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CNS &
Neurological Disorders - Drug Targets
ISSN: 1871-5273
Current Drug Targets - CNS
& Neurological Disorders
Volume 4, Number 6, December 2005
Contents
The Endocannabinoid System in the Brain: From Biology
to Therapy
Guest Editor: Mauro Maccarrone
Editorial Pp. 613
Endocannabinoid Metabolic Pathways and Enzymes Pp.
615-623
Alessia Ligresti, Maria Grazia Cascio and Vincenzo Di Marzo
[Abstract]
Molecular Biology of the Enzymes that Degrade Endocannabinoids
Pp. 625-631
Robyn A. Puffenbarger
[Abstract]
Endocannabinoids in the Central Nervous System:
From Neuronal Networks to Behavior Pp. 633-642
Ester Fride
[Abstract]
Endocannabinoids and Drug Dependence Pp.
643-655
Daniela Parolaro, Daniela Viganò and Tiziana Rubino
[Abstract]
Endocannabinoids in Neuroimmunology and Stress
Pp. 657-665
Erica J. Carrier, Sachin Patel and Cecilia J. Hillard
[Abstract]
From Cannabis to Endocannabinoids in Multiple
Sclerosis: A Paradigm of Central Nervous System Autoimmune
Diseases Pp. 667-675
Anna Maria Malfitano, Giuseppe Matarese and Maurizio Bifulco
[Abstract]
Cannabinoids: Between Neuroprotection and Neurotoxicity
Pp. 677-684
Yosef Sarne and Raphael Mechoulam
[Abstract]
Pharmacological Properties and Therapeutic Possibilities
for Drugs Acting Upon Endocannabinoid Receptors Pp.
685-696
Christopher J. Fowler
[Abstract]
Therapeutic Perspectives of Inhibitors of Endocannabinoid
Degradation Pp. 697-707
Silvia Ortega-Gutiérrez
[Abstract]
Partial QSAR Analysis of Some Selected Natural Inhibitors
of FAAH Suggests a Working Hypothesis for the Development
of Endocannabinoid-Based Drugs Pp. 709-714
Enrico Dainese, Valeria Gasperi and Mauro Maccarrone
[Abstract]
Abstracts
[Back to top]
Editorial
This theme issue is dedicated to my children, Giuseppe and
Claudia and to my wife, Gianna.
Marijuana is one of the most widely used drugs in the world,
and its extracts have been used for centuries in folklore
medicine. Yet the identity of its psychoactive constituent,
delta-9-tetrahydrocannabinol (D9-THC), remained elusive until
1964, when Raphael Mechoulam’s group revealed it. Then,
the field had to wait until 1988 for the first evidence, presented
by Allyn Howlett and colleagues, that a specific cannabinoid
receptor exists in the brain. This discovery raised the question
of the reason why our brain, as well as most peripheral tissues,
contain cannabinoid receptors, that are unlikely to exist
in mammalian tissues for the sake of a plant constituent like
D9-THC. On this background, several groups have started intense
research aimed at finding the endogenous ligands of cannabinoid
receptors, the so-called “endocannabinoids”. Two
of such molecules were discovered in the early ‘90s:
N-arachidonoylethanolamine (anandamide) was found in 1992
by Mechoulam’s group, and 2-archidonoylglycerol was
reported in 1995, independently by the group of Takayuki Sugiura
and by that of Mechoulam. Since then the field has attracted
growing interest, and a bunch of molecules and proteins have
been discovered. These include endocannabinoids and endocannabinoid-like
compounds (i.e., amides, esters and ethers of (poly-un)saturated
fatty acids), cannabinoid and non-cannabinoid receptors, synthetic
and degradative enzymes, as well as membrane transporters,
that are at the moment the most debated topic in the field.
Overall, these components form the “endocannabinoid
system”.
The growing interest towards this endogenous system of lipids
and proteins is demonstrated by the number of papers that
appeared in PubMed over the last decade. The word “endocannabinoid”
scores 37 entries in 1992-1995, 240 in 1997-2000, and 659
in 2002-2005 (“cannabinoid” scores 428, 911 and
1600 in the same periods of time). If “endocannabinoid”
is matched with “central nervous system (CNS)”
the entries are 15, 83 and 246, suggesting that more than
one third of the field is strictly related to the CNS. The
same indication comes from the analysis of “cannabinoid”,
that counts 106, 298 and 466 entries, when matched with “CNS”.
