The Endocannabinoid System in Targeting Inflammatory Neurodegenerative Diseases

Thread starter #1
Diego Centonze1,2, Alessandro Finazzi-Agro` 3, Giorgio Bernardi1,2
and Mauro Maccarrone2,4
1 Neurological Clinics, Department of Neurosciences, University of Rome Tor Vergata, Rome 00133, Italy
2 European Center for Brain Research (CERC) and Santa Lucia Foundation, Rome 00196, Italy
3 Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome 00133, Italy
4 Department of Biomedical Sciences, University of Teramo, Teramo 64100, Italy

The classical divide between degenerative and
inflammatory disorders of the CNS is vanishing as
accumulating evidence shows that inflammatory processes
are important in the pathophysiology of primarily
degenerative disorders, and neurodegeneration complicates
primarily inflammatory diseases of the brain
and spinal cord. Here, we review the contribution of
degenerative and inflammatory processes to CNS disorders
such as Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, multiple sclerosis and
HIV-associated dementia. An early combination of neuroprotective
and anti-inflammatory approaches to these
disorders seems particularly desirable because isolated
treatment of one pathological process might worsen
another. We also discuss the apparently unique opportunity
to modify neurodegeneration and neuroinflammation
simultaneously by pharmacological manipulation of
the endocannabinoid systemin theCNSand in peripheral
immune cells. Current knowledge of this system and
its involvement in the above CNS disorders are also
reviewed.
Inflammation is linked to neurodegeneration
A strong link between inflammation and
neurodegeneration has recently emerged with evidence
indicating that the two processes coexist from the very
early stages of both classical neurodegenerative disorders
and classical inflammatory diseases of the CNS. Alzheimer's
disease (AD), Parkinson's disease (PD) and amyotrophic
lateral sclerosis (ALS) are among the best
examples of neurodegenerative disorders associated with
intense inflammation, whereas multiple sclerosis (MS) and
HIV-associated dementia are inflammatory disorders that
lead to diffuse neuronal damage (see Glossary). Indeed,
recognition of the inflammatory reaction accompanying
neurodegeneration and the neurodegeneration accompanying
inflammation is not new. For example, activation of
microglia and of astrocytes, which are part of the innate
immune system in the CNS, has been identified as a
cardinal feature of AD pathology in the brain. Similarly,
neuronal injury has been known to be involved in MS since
the first description of the disease by Charcot [1]. Such
findings did not attract much attention in the past, however,
because reactive gliosis was considered to be only an
unspecific, scar-like response to neuronal death during
degenerative damage, and neuronal loss was thought to be
a late consequence of axon demyelination in MS.
Recent discoveries have now imposed reconsideration of
the perceived relationship between inflammation and neurodegeneration,
by making it clear that one is not simply a
culmination of the other. Indeed, inflammation and neurodegeneration
seem to occur in parallel rather than in
series, and thus have a mutual influence on many neurological
diseases. Common molecular pathways that bring
these two processes together have been described [2,3], in
addition to the capacity of activated immune cells to
damage neurons in the absence of any antigen specificity
[4,5] and the ability of damaged neurons to trigger local
immune responses [6].
On the basis of these considerations, an early
combination of neuroprotective and anti-inflammatory
strategies seems a rational approach to CNS diseases,
irrespective of the nature of the primary insult. Such an
approach is particularly desirable because isolated treatment
of one pathological process might even worsen
another. In treatment of MS with interferon-b, for example,
the inflammatory component of the disease is controlled,
whereas neuronal survival can be negatively affected, by
this immunomodulatory agent [7].
In this review, we discuss the contribution of
inflammation to neurodegenerative diseases and, conversely,
that of degeneration to neuroinflammatory disorders.
In addition, we review the current knowledge of the endocannabinoid
system and its involvement in these CNS
disorders.
