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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 23, 2008
Contents
Endocannabinoid Signaling and Neuroinflammatory Diseases
Executive Editor: Mauro Maccarrone
Editorial: Pp. 2252-2253
“The Tools of the Trade” – An Overview
of the Pharmacology of the Endocannabinoid System Pp.
2254-2265
C.J. Fowler
[Abstract]
CNS Immune Surveillance and Neuroinflammation:
Endocannabinoids Keep Control Pp. 2266-2278
S.A. Wolf, S. Tauber and O. Ullrich
[Abstract]
Mechanisms of Control of Neuron Survival
by the Endocannabinoid System Pp. 2279-2288
I. Galve-Roperh, T. Aguado, J. Palazuelos and
M. Guzmán
[Abstract]
Expression and Function of the Endocannabinoid
System in Glial Cells Pp. 2289-2298
P. Massi, M. Valenti, D. Bolognini and D. Parolaro
[Abstract]
The Role of the Endocannabinoid System
in Alzheimer's Disease: Facts and Hypotheses Pp.
2299-2305
T. Bisogno and V. Di Marzo
[Abstract]
The Endocannabinoid System in Amyotrophic
Lateral Sclerosis Pp. 2306-2316
L.G. Bilsland and L. Greensmith
[Abstract]
The Endocannabinoid System in Huntington’s
Disease Pp. 2317-2325
M.R. Pazos, O. Sagredo and J. Fernández-Ruiz
[Abstract]
The Endocannabinoid System and Multiple
Sclerosis Pp. 2326-2336
D. Baker and G. Pryce
[Abstract]
The Endocannabinoid System in Parkinson’s
Disease Pp. 2337-2346
M. Di Filippo, B. Picconi, A. Tozzi, V.
Ghiglieri, A. Rossi and P. Calabresi
[Abstract]
Role of Cannabinoids and Endocannabinoids
in Cerebral Ischemia Pp. 2347-2361
C.J. Hillard
[Abstract]
Endocannabinoids in Liver Disease and
Hepatic Encephalopathy Pp. 2362-2369
I. Magen, Y. Avraham, E. Berry and R. Mechoulam
[Abstract]
The Endocannabinoid System in Peripheral
Lymphocytes as a Mirror of Neuroinflammatory Diseases
Pp. 2370-2382
D. Centonze, L. Battistini and M. Maccarrone
[Abstract]
Abstracts
[Back to top]
Editorial: Endocannabinoid Signaling and
Neuroinflammatory Diseases
Endocannabinoids are endogenous agonists of cannabinoid
receptors, and comprise amides, esters and ethers of long
chain polyunsaturated fatty acids. Anandamide (N
arachidonoylethanolamine) and 2-arachidonoylglycerol are the
best studied members of this new class of lipid mediators
[1]. It is now widely accepted that the in vivo concentration
and biological activity of endocannabinoids are largely dependent
on a “metabolic control”. Therefore, the proteins
that synthesize, transport and degrade endocannabinoids, and
that together with the target receptors form the so-called
“endocannabinoid system (ECS)”, are the focus
of intense research. This new system will be presented in
this Hot Topic issue of Current Pharmaceutical
Design, in order to put in a better perspective the role
of endocannabinoid signaling in the immune surveillance of
the central nervous system (CNS) [2], and in the control of
neuronal [3] and glial [4] cell survival and death. The impact
of ECS on neuroinflammatory diseases like Alzheimer’s
disease (AD) [5], amyotrophic lateral sclerosis (ALS) [6],
Huntington’s disease (HD) [7], multiple sclerosis (MS)
[8], and Parkinson’s disease (PD) [9], as well as in
pathological conditions like ischemia/ repurfusion injury
[10] and encephalopathia [11], will be also presented in detail
in specific chapters, contributed by leading scientists in
the field. In addition, the pharmacology of synthetic and
plant-derived agonists and antagonists of endocannabinoid
receptors, or of inhibitors of endocannabinoid metabolism
[12], will be discussed in the context of their potential
exploitation as therapeutics, able to delay or arrest the
onset and/or progression of neuroinflammatory disorders. Finally,
ECS alterations in blood cells that mirror CNS dysfunctions,
and thus might be exploited as diagnostic markers or therapeutic
targets of neuroinflammatory diseases, will be reviewed [13].