Of interest is also the fact that the therapeutic implications
of (endo)cannabinoid-oriented drugs have expanded over the
last few years, thus the match “endocannabinoid”
and “drug development” leads to 0 entries in 1992-1995,
15 in 1997-2000, and 65 in 2002-2005 (for the match with “cannabinoid”
the figures are 23, 57 and 146, respectively). As a matter
of fact, at least two synthetic cannabinoids are in advanced
phase III clinical trials: SR141716 (rimonabant), and HU-211
(dexanabinol). The first compound has been developed by Sanofi-Aventis,
and is an appetite modulator; the second compound, developed
by Pharmos, is a neuroprotectant in head trauma. Both drugs
may represent pharmaceutical breakthroughs in important therapeutic
areas of human disease. This brings to the present book.
This theme-issue is an outstanding collection of hot topics
in the endocannabinoid research, and the review articles should
form the basis to better understand the molecular background
of the ongoing clinical applications of endocannabinoid-targeted
drugs, which have generated great expectations as conceptually
new therapeutics. I hope that the aspects of endocannabinoid
research summarized in this book may foster novel ideas, boosting
investigations into new directions of basic science and clinic,
thus ultimately improving our understanding and therapeutic
exploitation of the endocannabinoid system.
Mauro Maccarrone
Department of Biomedical Sciences
University of Teramo
Italy
E-mail: mmaccarrone@unite.it
[Back to top]
Endocannabinoid Metabolic Pathways and Enzymes
Alessia Ligresti, Maria Grazia Cascio and Vincenzo Di
Marzo
Endocannabinoids, defined in 1995 as endogenous agonists
of cannabinoid receptors, their anabolic and catabolic pathways,
and the enzymes involved in these pathways (the “endocannabinoid
enzymes”), are the subject of this review. A general
strategy seems to apply to the regulation of the levels of
the two major endocannabinoids, anandamide and 2-arachidonoylglycerol
(2-AG). Five endocannabinoid enzymes have been cloned to date:
two are responsible for the biosynthesis and degradation of
anandamide, the NAPE-selective phospholipase D and the fatty
acid amide hydrolase, respectively; the other three catalyse
the biosynthesis and degradation of 2-AG, the sn-1-selective
diacylglycerol lipases α
and β
and the monoacylglycerol lipase, respectively. The major features
of these five proteins, their relative weight in determining
endocannabinoid levels, and the possible targeting of some
of them for therapeutic purpose, as well as the possibility
of the existence of alternative anabolic and catabolic pathways
are discussed.
[Back to top]
Molecular Biology of the Enzymes that Degrade Endocannabinoids
Robyn A. Puffenbarger
Endocannabinoid circuits have been shown to regulate a number
of important pathways including pain, feeding, memory and
motor coordination. Direct manipulation of endocannabinoid
tone, therefore, may relieve disease symptoms related to analgesia,
obesity, Alzheimer’s and Parkinson’s in humans.
The endocannabinoid circuit involves two cloned receptors:
CB1 in the CNS and CB2 in the periphery; endogenously produced
ligands including anandamide, 2-arachidonylglycerol and palmitoylethanolamide;
and enzymes that degrade endocannabinoid ligands to terminate
signaling. Currently, three enzymes have been characterized
with the ability to hydrolyze endocannabinoids: fatty acid
amide hydrolase (FAAH), monoglyceride lipase (MGL) and N-acylethanolamine-hydrolyzing
acid amidase (NAAA). The purpose of this review is to examine
the molecular biology for the enzymes that hydrolyze endocannabinoids
covering the protein activity and expression, mRNA characterization,
genomic locus organization, promoter analysis and knockout
phenotypes.
[Back to top]
Endocannabinoids in the Central Nervous System: From
Neuronal Networks to Behavior
Ester Fride
Retrograde synaptic signaling influences both short-term
and long-term plasticity of the brain, in both excitatory
and inhibitory synapses. During the last few years it has
become apparent that the endogenous ligands for the cannabinoid
CB1 receptor, the "endocannabinoids",
fulfill an essential role in the brain as retrograde synaptic
messengers, in a number of structures including the hippocampus,
cerebellum and the limbic and mesocortical systems. This seminal
discovery provides a cellular basis for the well known ubiquitous
role of the endocannabinoids and their receptors (together,
the "ECBR" system) in virtually all brain functions
studied.
This review will relate the anatomical distribution of the
endocannabinoids and their CB1 receptors to functions
of the ECBR system, as much as possible in light of the endocannabinoids
as retrograde synaptic messengers. Functional implications
of the high rates of co-localization with cholecystokinin
(CCK), will also be considered. The most obvious function
to be profoundly affected by the retrograde synaptic role
of the endocannabinoids is memory. However, additional functions
and dysfunctions such as reward and addiction, motor coordination,
pain perception, feeding and appetite, coping with stress,
schizophrenia and epilepsy will also be reviewed. Finally,
the widespread presence of the ECBR system in the brain also
lends a scientific basis for the development of cannabinoid-based
medicines. The same ubiquity of the ECBR system however, should
also be taken into consideration with respect to possible
adverse side effects and addictive potential of such pharmaceutical
developments.