Inflammation in neurodegenerative disorders
The identification of brain astroglia and microglia as
important components of innate immunity has been crucial
to understanding the role of inflammation in neurodegenerative
disorders. Reactive gliosis, in fact, is well-known to
accompany both acute and chronic neuronal damage, but
its importance as part of a harmful inflammatory response
had been neglected until recently.
Activated astroglia can mediate both protective and
toxic effects during neurodegenerative diseases [8]. By
contrast, microglia have an active role in the defensive
attack against viruses and bacteria, but intense microglial
activation, such as that produced to clear up apoptotic cells
or neuron debris during neurodegenerative disorders, can
be detrimental to the survival of neighboring cells. Cytokines,
bioactive peptides produced through complement
activation, and other soluble factors mediate the toxic
effects of microglia-produced inflammatory milieu on
neurons [3,9]. Indeed, several inflammatory mediators
are increased in the brain tissues or cerebrospinal fluid
of individuals affected with AD, PD and ALS [3,9].
Alzheimer's disease
Since the discovery of MHC class II antigens in the
microglia surrounding amyloid plaques and dystrophic
neuritis, several inflammatory processes have been described
in the brains of individuals affected with AD [10].
These processes include complement and glial cell activation,
acute phase protein synthesis, and chemokine expression
[3,9]. The role of inflammatory neurodegeneration
in AD is supported by studies demonstrating associations
between the disease and polymorphisms in genes encoding
some cytokines or acute phase proteins [11], and by data
showing the protective action against the disease exerted
by anti-inflammatory agents [12].
Parkinson's disease
More recently, the importance of neuroinflammation in PD
pathophysiology has also emerged. Indeed, activated
microglia have been described in close proximity to degenerating
dopamine neurons in individuals with PD, and
activation of microglia into the substantia nigra has been
shown to cause selective destruction of dopamine neurons
[13]. Furthermore, experimental parkinsonism, induced by
neurotoxins specific to dopamine neurons, is coupled with
the activation of nigral and striatal microglia and with the
production of proinflammatory molecules. In addition, in
models of PD, inhibition of microglia is neuroprotective [3].
As in AD, polymorphisms of some cytokines have been
identified as risk factors for PD, whereas epidemiological
studies have reported that chronic users of anti-inflammatory
drugs have a decreased risk for PD [14].
By contrast, recent data have shown that prior delivery
of a peripheral, pro-inflammatory stimulus induces neuroprotection
in a rodent model of PD. This protective effect
is paralleled by a concomitant reduction in the associated
microglial response and moderate, transient increases in
cytokine levels at the sites of neurodegeneration [15].
Therefore, modulation of the neuroprotective effect of peripheral
inflammation might be exploited for improving the
treatment of PD.
Amyotrophic lateral sclerosis
A strong inflammatory process has been described in the
brains of individuals with ALS, and a correlation between
the intensity of inflammation and progression of the disease
has also been observed [16]. Studies on postmortem
spinal cord tissues have found that the number of activated
microglia is greater in individuals with ALS than in controls
[17]. Further evidence of microglial involvement in
ALS pathology has come from studies showing pro-survival
effects of the pharmacological suppression of microglial
activation on rat spinal cord neurons exposed to cerebrospinal
fluid from individuals with ALS [18]. Lastly, antiinflammatory
agents prolong the survival of transgenic
mice expressing human SOD1 with a G93A mutation
(hSOD1G93A), an animal model of familial ALS [19],
and a clinical trial exploring the effect of a immunomodulatory
agent in individuals with ALS is currently ongoing
[20].
Neurodegeneration in inflammatory disorders
Neurons are unusual targets of inflammatory diseases.
Normally, in fact, theydo notexpressMHCmolecules,which
is an essential requirement for cell susceptibility to immune
attacks [1]. Nevertheless, the neuronal compartment of the
CNS is frequently injured during inflammatory responses
against glial cells, as is the case inMS, a chronic inflammatory
disease of oligodendrocytes and myelin sheaths, and in
HIV-associateddementia,adisorder secondary toHIVinfection
of microglia. Inflammatory autoimmune responses can
also counteract neurodegeneration, however, indicating
that the relationship between the two processes is far more
complex [21].
