferentially targeted by neurotoxins? Lancet
Neurol., 2003, 2, 531-538.
[4] Farrer, M.J. Genetics of Parkinson disease: paradigm shifts and
future prospects. Nat. Rev. Genet., 2006, 7, 306-318.
[5] Allam, M.F.; Del Castillo, A.S.; Navajas, R.F. Parkinson's disease
risk factors: genetic, environmental, or both? Neurol. Res., 2005,
27, 206-208.
[6] Olanow, C.W. The pathogenesis of cell death in Parkinson's disease
- 2007. Mov. Disord. 2007, Suppl 17, S335-S342.
[7] Carlsson, A. Treatment of Parkinson's with L-DOPA: the early
discovery phase, and a comment on current problems. J. Neural
Transm., 2002, 109, 777-787.
[8] Mller, T.; Russ, H. Levodopa, motor fluctuations and dyskinesia
in Parkinson's disease. Expert Opin. Pharmacother., 2006, 7, 1715-
1730.
[9] Sagredo, O.; Garca-Arencibia, M.; de Lago, E.; Finetti, S.; Decio,
A.; Fernndez-Ruiz, J. Cannabinoids and neuroprotection in basal
ganglia disorders. Mol. Neurobiol., 2007, 36, 82-91.
[10] Fernndez-Ruiz, J.; Gonzlez, S. Handbook of Experimental
Pharmacology. In Cannabinoids; Pertwee, R.G., Ed.; Springer-
Verlag: Heidelberg, Germany, 2005, Vol. 168, pp. 479-507.
[11] Gerdeman, G.L.; Fernndez-Ruiz, J. In: Cannabinoids and the Brain;
Kofalvi, A.; Ed.; Springer-Verlag: Heidelberg, Germany, 2008, pp.
423-483.
[12] Esposito, E.; Di Matteo, V.; Di Giovanni, G. Death in the
substantia nigra: a motor tragedy. Expert Rev. Neurother., 2007, 7,
677-697.
[13] Garca-Arencibia, M.; Garca, C.; Kurz, A.; Rodrguez-Navarro,
J.A.; Gispert-Snchez, S.; Mena, M.A.; Auburger, G.; Garca de
Ybenes, J.; Fernndez-Ruiz, J. Cannabinoid CB1 receptors are
early down-regulated followed by a further up-regulation in the
basal ganglia of mice with deletion of specific park genes. J.
Neural Transm. Suppl., 2009, 73, 269-275.
[14] van der Stelt, M.; Veldhuis, W.B.; Maccarrone, M.; Bar, P.R.;
Nicolay, K.; Veldink, G.A.; Di Marzo, V.; Vliegenthart, J.F. Acute
neuronal injury, excitotoxicity, and the endocannabinoid system.
Mol. Neurobiol., 2002, 26, 317-346.
[15] Centonze, D.; Finazzi-Agro, A.; Bernardi, G.; Maccarrone, M. The
endocannabinoid system in targeting inflammatory neurodegenera-
tive diseases. Trends Pharmacol. Sci. 2007, 28, 180-187.
438 CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6
[16] Lastres-Becker, I.; Cebeira, M.; de Ceballos, M.; Zeng, B.-Y.;
Jenner, P.; Ramos, J.A.; Fernndez-Ruiz, J. Increased cannabinoid
CB1 receptor binding and activation of GTP-binding proteins in the
basal ganglia of patients with Parkinson's syndrome and of MPTP-
treated marmosets. Eur. J. Neurosci., 2001, 14, 1827-1832.
[17] Pisani, A.; Fezza, F.; Galati, S.; Battista, N.; Napolitano, S.;
Finazzi-Agro, A.; Bernardi, G.; Brusa, L.; Pierantozzi, M.;
Stanzione, P.; Maccarrone, M. High endogenous cannabinoid
levels in the cerebrospinal fluid of untreated Parkinson's disease
patients. Ann. Neurol., 2005, 57, 777-779.
[18] Romero, J.; Berrendero, F.; Prez-Rosado, A.; Manzanares, J.;
Rojo, A.; Fernndez-Ruiz, J.; de Ybenes, J.G.; Ramos, J.A.
Unilateral 6-hydroxydopamine lesions of nigrostriatal
dopaminergic neurons increased CB1 receptor mRNA levels in the
caudate-putamen. Life Sci., 2000, 66, 485-494.
[19] Gonzlez, S.; Mena, M.A.; Lastres-Becker, I.; Serrano, A.; de
Ybenes, J.G.; Ramos, J.A.; Fernndez-Ruiz, J. Unilateral 6-
hydroxydopamine lesions of nigrostriatal dopaminergic neurons
increased CB1 receptor mRNA levels in the caudate-putamen.
Brain Res., 2005, 1046, 195-206.