It should be recalled that the classical distinction between
degenerative and inflammatory disorders of the CNS is vanishing,
because growing evidence demonstrates that inflammatory processes
are important in the pathophysiology of primarily degenerative
disorders, and conversely neurodegeneration complicates primarily
inflammatory diseases of the brain and spinal cord. In particular,
evidence has been accumulated to suggest that these two processes
coexist from the very early stages of both classical neurodegenerative
disorders and classical inflammatory diseases of the CNS.
As a matter of fact, recognition of the inflammatory reaction
accompanying neurodegeneration, and of the neurodegeneration
accompanying inflammation, is not unprecedented. 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 (reviewed
in ref. [14]). Yet, such findings did not attract much attention
in the past, because reactive gliosis was considered 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. Later discoveries
have imposed reconsideration of the perceived relationship
between inflammation and neurodegeneration, and common molecular
pathways that bring these two processes together have been
described [15, 16]. Also the capacity of activated immune
cells to damage neurons in the absence of any antigen specificity
[17, 18], and the ability of damaged neurons to trigger local
immune responses [19], has been clearly demonstrated. Recently,
the contribution of degenerative and inflammatory processes
to CNS disorders such as AD, ALS, PD, MS and HIV-associated
dementia has been extensively reviewed [20]. It should be
highlighted that AD, ALS and PD are among the best examples
of neurodegenerative disorders associated with intense inflammation,
whereas MS and HIV-associated dementia are inflammatory disorders
that lead to diffuse neuronal damage. Interestingly, 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.
In this context, ECS seems to offer the apparently unique
opportunity to modify neurodegeneration and neuroinflammation
simultaneously, by pharmacological manipulation of its different
elements (i.e., receptors, purported transporters and/or metabolic
enzymes), both in the CNS and in peripheral immune cells (see
ref. [21] for a comprehensive review). The relevance of these
findings for human health is demonstrated also by the interest
that the scientific community has attached to the role of
endocannabinoids in neurodegeneration and neuroinflammation,
compared to other disease conditions. Table 1
summarizes the results of a medline search through the PubMed,
in contiguous 5-year-time windows, starting from the year
after the discovery of anandamide [22]. It seems evident that
the interest towards neurodegenerative and neuroinflammatory
diseases steadly increased over the years, to such an extent
that approximately 15% of all studies on endocannabinoids
and disease have been represented by these pathologies in
the 2003 - 2007 time window (Table 1). Incidentally,
the impact of endocannabinoids on degeneration and inflammation
has been the focus of approximately 52% of all studies on
endocannabinoids and disease (Table 1). On
this basis, I believe that this book is really timely and
of broad interest, and I hope that it can foster novel ideas
within the scientific community.
I wish to dedicate this theme issue to my wife, Gianna, and
to my children, Giuseppe and Claudia.
References
[1] Piomelli D. The molecular logic of endocannabinoid signalling.
Nat Rev Neurosci 2003; 4: 873-84.
[2] Fowler CJ. “The tools of the trade” –
an overview of the pharmacology of the endocannabinoid system.
Curr Pharm Des 2008; 14(23): 2254-2265.
[3] Wolf S, Tauber S, Ullrich O. CNS immune surveillance and
neuroinflammation: endocannabinoids keep control. Curr Pharm
Des 2008; 14(23): 2266-2278.
[4] Galve-Roperh I, Aguado T, Palazuelos J, Guzmán
M. Mechanisms of control of neuronal survival by the endocannabinoid
system. Curr Pharm Des 2008; 14(23): 2279-2288.
[5] Massi P, Valenti M, Bolognini D, Parolaro D. Control of
glial cell survival and death by endocannabinoids. Curr Pharm
Des 2008; 14(23): 2289-2298.