Multiple sclerosis
Accumulating evidence indicates that neurodegeneration
might occur not only as a late consequence of axon demyelination
in MS, but also as a very early event in the course
of the disease. Accordingly, neuronal damage and axonal
loss are common and abundant in MS, affecting both overt
inflammatory lesions and normal-appearing white matter
[22]. In addition, neuronal loss in gray matter also contributes
to brain damage in MS, as indicated by the extensive
cortical and subcortical deposition of iron, caudate
atrophy and neuronal apoptosis observed in MS brains.
Several mechanisms have been proposed to explain the
massive involvement of neurons in MS, including axon
transection by cytotoxic T cells and damage by soluble
products released by resident and invading inflammatory
cells. These products include axon-specific antibodies,
complement, nitric oxide, oxygen radicals, proteases and
eicosanoids [23]. Acquired neuronal channelopathies,
altered activity of Na+—Ca2+ exchangers, glutamatemediated
excitotoxicity, intraneuronal Ca2+ accumulation
and inhibition of mitochondrial respiratory chain are other
crucial factors that contribute to neuronal damage during
the course of MS and experimental MS [23,24].
HIV-associated disease
HIV-associated dementia is characterized by severe brain
atrophy and neuronal apoptosis in the absence of the direct
localization of HIV in neurons. The mechanisms by which a
primary infection of glial cells damages neurons are not
fully understood, but the release of neurotoxic cytokines
and chemokines from activated astrocytes and microglia
seems to be important. The presence of chemokine receptors
on neurons indicates that they might have a role in
neuronal damage by favoring glutamate-mediated excitotoxicity
and Ca2+ entry through voltage-dependent Ca2+
channels. In addition, microglia and macrophages activated
by HIV seem to damage neurons through the release
of neurotoxins such as arachidonic acid, glutamate, tumor
necrosis factor-a and interleukin-1 [25].
Anti-inflammatory and neuroprotective effects of
endocannabinoids
A unique opportunity to improve inflammation and
neurodegeneration simultaneously might be offered by
pharmacological agents that can modulate the activity of
cannabinoid (CB) receptors (Box 1). Indeed, both CB receptor
subtypes, CB1 and CB2, are abundantly expressed in
neurons and in central and peripheral immune cells, and
regulate degeneration and inflammation in diseases of the
CNS. Despite the potential benefits of drugs acting on CB
receptors, however, their clinical use is hampered mainly
because of their psychotropic effects [26].
Progressive characterization of the biochemical
machinery that regulates the synthesis, transport and
degradation of the endogenous ligands of CB receptors —
namely, endocannabinoids — has prompted extensive investigations
into the therapeutic effects of agents targeting the
'endocannabinoid system' (ECS) in several pathological
conditions, including CNS degenerative and inflammatory
disorders [27—29]. In this context, we recall that the release
of endocannabinoids during neuronal injury might constitute
a protective response [30]. Indeed, exogenous and
endogenous cannabinoids have been shown to exert neuroprotection
in various in vitro and in vivo models of neuronal
injury [31,32].
This neuroprotective activity occurs through different
mechanisms, including (i) prevention of excitotoxicity by
CB1-receptor-mediated inhibition of glutamate-mediated
transmission via the closing of N- and P/Q-type Ca2+
channels; (ii) reduction of Ca2+ influx at both the preand
postsynaptic level, followed by inhibition of subsequent
noxious cascades; (iii) antioxidant activity, mainly
owing to the phenol group of various resorcinol-type cannabinoids;
(iv) suppression of the production of tumor
necrosis factor-a; (v) activation of the phosphatidylinositol
3-kinase and protein kinase B pathway; (vi) induction of
phosphorylation of extracellular regulated kinases; and
(vii) induction of the expression of transcription factors
and neurotrophins.