[20] Di Marzo, V.; Hill, M.P.; Bisogno, T.; Crossman, A.R.; Brotchie,
J.M. Enhanced levels of endogenous cannabinoids in the globus
pallidus are associated with a reduction in movement in an animal
model of Parkinson's disease. FASEB J., 2000, 14, 1432-1438.
[21] Gubellini, P.; Picconi, B.; Bari, M.; Battista, N.; Calabresi, P.;
Centonze, D.; Bernardi, G.; Finazzi-Agr, A.; Maccarrone, M.
Experimental parkinsonism alters endocannabinoid degradation:
implications for striatal glutamatergic transmission. J. Neurosci.,
2002, 22, 6900-6907.
[22] van der Stelt, M.; Fox, S.H.; Hill, M.; Crossman, A.R.; Petrosino,
S.; Di Marzo, V.; Brotchie, J.M. A role for endocannabinoids in the
generation of parkinsonism and levodopa-induced dyskinesia in
MPTP-lesioned non-human primate models of Parkinson's disease.
FASEB J., 2005, 19, 1140-1142.
[23] Maccarrone, M.; Gubellini, P.; Bari, M.; Picconi, B.; Battista, N.;
Centonze, D.; Bernardi, G.; Finazzi-Agro, A.; Calabresi, P.
Levodopa treatment reverses endocannabinoid system
abnormalities in experimental parkinsonism. J. Neurochem., 2003,
85, 1018-1025.
[24] Fernndez-Ruiz, J.; Romero, J.; Velasco, G.; Toln, R.M.; Ramos,
J.A.; Guzmn, M. Cannabinoid CB2 receptor: a new target for
controlling neural cell survival? Trends Pharmacol. Sci., 2007, 28,
39-45.
[25] Fernndez-Ruiz, J.; Pazos, M.R.; Garca-Arencibia, M.; Sagredo,
O.; Ramos, J.A. Role of CB2 receptors in neuroprotective effects of
cannabinoids. Mol. Cell. Endocrinol., 2008, 286, S91-S96.
[26] McGeer, P.L.; McGeer, E.G. Glial reactions in Parkinson's disease.
Mov. Disord., 2008, 23, 474-483.
[27] Garca-Arencibia, M.; Gonzlez, S.; de Lago, E.; Ramos, J.A.;
Mechoulam, R.; Fernndez-Ruiz, J. Evaluation of the
neuroprotective effect of cannabinoids in a rat model of Parkinson's
disease: importance of antioxidant and cannabinoid receptor-
independent properties. Brain Res., 2007, 1134, 162-170.
[28] Romero, J.; Lastres-Becker, I.; de Miguel, R.; Berrendero, F.;
Ramos, J.A.; Fernndez-Ruiz, J. The endogenous cannabinoid
system and the basal ganglia. biochemical, pharmacological, and
therapeutic aspects. Pharmacol. Ther., 2002, 95, 137-152.
[29] Consroe, P. Brain cannabinoid systems as targets for the therapy of
neurological disorders. Neurobiol. Dis., 1998, 5, 534-551.
[30] Mller-Vahl, K.R.; Kolbe, H.; Schneider, U.; Emrich, H.M.
Cannabis in movement disorders. Forsch Komplementarmed.,
1999, 6, 23-27.
[31] Venderov, K.; Ruzicka, E.; Vorsek, V.; Visnovsk, P. Survey on
cannabis use in Parkinson's disease: subjective improvement of
motor symptoms. Mov. Disord., 2004, 19, 1102-1106.
[32] Meschler, J.P.; Howlett, A.C.; Madras, B.K. Cannabinoid receptor
agonist and antagonist effects on motor function in normal and 1-
methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated non-
human primates. Psychopharmacology, 2001, 156, 79-85.
[33] Mesnage, V.; Houeto, J.L.; Bonnet, A.M.; Clavier, I.; Arnulf, I.;
Cattelin, F.; Le Fur, G.; Damier, P.; Welter, M.L.; Agid, Y.
Neurokinin B, neurotensin, and cannabinoid receptor antagonists and
Parkinson disease. Clin. Neuropharmacol., 2004, 27, 108-110.
[34] Fernndez-Espejo, E.; Caraballo, I.; Rodrguez de Fonseca, F.; El
Banoua, F.; Ferrer, B.; Flores, J.A.; Galn-Rodrguez, B.
Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only
Garca-Arencibia et al.
in rats with very severe nigral lesion in experimental parkinsonism.
Neurobiol. Dis., 2005, 18, 591-601.
[35] Gonzlez, S.; Scorticati, C.; Garca-Arencibia, M.; de Miguel, R.;
Ramos, J.A.; Fernndez-Ruiz, J. Effects of rimonabant, a selective
cannabinoid CB1 receptor antagonist, in a rat model of Parkinson's
disease. Brain Res., 2006, 1073-1074, 209-219.