[6] Bisogno T, Di Marzo R. The role of the endocannabinoid
system in Alzheimer’s disease: facts and hypotheses.
Curr Pharm Des 2008; 14(23): 2299-2305.
[7] Bilsland LG, Greensmith L. The endocannabinoid system
in amyotrophic lateral sclerosis. Curr Pharm Des 2008; 14(23):
2306-2316.
[8] Pazos MR, Sagredo O, Fernandez-Ruiz J. The endocannabinoid
system in Huntington’s disease. Curr Pharm Des 2008;
14(23): 2317-2325.
[9] Pryce G, Baker D. Endocannabinoids and multiple sclerosis.
Curr Pharm Des 2008; 14(23): 2326-2336.
[10] Di Filippo M, Picconi B, Tozzi A, Ghiglieri V, Rossi
A, Calabresi P. The endocannabinoid system in Parkinson’s
disease. Curr Pharm Des 2008; 14(23): 2337-2346.
[11] Hillard C. Roles of the cannabinoids and endocannabinoids
in cerebral ischemia. Curr Pharm Des 2008; 14(23): 2347-2361.
[12] Magen I, Avraham Y, Berry E, Mechoulam E. Endocannabinoids
in liver disease and hepatic encephalopathy. Curr Pharm Des
2008; 14(23): 2362-2369.
[13] Centonze D, Battistini L, Maccarrone M. The endocannabinoid
system in peripheral lymphocytes as a mirror of neuroinflammatory
diseases. Curr Pharm Des 2008; 14(23): 2370-2380.
[14] Zipp F, Aktas O. The brain as a target of inflammation:
common pathways link inflammatory and neurodegenerative diseases.
Trends Neurosci 2006; 29: 518-27.
[15] Aktas O, Smorodchenko A, Brocke S, Infante-Duarte C,
Schulze Topphoff U, Vogt J, et al. Neuronal damage
in autoimmune neuroinflammation mediated by the death ligand
TRAIL. Neuron 2005; 46: 421-32.
[16] Block ML, Hong JS. Microglia and inflammationmediated
neurodegeneration: multiple triggers with a common mechanism.
Prog Neurobiol 2005; 76: 77-98.
[17] Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and
neuronal injury. Nat Rev Immunol 2005; 5: 629-40.
[18] Linker RA, Rott E, Hofstetter HH, Hanke T, Toyka KV,
Gold R. EAE and beta-2-microglobulin-deficient mice: axonal
damage is not dependent on MHC-I restricted immune responses.
Neurobiol Dis 2005; 19: 218-28.
[19] Babcock AA, Kuziel WA, Rivest S, Owens T. Chemokine expression
by glial cells directs leukocytes to sites of axonal injury
in the CNS. J Neurosci 2003; 23: 7922-30.
[20] Maccarrone M, Battista N, Centonze D. The endocannabinoid
pathway in Huntington’s disease: a comparison with other
neurodegenerative diseases. Prog Neurobiol 2007; 81: 349-79.
[21] Centonze D, Finazzi-Agrò A, Bernardi G, Maccarrone
M. The endocannabinoid system in targeting inflammatory neurodegenerative
diseases. Trends Pharmacol Sci 2007; 28: 180-7.
[22] Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA,
Griffin G, et al. Isolation and structure of a brain
constituent that binds to the cannabinoid receptor. Science
1992; 258: 1946-9.
Mauro Maccarrone
Department of Biomedical Sciences
University of Teramo
Piazza A. Moro 45
64100 Teramo
Italy
Tel: 39-0861-266875
Fax: 39-0861-266877
E-mail: mmaccarrone@unite.it
[Back to top]
“The Tools of the Trade” – An Overview
of the Pharmacology of the Endocannabinoid System
C.J. Fowler
The endocannabinoid system can be manipulated pharmacologically
in a variety of ways, including directly acting agonists and
inverse agonists, and indirectly acting compounds which affect
the synthesis, cellular accumulation and metabolism of the
two main endocannabinoids, anandamide and 2-arachidonoylglycerol.