A central point of contention has been, and still
remains, the receptor dependency of (endo)cannabinoid
neuroprotection, because several not fully defined CB
receptors are certainly part of the ECS, and at present
we have only a vague idea about the possible interaction of
the (endo)cannabinoidswith these targets [31,32]. Several
elements of the ECS have been characterized so far
(Figure 1). The list of characterized ECS elements often
includes the type-1 vanilloid receptor (TRPV1), although
this receptor does not strictly belong to the ECS. In fact,
TRPV1 has emerged as a key target of the amide
N-arachidonoylethanolamine (AEA; also known as 'anandamide')
— the most prominent member of the endocannabinoids
— to such an extent that AEA is also considered
to be a true 'endovanilloid' [33]. Below, we summarize the
involvement of ECS components in neurodegenerative
disorders.
Alzheimer's disease
Stimulation of CB1, CB2, and non-CB1 or non-CB2
receptors (such as that obtained with cannabidiol) prevents
microglial activation and microglia-mediated neurotoxicity
and neurodegeneration in experimental models of
AD [34]. Similar effects can be achieved by increasing
endogenous levels of endocannabinoids through inhibition
of the cellular uptake of AEA (by compounds that we term
'AMT inhibitors') [35] (Table 1).
Parkinson's disease
Degeneration of dopamine neurons during experimental
PD can be reduced by agonists of CB1, CB2, and non-CB1
or non-CB2 receptors — an effect that involves modulating
the interactions between glial cells and neurons [36]. CB1
receptors, however, also exert detrimental effects on
dopamine cell survival by potentiating the toxic effects of
the TRPV1 agonist capsaicin [37]. It is thus conceivable
that endocannabinoids such as AEA, which activates
both TRPV1 and CB1 receptors [33], might contribute to
PD pathophysiology by favoring apoptosis of dopamine
neurons.
Amyotrophic lateral sclerosis
Pharmacological agonists of CB receptors and increased
levels of endocannabinoids, obtained through genetic
ablation of fatty acid amide hydrolase (FAAH) [38], exert
robust anti-inflammatory and neuroprotective effects in
hSOD1G93A mice, delaying disease progression [39,40].
The neuroprotective effects observed in hSOD1G93A mice
after pharmacological and genetic augmentation of endocannabinoids
levels seem to be selectively dependent on
stimulation of the CB2 receptor; by contrast, activation of
the CB1 receptor has a negative influence on motor neuron
survival [40].
Multiple sclerosis
The use of cannabis-based medicine for the treatment of
MS has a long history, and has been recently reviewed [41].
In models of experimental MS, stimulation of CB1 and of
CB2 receptors has been shown to be beneficial against the
inflammatory process [42,43], lending support to early
findings showing that individuals with MS experience a
reduction in the frequency of relapses when smoking marijuana
[44]. Anti-inflammatory effects have also been
reported in experimental MS in response to pharmacological
AMT inhibitors, which can increase levels of AEA
[45,46]. Interestingly, stimulation of CB1 receptors also
ensures neuroprotection in mice with experimental MS
[47].
HIV-associated dementia
Cannabinoids have been proposed to exert beneficial
effects in HIV-associated dementia, owing to their ability
to modulate microglia activation [48]; however, the
absence of reliable animal models of this disorder prevents
direct exploration of this possibility.
Therapeutic potential of ECS-targeting drugs in CNS
disorders
Although still at its infancy, exploration of the therapeutic
effects of drugs targeting endocannabinoid metabolism is
increasingly encouraging with evidence showing altered
levels of endocannabinoids in several pathological conditions
of the CNS [26—29]. There are now several
examples of the successful use of ECS-directed drugs to
alleviate the clinical symptoms of degenerative and inflammatory
neurological diseases in animal models [36,49]
(Table 1).