[36] Garca-Arencibia, M.; Ferraro, L.; Tanganelli, S.; Fernndez-Ruiz, J.
Enhanced striatal glutamate release after the administration of
rimonabant to 6-hydroxydopamine-lesioned rats. Neurosci. Lett.,
2008, 438, 10-13.
[37] de Lago, E.; de Miguel, R.; Lastres-Becker, I.; Ramos, J.A.;
Fernndez-Ruiz, J. Involvement of vanilloid-like receptors in the
effects of anandamide on motor behavior and nigrostriatal
dopaminergic activity: in vivo and in vitro evidence. Brain Res.,
2004, 1007, 152-159.
[38] Mezey, E.; Toth, Z.E.; Cortright, D.N.; Arzubi, M.K.; Krause, J.E.;
Elde, R.; Guo, A.; Blumberg, P.M.; Szallasi, A. Distribution of
mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like
immunoreactivity, in the central nervous system of the rat and
human. Proc. Natl. Acad. Sci. USA, 2000, 97, 3655-3660.
[39] Lastres-Becker, I.; Molina-Holgado, F.; Ramos, J.A.; Mechoulam,
R.; Fernndez-Ruiz, J. Cannabinoids provide neuroprotection against
6-hydroxydopamine toxicity in vivo and in vitro: relevance to
Parkinson's disease. Neurobiol. Dis. 2005, 19, 96-107.
[40] Brotchie, J.M. CB1 cannabinoid receptor signalling in Parkinson's
disease.Curr. Opin. Pharmacol., 2003, 3, 54-61.
[41] Brotchie, J.M. The neural mechanisms underlying levodopa-induced
dyskinesia in Parkinson's disease. Ann. Neurol., 2000, 47, S105-
S114.
[42] Fox, S.H.; Lang, A.E.; Brotchie, J.M. Translation of
nondopaminergic treatments for levodopa-induced dyskinesia from
MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys
to success and roads to failure. Mov. Disord., 2006, 21, 1578-1594.
[43] Cao, X.; Liang, L.; Hadcock, J.R.; Iredale, P.A.; Griffith, D.A.;
Menniti, F.S.; Factor, S.; Greenamyre, J.T.; Papa, S.M. Blockade of
cannabinoid type 1 receptors augments the antiparkinsonian action of
levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine-treated rhesus monkeys. J. Pharmacol. Exp. Ther.,
2007, 323, 318-326.
[44] Brotchie, J.M. Adjuncts to dopamine replacement: a pragmatic
approach to reducing the problem of dyskinesia in Parkinson's
disease. Mov. Disord., 1998, 13, 871-876.
[45] Sieradzan, K.A.; Fox, S.H.; Hill, M.; Dick, J.P.; Crossman, A.R.;
Brotchie, J.M. Cannabinoids reduce levodopa-induced dyskinesia in
Parkinson's disease: a pilot study. Neurology, 2001, 57, 2108-2111.
[46] Fox, S.H.; Henry, B.; Hill, M.; Crossman, A.; Brotchie, J.M.
Stimulation of cannabinoid receptors reduces levodopa-induced
dyskinesia in the MPTP-lesioned nonhuman primate model of
Parkinson's disease. Mov. Disord., 2002, 17, 1180-1187.
[47] Ferrer, B.; Asbrock, N.; Kathuria, S.; Piomelli, D.; Giuffrida, A.
Effects of levodopa on endocannabinoid levels in rat basal ganglia:
implications for the treatment of levodopa-induced dyskinesias. Eur.
J. Neurosci., 2003, 18, 1607-1614.
[48] Saudo-Pea, M.C.; Patrick, S.L.; Khen, S.; Patrick, R.L.; Tsou, K.;
Walker, J.M. Cannabinoid effects in basal ganglia in a rat model of
Parkinson's disease. Neurosci. Lett., 1998, 248, 171-174.
[49] Saudo-Pea, M.C.; Tsou, K.; Walker, J.M. Motor actions of
cannabinoids in the basal ganglia output nuclei. Life Sci., 1999, 65,
703-713.
[50] Frankel, J.P.; Hughes, A.; Lees, A.J.; Stern, G.M. Marijuana for
parkinsonian tremor. J. Neurol. Neurosurg. Psychiatry, 1990, 53,
436-436.
[51] Martn, A.B.; Fernndez-Espejo, E.; Ferrer, B.; Gorriti, M.A.; Bilbao,
A.; Navarro, M.; Rodrguez de Fonseca, F.; Moratalla, R. Expression
and function of CB1 receptor in the rat striatum: localization and
effects on D1 and D2 dopamine receptor-mediated motor behaviors.