In this overview, the most commonly used compounds are discussed,
primarily with respect to their targets of action and to their
selectivities vis a vis “off targets”. For direct
acting compounds such as cannabinoid receptor agonists, it
is suggested that the use of several compounds with different
chemical structures at relevant doses or concentrations is
likely to minimise the risk of misinterpreting an “off
target” effect as being an action mediated by cannabinoid
receptors. For indirectly acting compounds, the same reasoning
applies, and in the case of compounds affecting the accumulation
of anandamide, it is important to recognize that the molecular
target of these compounds is far from clear. Nonetheless,
judicious use of the array of pharmacological tools currently
available, and combination of these tools with RNA interference
techniques and the use of genetically modified animals, provides
a powerful approach with which to characterize the endocannabinoid
system in the body.
[Back to top]
CNS Immune Surveillance and Neuroinflammation: Endocannabinoids
Keep Control
S.A. Wolf, S. Tauber and O. Ullrich
To avoid inflammatory escalation, the central nervous system
(CNS) harbors an impressive arsenal of cellular and molecular
mechanisms enabling strict control of immune reactions. We
here summarize studies suggesting that the old paradigm of
the “CNS immune privilege” is overly simplistic.
The immune system is allowed to keep the CNS under surveillance,
but in a strictly controlled, limited and well-regulated manner.
The first line of defense lies outside the brain parenchyma
to spare neuronal tissue from the detrimental effects of an
inflammatory immune response. As a second line of defense
neuroinflammation is unavoidable when pathogens infiltrate
the brain or the CNS-immune-homeostasis fails. Inflammation
in the CNS is often accompanied by divers brain pathologies.
We here review recent strategies to maintain brain homeostasis
and modulate neuroinflammation. We focus on Multiple Sclerosis
as an example of a complex neuroin-flammatory disease. In
the past years, several in vitro, in vivo and clinical
studies suggested that the endocannabinoid system participates
crucially in the immune control and protection of the CNS.
We discuss here the endocannabinoid system as a key regulator
mechanism of the cross talk between brain and the immune system
as well as its potential as a therapeutic target.
[Back to top]
Mechanisms of Control of Neuron Survival by the Endocannabinoid
System
I. Galve-Roperh, T. Aguado, J. Palazuelos and
M. Guzmán
Endocannabinoids act as retrograde messengers that, by inhibiting
neurotransmitter release via presynaptic CB1
cannabinoid receptors, regulate the functionality of many
synapses. In addition, the endocannabinoid system participates
in the control of neuron survival. Thus, CB1
receptor activation has been shown to protect neurons from
acute brain injury as well as in neuroinflammatory conditions
and neurodegenerative diseases. Nonetheless, some studies
have reported that cannabinoids can also exert neurotoxic
actions. Cannabinoid neuroprotective activity relies on the
inhibition of glutamatergic neurotransmission and on other
various mechanisms, and is supported by the observation that
the brain overproduces endocannabinoids upon damage. Coupling
of neuronal CB1 receptors
to cell survival routes such as the phosphatidylinositol 3-kinase/Akt
and extracellular signal-regulated kinase pathways may contribute
to cannabinoid neuroprotective action. These prosurvival signals
occur, at least in part, by the crosstalk between CB1
receptors and growth factor tyrosine kinase receptors. Besides
promoting neuroprotection, a role for the endocannabinoid
system in the control of neurogenesis from neural progenitors
has been put forward. In addition, activation of CB2
cannabinoid receptors on glial cells may also participate
in neuroprotection by limiting the extent of neuroinflammation.
Altogether, these findings support that endocannabinoids constitute
a new family of lipid mediators that act as instructive signals
in the control of neuron survival.
[Back to top]
Expression and Function of the Endocannabinoid System in Glial
Cells
P. Massi, M. Valenti, D. Bolognini and D. Parolaro
In the last few years the role and significance of the glia
in CNS function and pathology have been drastically reassessed.