Promising results have been reported with AMT
inhibitors such as AM404 (see Chemical names), VDM11
and UCM707. Indeed, treatment with AM404 reduces the
neurochemical defects associated with neurodegenerative
damage, but this action seems to be due to the synthesis
of new AEA after the direct activation of TRPV1 by AM404,
rather than to AMT inhibition. Furthermore, AM404
also inhibits purified cyclooxygenase-1 and cyclooxygenase-
2 — and thus prostaglandin synthesis — in activated
macrophages [50]. Therefore, AM404 might also directly
curb the inflammatory component of neurological disorders.
Administration of AM404 or VDM11 has been
shown to reduce significantly the frequency of spontaneous
glutamate-mediated activity recorded from striatal
neurons in an experimental model of PD, thereby exerting
anti-excitotoxic effects. Notably, another AMT inhibitor,
UCM707, significantly protects mice against the excitotoxin
kainic acid. Similarly, systemic administration of
AM404 improves akinesia and sensorimotor orientation
— two anti-parkinsonian effects. Indeed, it has been found
that administration of AM404 and VDM11 in mice
suffering from chronic relapsing experimental allergic
encephalomyelitis, a model of MS, markedly ameliorates
spasticity.
Several studies have provided strong evidence that
FAAH, owing to its broad distribution, might represent
an attractive therapeutic target for the treatment of
neurological diseases (Table 1). For example, inhibition
of FAAH by URB597 can augment endogenous brain levels
of AEA and produce anxiolytic, analgesic and anti-nociceptive
actions. These effects are mediated by CB1 receptor
stimulation, suggesting that URB597 might exert not only
symptomatic but also neuroprotective effects in CNS disorders.
Similarly, AM374, another FAAH inhibitor, has
been shown to exert potent neuroprotective effects in vivo
and in vitro by enhancing CB1-dependent activation of
mitogen-activated protein kinase [51]. The advantage of
these compounds is that they do not seem to induce the
side-effects common to typical agonists of CB receptors,
such as hypomotility, catalepsy or hypothermia, because
they do not interact directly with CB receptors. Furthermore,
another selective and powerful FAAH inhibitor that
has been used for the treatment of pathological states is
OL135 — a reversible a-keto heterocyclic inhibitor that
enhances AEA-induced analgesia in vivo.
A recent study has demonstrated that the high level of
interferon-g in the CNS in mice affected with experimental
autoimmune encephalomyelitis (EAE), a model of MS,
disrupts endocannabinoid-mediated neuroprotection,
although functional CB receptors are maintained [52].
Therefore, this study provides additional support for the
concept that the balance between inflammation and
neurodegeneration has considerable bearing on the endocannabinoid
tone, and thus favors the use of FAAH
inhibitors to treat the inflammatory and neurodegenerative
damage associated with pathological conditions such
as MS.
By contrast, the recent discovery of potent and specific
inhibitors of diacylglycerol lipase (DAGL), such as O3841
[53] (Table 1), suggests that it could become possible to
dissect the contribution of 2-arachidonoylglycerol (2-AG)
and that of AEA to neurological disorders. In addition,
there is active search for selective inhibitors of monoacylglycerol
lipase (MAGL): the availability of such
inhibitors might be crucial to design therapeutic strategies
based on the preferential recruitment of one endocannabinoid
over the other depending on the clinical
context. Indeed, AEA and 2-AG have distinct pharmacological
profiles on CB1, CB2 and TRPV1 receptors; thus,
it can be anticipated that differential modulation of
endocannabinoid levels might be indicated in distinct
diseases. In general terms, the higher affinity of 2-AG
versus AEA for CB1 receptors [54], coupled with the fact
that AEA but not 2-AG binds to TRPV1 [33], suggests
that agents that can modulate 2-AG levels within the
CNS could be more suitable for treating diseases in
which the neurodegenerative aspect prevails over inflammation.
Stimulation of CB1 receptors, in fact, reduces
transmitter release at excitatory synapses and exerts
clear anti-excitotoxic effects [30]. By contrast, stimulation
of TRPV1 favors inflammation [27]; as a result,
modulation of AEA-dependent activation of vanilloid
receptors is likely to be more effective for treatment
of the inflammatory component of neurodegenerative
diseases [55]. These ideas can be formulated into a
working model of the modulation of degeneration and
inflammation in the CNS by the ECS (Figure 2).