Neuropsychopharmacology, 2008, 33, 1667-1679.
[52] Meschler, J.P.; Howlett, A.C. Signal transduction interactions
between CB1 cannabinoid and dopamine receptors in the rat and
monkey striatum. Neuropharmacology, 2001, 40, 918-926.
[53] Anderson, L.A.; Anderson, J.J.; Chase, T.N.; Walters, J.R. The
cannabinoid agonists WIN 55,212-2 and CP 55,940 attenuate
rotational behavior induced by a dopamine D1 but not a D2 agonist
in rats with unilateral lesions of the nigrostriatal pathway. Brain
Res., 1995, 691, 106-114.
 Cannabinoids and Parkinsons Disease
[54] Saudo-Pea, M.C.; Force, M.; Tsou, K.; Miller, A.S.; Walker,
J.M. Effects of intrastriatal cannabinoids on rotational behavior in
rats: interactions with the dopaminergic system. Synapse, 1998, 30,
221-226.
[55] Kreitzer, A.C.; Malenka, R.C. Endocannabinoid-mediated rescue of
striatal LTD and motor deficits in Parkinson's disease models.
Nature, 2007, 445, 643-647.
[56] Fernndez-Ruiz, J.; Gonzlez, S.; Romero, J.; Ramos, J.A. In:
Cannabinoids as Therapeutics (MDT); Mechoulam, R., Ed.;
Birkhaser Verlag: Switzerland, 2005, pp. 79-109.
[57] de Lago, E.; Fernndez-Ruiz, J.; Ortega-Gutierrez, S.; Cabranes,
A.; Pryce, G.; Baker, D.; Lpez-Rodriguez, M.; Ramos, J.A.
UCM707, an inhibitor of the anandamide uptake, behaves as a
symptom control agent in models of Huntington's disease and
multiple sclerosis, but fails to delay/arrest the progression of
different motor-related disorders. Eur. Neuropsychopharmacol.,
2006, 16, 7-18.
[58] Locke, C.J.; Fox, S.A.; Caldwell, G.A.; Caldwell, K.A.
Acetaminophen attenuates dopamine neuron degeneration in
animal models of Parkinson's disease. Neurosci. Lett., 2008, 439,
129-133.
[59] Hgesttt, E.D.; Jnsson, B.A.; Ermund, A.; Andersson, D.A.;
Bjrk, H.; Alexander, J.P.; Cravatt, B.F.; Basbaum, A.I.; Zygmunt,
P.M. Conversion of acetaminophen to the bioactive
N-acylphenolamine AM404 via fatty acid amide hydrolase-
Received: September 29, 2009 Revised: October 8, 2009
View publication stats
CNS & Neurological Disorders - Drug Targets, 2009, Vol. 8, No. 6 439
dependent arachidonic acid conjugation in the nervous system.
J. Biol. Chem., 2005, 280, 31405-31412.
[60] Jimnez-del-Ro, M.; Daza-Restrepo, A.; Velez-Pardo, C. The
cannabinoid CP55,940 prolongs survival and improves locomotor
activity in Drosophila melanogaster against paraquat: implications
in Parkinson's disease. Neurosci. Res., 2008, 61, 404-411.
[61] Hampson, A.J.; Grimaldi, M.; Axelrod, J.; Wink, D. Cannabidiol
and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxi-
dants. Proc. Natl. Acad. Sci. USA, 1998, 95, 8268-8273.
[62] Sagredo, O.; Ramos, J.A.; Decio, A.; Mechoulam, R.; Fernndez-
Ruiz, J. Cannabidiol reduced the striatal atrophy caused 3-
nitropropionic acid in vivo by mechanisms independent of the
activation of cannabinoid, vanilloid TRPV1 and adenosine A2A
receptors. Eur. J. Neurosci., 2007, 26, 843-851.
[63] Wright, S. Cannabinoid-based medicines for neurological
disorders--clinical evidence. Mol. Neurobiol., 2007, 36, 129-136.
[64] Aguado, T.; Monory, K.; Palazuelos, J.; Stella, N.; Cravatt, B.;
Lutz, B.; Marsicano, G.; Kokaia, Z.; Guzmn, M.; Galve-Roperh, I.
The endocannabinoid system drives neural progenitor proliferation.
FASEB J., 2005, 19, 1704-1706.
[65] Galve-Roperh, I.; Aguado, T.; Palazuelos, J.; Guzmn, M. The
endocannabinoid system and neurogenesis in health and disease.
Neuroscientist, 2007, 13, 109-114.
[66] Maccarrone, M.; Battista, N.; Centonze, D. The endocannabinoid
pathway in Huntington's disease: a comparison with other
neurodegenerative diseases. Prog. Neurobiol., 2007, 81, 349-379.
Accepted: October 9, 2009