[Back to top]
Endocannabinoids and Drug Dependence
Daniela Parolaro, Daniela Viganò and Tiziana Rubino
Drug dependence is a chronically relapsing disorder, manifested
as an intense desire for the drug, with impaired ability to
control the urges to take the drug, even at the expense of
serious adverse consequences. These behavioral abnormalities
develop gradually during repeated exposure to a drug of abuse,
and can persist for months or years after discontinuation
of use, suggesting that this addiction can be considered a
form of drug-induced neural plasticity. Many neurotransmitters,
including gamma-aminobutyrric acid (GABA), glutamate, acetylcholine,
dopamine, serotonin and endogenous opioid peptides, have been
implicated in the effects of the various drugs of abuse. Dopamine
has been consistently associated with the reinforcing effects
of most of them. There is, in addition, a growing body of
evidence that the endogenous cannabinoid system might participate
in the motivational and dopamine-releasing effects of several
drugs of abuse.
This review will discuss the latest advances on the mechanisms
of cannabinoid dependence and the possible role of the endocannabinoid
system in the treatment of addiction, not only to marijuana
but also to the other common illicit drugs.
[Back to top]
Endocannabinoids in Neuroimmunology and Stress
E. J. Carrier, S. Patel and C.J. Hillard
Two topics are presented in this review. In the first section,
we review data regarding the effects of the endocannabinoids
(eCBs) and cannabinoid receptors on neuroimmune function.
The function of eCBs in the interaction between the immune
system and the central nervous system (CNS) is of particular
interest, since the CNS itself is a rich source of eCBs while
being exquisitely sensitive to inflammation. There are several
sites at which cannabinoids can influence neuroinflammation.
Microglial cells express both CB receptors and make eCBs.
Activation of CB receptors on these cells seems to promote
migration and proliferation but to reduce activation to macrophages.
In several neurodegenerative diseases, up-regulation of microglial
CB2 receptors have been observed. It is our hypothesis that
microglial CB receptor activity is anti-inflammatory and could
be exploited to manipulate neuroinflammatory processes with
a minimum of unwanted effects. The second topic discussed
suggests that the eCB/CB1 receptor pair is involved in the
responses of animals to acute, repeated and variable stress.
The roles of this pair are complex and dependent upon previous
stress, among other things. Dysfunctional responding to stress
is a component of several human neuropsychiatric disorders,
including anxiety and panic disorders, post-traumatic stress
disorders, premenstrual dysphoria and quite possibly, drug
abuse. While it is too early to say with certainty, it is
very possible that either inhibition or potentiation of endocannabinoid
signaling will be an efficacious novel therapeutic approach
to more than one human psychiatric disease.
[Back to top]
From Cannabis to Endocannabinoids in Multiple Sclerosis:
A Paradigm of Central Nervous System Autoimmune Diseases
Anna Maria Malfitano, Giuseppe Matarese and Maurizio
Bifulco
An Increasing body of evidence suggests that cannabinoids
have beneficial effects on the symptoms of multiple sclerosis,
including spasticity and pain. Endogenous molecules with cannabinoid-like
activity, such as the “endocannabinoids”, have
been shown to mimic the anti-inflammatory properties of cannabinoids
through the cannabinoid receptors. Several studies suggest
that cannabinoids and endocannabinoids may have a key role
in the pathogenesis and therapy of multiple sclerosis. Indeed,
they can down regulate the production of pathogenic T helper
1-associated cytokines enhancing the production of T helper
2-associated protective cytokines. A shift towards T helper
2 has been associated with therapeutic benefit in multiple
sclerosis. In addition, cannabinoids exert a neuromodulatory
effect on neurotransmitters and hormones involved in the neurodegenerative
phase of the disease. In vivo studies using mice
with experimental allergic encephalomyelitis, an animal model
of multiple sclerosis, suggest that the increase of the circulating
levels of endocannabinoids might have a therapeutic effect,
and that agonists of endocannabinoids with low psychoactive
effects could open new strategies for the treatment of multiple
sclerosis.