In addition, 2-AG might further control the balance
between neurodegeneration and neuroinflammation at
the peripheral level, where CB2 receptors are most
abundant [54]. Unlike AEA, which is a weak partial
agonist for CB2 receptors, 2-AG fully activates these
receptors [56] and regulates the release and function
of cytokines [55]. As a result, drugs directed towards
DAGL or MAGL might be better suited to modulate the
contribution of peripheral cells to neurodegenerative
disorders. In the same context, it should be kept in mind
that essential activities of 2-AG that are independent
of those of AEA are emerging in both the CNS [57] and
the periphery [58]; therefore, an understanding of
MAGL and DAGL regulation and the role of these
lipases in maintaining the endocannabinoid tone
in vivo is of utmost importance, as it has been for
N-acylphosphatidylethanolamine (NAPE)-specific phospholipase
D (NAPE-PLD) [59] and FAAH [60,61] with
respect to AEA. Notably, it seems that our hypothesis
that a balance between CB receptors and TRPV1 modulates
the dual nature of neurological diseases finds a
nice parallel in pathological pain sensation, where it
has been demonstrated that TRPV1 functions to oppose
CB-receptor-dependent effects [62].
Concluding remarks and future perspectives
The role of the ECS in regulating brain activity during
physiological and pathological conditions is emerging. For
example, control of the cellular activity of AEA seems to be
largely dependent on its hydrolysis by FAAH, rather than
on its synthesis by Ca2+-dependent N-acyltransferase or
NAPE-PLD. Overall, it seems that modulating endocannabinoid
metabolism, rather than agonizing or antagonizing
CB and non-CB receptors, might be the way to
understand better the pathophysiological implications of
these bioactive lipids and to exploit them for therapeutic
purposes [27—29]. If not therapeutic agents per se, inhibitors
of NAPE-PLD, FAAH, AMT, DAGL or MAGL could be
used together with AEA or 2-AG analogs to lower the doses
or to shorten the treatment necessary in vivo to observe an
effect, and thus to minimize the possible psychotropic sideeffects
of endocannabinoids when they are used as pharmaceutical
agents. Along this line, novel compounds such
as cannabidiol, a major non-psychotropic constituent of
cannabis that does not bind to CB1 or CB2 receptors, have
promising anti-convulsive, anti-anxiety and anti-psychotic
properties [54]. The mechanism of action of cannabidiol
relies on AMT and FAAH inhibition, and on antioxidative
properties; as a result, this natural drug might be a lead
compound for the development of therapeutics against the
inflammatory component of neurodegenerative disorders.
Lastly, it seems necessary to recall that, first, several
endogenous endocannabinoids or endocannabinoid-like
compounds, whose functions are not understood, are present
in our body, and their biological activity might be
affected in unexpected ways by drugs that modulate known
or unknown proteins of the ECS; and second, metabolic
enzymes have been recently identified that hydrolyze AEA
analogs such as N-palmitoylethanolamine [63] and that
catalyze novel biosynthesis [64] or hydrolysis [65] pathways
of AEA, and it remains to be elucidated how these
pathways might contribute to the overall tone and biological
activity of endocannabinoids.
Acknowledgements
We thank all colleagues who have contributed over the years to our studies
of the endocannabinoid system in the CNS, and Natalia Battista and
Andrea Paradisi for the artwork. This work was supported by funding from
the Ministero dell'Istruzione, dell'Universita` e della Ricerca (FIRB 2006) to
D.C. and M.M., the Ministero della Salute (grants 2006) to D.C., the
Agenzia Spaziale Italiana (DCMC and MoMa projects) to A.F-A. and M.M.,
and the Fondazione TERCAS (Research Programs 2004 and 2005) to M.M.
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Source: The Endocannabinoid System in Targeting Inflammatory Neurodegenerative Diseases