Glial cells physiology appears very different in healthy versus
pathological brain and the recent identification of cannabinoid
receptors and their endogenous ligands in glia has triggered
a number of studies exploring the role of (endo)cannabinoid
system in glia functionality and disease. (Endo)cannabinoids
exert their effects in these cells directly affecting some
important peculiar functions of the glia and actively promoting
biochemical signals ending in a prosurvival fate for these
cells. By contrast, (endo)cannabinoids induce a selective
death in glia-derived tumor cells. Of special physiological
and therapeutic relevance is the reported ability of glial
cells during neuropathological conditions to release an increased
amount of endocannabinoids and to overexpress cannabinoid
receptors. This evidence has suggested that the endocannabinoids
production by glial cells may constitute an endogenous defense
mechanism preventing the propagation of neuroinflammation
and cell damage. The present paper will review the evidence
supporting the regulatory role of (endo)cannabinoids in glia
function, holding in consideration their therapeutic potential
as neuroprotective and/or anticancer agents.
[Back to top]
The Role of the Endocannabinoid System in Alzheimer's Disease:
Facts and Hypotheses
T. Bisogno and V. Di Marzo
Unlike other neuroinflammatory disorders, like Parkinson’s
disease, Huntington’s disease and multiple sclerosis,
little is still known of the role of the endocannabinoid system
in Alzheimer’s disease (AD). This is partly due to the
poor availability of animal models that are really relevant
to the human disease, and to the complexity of AD as compared
to other neurological states. Nevertheless, the available
data indicate that endocannabinoids are likely to play in
this disorder a role similar to that suggested in other neurodegenerative
diseases, that is, to represent an endogenous adaptive response
aimed at counteracting both the neurochemical and inflammatory
consequences of β-amyloid-induced
tau protein hyperactivity, possibly the most important
underlying cause of AD. Furthermore, plant and synthetic cannabinoids,
and particularly the non-psychotropic cannabidiol, might also
exert other, non-cannabinoid receptor-mediated protective
effects, including, but not limited to, anti-oxidant actions.
There is evidence, from in vivo studies on β-amyloid-induced
neurotoxicity, also for a possible causative role of endocannabinoids
in the impairment in memory retention, which is typical of
AD. This might open the way to the use of cannabinoid receptor
antagonists as therapeutic drugs for the treatment of cognitive
deficits in the more advanced phases of this disorder. The
scant, but nevertheless important literature on the regulation
and role of the endocannabinoid system in AD, and on the potential
treatment of this disorder with cannabinoids and endocannabinoid-based
drugs, are discussed in this mini-review.
[Back to top]
The Endocannabinoid System in Amyotrophic Lateral Sclerosis
L.G. Bilsland and L. Greensmith
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative
condition characterised by the selective loss of motor neurons
from the spinal cord, brainstem and motor cortex. Although
the pathogenic mechanisms that underlie ALS are not yet fully
understood, there is significant evidence that several neurotoxic
mechanisms including excitotoxicity, inflammation and oxidative
stress, all contribute to disease pathogenesis. Furthermore,
recent results have established that although primarily a
motor neuron specific disorder, ALS is not cell-autonomous
and non-neuronal cells including astroglia and microglia play
a critical role in mechanism of disease. Currently the only
licensed therapy available for the treatment of ALS is the
anti-glutamatergic agent Riluzole, which has limited therapeutic
effects. However, there is increasing evidence that cannabinoids
and manipulation of the endocannabinoid system may have therapeutic
value in ALS, in addition to other neurodegenerative conditions.
Cannabinoids exert anti-glutamatergic and anti-inflammatory
actions through activation of the CB1
and CB2 receptors, respectively.
Activation of CB1 receptors
may therefore inhibit glutamate release from presynaptic nerve
terminals and reduce the postsynaptic calcium influx in response
to glutamate receptor stimulation. Meanwhile, CB2
receptors may influence inflammation, whereby receptor activation
reduces microglial activation, resulting in a decrease in
microglial secretion of neurotoxic mediators. Finally, cannabinoid
agents may also exert anti-oxidant actions by a receptor-independent
mechanism. Therefore the ability of cannabinoids to target
multiple neurotoxic pathways in different cell populations
may increase their therapeutic potential in the treatment
of ALS. Recent studies investigating this potential in models
of ALS, in particular those that focus on strategies that
activate CB2 receptors, are
discussed in this review.