[Back to top]
Cannabinoids: Between Neuroprotection and Neurotoxicity
Yosef Sarne and Raphae Mechoulam
Cannabinoids, such as the Δ9- tetrahydrocannabinol
(THC), present in the cannabis plant, as well as anandamide
and 2-arachidonoyl glycerol, produced by the mammalian body,
have been shown to protect the brain from various insults
and to improve several neurodegenerative diseases. The current
review summarizes the evidence for cannabinoid neuroprotection
in vivo, and refers to recent in vitro studies,
which help elucidate possible molecular mechanisms underlying
this protective effect. Some of these mechanisms involve the
activation of CB1 and CB2 cannabinoid receptors, while others
are not dependent on them. In some cases, protection is due
to a direct effect of the cannabinoids on neuronal cells,
while in others, it results from their effects on non-neuronal
elements within the brain. In many experimental set-ups, cannabinoid
neurotoxicity, particularly by THC, resides side by side with
neuroprotection. The current review attempts to shed light
on this dual activity, and to dissociate between the two contradictory
effects
[Back to top]
Pharmacological Properties and Therapeutic Possibilities
for Drugs Acting Upon Endocannabinoid Receptors
Christopher J. Fowler
Clinical trial data are beginning to emerge with respect
to the therapeutic efficacy of cannabis extracts for the treatment
of chronic pain. Although there is some evidence of efficacy,
a major issue concerns the narrow margin between doses producing
therapeutic effects and those producing the ”highs”
associated with cannabis misuse. In addition, long-term use
is associated with an increased risk of psychiatric illness.
These negative aspects constrain the doses of cannabis extracts
and psychoactive cannabinoids that can be given to patients,
and raise the risk that properly conducted clinical trials
with too low dosages will impact negatively on subsequent
drug development in this field. However, recent research has
opened up a number of avenues whereby compounds acting directly
upon cannabinoid (CB) receptors may have therapeutic potential.
In this review, two such areas are discussed, namely a) the
possible use of peripherally acting CB agonists and CB2
receptor-selective agonists for the treatment of pain, and
b) the possible utility of CB2 receptor agonists
for the prevention of stress-induced exacerbations of skin
disorders such as psoriasis. A second area of drug development
at present is that of CB1 receptor antagonists
/ inverse agonists, spearheaded by rimonabant, for the treatment
of obesity and as an aid for smoking cessation. An important
aspect of these compounds is their efficacy and selectivity,
and this is discussed in detail in the present review.
[Back to top]
Therapeutic Perspectives of Inhibitors of Endocannabinoid
Degradation
Silvia Ortega-Gutiérrez
The study of the cannabinoids can be established in the
middle sixties with the elucidation of the structure of the
active principle of Cannabis sativa plant, the Δ9-tetrahydrocannabinol.
However, the existence of an endogenous cannabinoid system
(ECS) has not been unequivocally accepted until recently.
The last two decades have witnessed an impressive advance
in the knowledge about cannabinoids, their chemistry, the
enzymes involved in their metabolism, and their physiological
and pathological roles. In particular, we have made progress
in modifying the activity of the ECS with selective compounds,
validating the ECS as a new therapeutic target. Endocannabinoids
play a role in physiological and pathological processes, and
their levels are affected in several disorders. Therefore,
it should be possible to ameliorate these pathologies by correcting
their altered levels. This review focuses on the current therapeutic
opportunities of endocannabinoid-directed drugs, and pays
special attention to the therapeutic possibilities underlying
the inhibition of the endocannabinoid inactivation. The strategy
of manipulating the ECS might open new avenues in the development
of therapeutic approaches for a number of disorders, both
central and peripheral, that lack as yet effective treatments.
[Back to top]
Partial QSAR Analysis of Some Selected Natural Inhibitors
of FAAH Suggests a Working Hypothesis for the Development
of Endocannabinoid-Based Drugs
Enrico Dainese, Valeria Gasperi and Mauro Maccarrone
The endogenous cannabinoids (endocannabinoids) are bioactive
signaling molecules, that show diverse cellular and physiological
effects and play various roles in the central nervous system,
as well as in the periphery. The discovery of N-arachidonoylethanolamine
(anandamide, AEA) and of the enzyme that terminates its signaling,
i. e. fatty acid amide hydrolase (FAAH), has inspired pharmacological
strategies to augment endocannabinoid tone and biological
activity through inhibition of FAAH. Here we discuss the role
of natural endocannabinoid derivatives, like the hydroxy-anandamides
(OH-AEAs) generated from AEA via lipoxygenase activity,
as powerful inhibitors of FAAH. We propose that these compounds,
by reversibly inhibiting FAAH, may control in vivo
the endocannabinoid tone. We consider the theoretical structural
properties of OH-AEAs and other natural inhibitors of FAAH,
based on the calculation of theoretical molecular descriptors
commonly used in Quantitative Structure Activity Relationship
(QSAR) studies. The QSAR properties of OH-AEAs and congeners
suggest that they could act at different specific sites of
FAAH, thus confirming their potential value as templates for
the development of next-generation therapeutics.
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