[Back to top]
The Endocannabinoid System in Huntington’s Disease
M.R. Pazos, O. Sagredo and J. Fernández-Ruiz
The hypokinetic profile of certain cannabinoid agonists
becomes these compounds as promising medicines to attenuate
the hyperkinesia that characterizes the first grades of Huntington’s
disease (HD) and that represents the major neurological abnormality
in this disease. The fact that CB1
receptors, the receptor type involved in motor effects of
cannabinoid agonists, are significantly reduced in the basal
ganglia during the progression of HD represents a convincing
explanation for the hyperkinesia typical of this disorder
and supports the usefulness of enhancing CB1
receptor signaling in HD. However, further studies revealed
that the key property that enables certain cannabinoid agonists
to reduce hyperkinesia is their capability to directly activate
vanilloid TRPV1 receptors.
Cannabinoids may also serve to delay/arrest the progression
of HD by protecting striatal projection neurons from death.
Several cannabinoid agonists have been tested for this purpose
in various animal models of HD, and these studies revealed
that the major characteristics that enable cannabinoids to
provide neuroprotection are three: (i) a reduction in inflammatory
events exerted through activating CB2
receptors located in glial cells; (ii) a normalization of
glutamate homeostasis, then limiting excitotoxicity, an effect
that would be exerted through CB1
receptors; and (iii) an antioxidant effect exerted by cannabinoid
receptor-independent mechanisms. The changes experienced by
the endocannabinoid signaling system during the striatal degeneration
support this neuroprotective effect, particularly the up-regulatory
responses proved by CB2 receptors
in glial cells recruited at lesioned sites. The present article
will review the neurochemical and pharmacological bases that
sustain the importance of the endocannabinoid system in the
pathophysiology of HD, trying to collect the present information
and the future lines for research on the therapeutic potential
of this system in this disorder.
[Back to top]
The Endocannabinoid System and Multiple Sclerosis
D. Baker and G. Pryce
Multiple sclerosis (MS) is a neurodegenerative disease
that is characterised by repeated inflammatory/demyel- inating
events within the central nervous system (CNS). In addition
to relapsing-remitting neurological insults, leading to loss
of function, patients are often left with residual, troublesome
symptoms such as spasticity and pain. These greatly diminish
“quality of life” and have prompted some patients
to self-medicate with and perceive benefit from cannabis.
Recent advances in cannabinoid biology are beginning to support
these anecdotal observations, notably the demonstration that
spasticity is tonically regulated by the endogenous cannabinoid
system. Recent clinical trials may indeed suggest that cannabis
has some potential to relieve, pain, spasms and spasticity
in MS. However, because the CB1
cannabinoid receptor mediates both the positive and adverse
effects of cannabis, therapy will invariably be associated
with some unwanted, psychoactive effects. In an experimental
model of MS, and in MS tissue, there are local perturbations
of the endocannabi-noid system in lesional areas. Stimulation
of endocannabinoid activity in these areas either through
increase of synthesis or inhibition of endocannabinoid degradation
offers the positive therapeutic potential of the cannabinoid
system whilst limiting adverse events by locally targeting
the lesion. In addition, CB1
and CB2 cannabinoid receptor
stimulation may also have anti-inflammatory and neuroprotective
potential as the endocannabinoid system controls the level
of neurodegeneration that occurs as a result of the inflammatory
insults. Therefore cannabinoids may not only offer symptom
control but may also slow the neurodegenerative disease progression
that ultimately leads to the accumulation of disability.
[Back to top]
The Endocannabinoid System in Parkinson’s Disease
M. Di Filippo, B. Picconi, A. Tozzi, V.
Ghiglieri, A. Rossi and P. Calabresi
Parkinson's disease (PD) is a chronic and progressive neurodegenerative
disorder of largely unknown etiology caused by a pathological
cascade resulting in the degeneration of midbrain dopaminergic
neurons of the substantia nigra pars compacta (SNpc)
projecting to the nucleus striatum, the main input station
of the basal ganglia neuronal circuit.
The components of the endocannabinoid (ECB) system are highly
expressed at different levels in the basal ganglia neural
circuit where they bidirectionally interact with dopaminergic,
glutamatergic and GABAergic signaling systems. In particular,
at synapses linking cortical and striatal neurons, endocannabinoids
(ECBs) are known to critically modulate synaptic transmission
and to mediate the induction of a particular form of synaptic
plasticity, the long-term depression.
The evidence that ECBs play a central role in regulating basal
ganglia physiology and motor function and the profound modifications
occurring in ECB signaling after dopamine depletion in both
experimental models of PD and patients suffering from the
disease, provide support for the development of pharmacological
compounds targeting the ECB system as symptomatic and neuroprotective
therapeutic strategies for PD.
[Back to top]
Role of Cannabinoids and Endocannabinoids in Cerebral Ischemia
C.J. Hillard
The human costs of stroke are very large and growing;
it is the third largest cause of death in the United States
and survivors are often faced with loss of ability to function
independently. There is a large need for therapeutic approaches
that act to protect neurons from the injury produced by ischemia
and reperfusion. The goal of this review is to introduce and
discuss the available data that endogenous cannabinoid signaling
is altered during ischemia and that it contributes to the
consequences of ischemia-induced injury. Overall, the available
data suggest that inhibition of CB1 receptor activation together
with increased CB2 receptor activation produces beneficial
effects.
[Back to top]
Endocannabinoids in Liver Disease and Hepatic Encephalopathy
I. Magen, Y. Avraham, E. Berry and R. Mechoulam
Chronic liver disease results from a variety of causes
such as hepatitis virus infections, autoimmune processes and
alcohol consumption. Its complications include fat deposition,
hemodynamic changes and fibrosis. Clinically there may be
progression to portal-hypertension and porto-systemic encephalopathy.
Pioneering research from the laboratory of Kunos at NIH has
stressed the importance of endocannabinoids (ECs) as mediators
of some of the pathological processes in chronic liver disease.
The present review summarizes the literature on the association
between ECs and liver disease, as well as the therapeutic
potential of ECs and exogenous cannabinoids in liver disease
with emphasis on hepatic encephalo-pathy.
[Back to top]
The Endocannabinoid System in Peripheral Lymphocytes as a
Mirror of Neuroinflammatory Diseases
D. Centonze, L. Battistini and M. Maccarrone
During immuno-mediated attack of the brain, activation of
endocannabinoids represents a protective mechanism, aimed
at reducing both neurodegenerative and inflammatory damage
through various and partially converging mechanisms that involve
neuronal and immune cells. Here, we review the main alterations
of the endocannabinoid system (ECS) within the central nervous
system and in peripheral blood mononuclear cells, in order
to discuss the intriguing observation that elements of the
peripheral ECS mirror central dysfunctions of endocannabinoid
signaling. As a consequence, elements of blood ECS might serve
as novel, non-invasive diagnostic tools of several neurological
disorders, and targeting the ECS might be useful for therapeutic
purposes. In addition, we discuss the appealing working hypothesis
that the presence of type-1 cannabinoid receptors on the luminal
side, and that of type-2 cannabinoid receptors on the abluminal
side of the blood-brain barrier, could drive a unidirectional
transport of AEA in the luminal →
abluminal direction (i.e., from blood to brain), thus implying
that blood may be a reservoir of AEA for the brain. On this
basis, it can be expected that an unbalance of the endogenous
tone of AEA in the blood may sustain a similar unbalance of
its level within the brain, as demonstrated in Huntington’s
disease, Parkinson’s disease, multiple sclerosis, attention-deficit/hyperactivity
disorder, schizophrenia, depression and headache.
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