Cannabinoid Receptor 2: Potential Role in Immunomodulation and Neuroinflammation

Article (PDF Available)inJournal of Neuroimmune Pharmacology 8(3) · March 2013with104 Reads
DOI: 10.1007/s11481-013-9445-9 · Source: PubMed
Abstract
An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection.

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INVITED REVIEW
Cannabinoid Receptor 2: Potential Role in Immunomodulation
and Neuroinflammation
Slava Rom & Yuri Persidsky
Received: 6 December 2012 / Accepted: 18 February 2013
#
Springer Science+Business Media New York 2013
Abstract An accumulating body of evidence suggests that
endocannabinoids and cannabinoid receptors type 1 and 2
(CB
1
,CB
2
) play a significant role in physiologic and patho-
logic processes, including cognitive and immune functions.
While the addictive properties of marijuana, an extract from
the Cannabis plant, are well recognized, there is growing
appreciation of the therapeutic potential of cannabinoids in
multiple pathologic conditions involving chronic inflammation
(inflammatory bowel disease, arthritis, autoimmune disorders,
multiple sclerosis, HIV-1 infection, stroke, Alzheimersdisease
to name a few), mainly mediated by CB
2
activation.
Development of CB
2
agonists as therapeutic agents has been
hampered by the complexity of their intracellular signaling,
relative paucity of highly selective compounds and insufficient
data regarding end effects in the target cells and organs.
This review attempts to summarize recent advances in
studies of CB
2
activation in the setting of neuroinflammation,
immunomodulation and HIV-1 infection.
Keywords Cannabinoid receptor
.
Endocannabinoids
.
Medical marijuan a
.
HIV-1
.
Monocyte/macrophage
.
Endothelial cells
Introduction
The cannabinoids are a group of terpenophenolic com-
pounds present in the marijuana plant, Cannabis sativa .At
present, three general types of cannabinoids have been iden-
tified: phytocannabinoids present uniquely in the cannabis
plant, endogenous cannabinoids produced in humans and an-
imals, and synthetic cannabinoids generated in a laboratory
(Sarfaraz et al. 2008). It is worth noting that Cannabis sativa
produces over 80 cannabinoids (Console-Bram et al. 2012).
The broader definition of cannabinoids refers to a group of
substances that are structurally related to Δ
9
-tetrahydrocannab-
inol (Δ
9
-THC) or that bind to cannabinoid receptors. The
chemical definition includes a variety of distinct chemical
classes: the cla ssi cal cannabinoids structurally related to
THC, the non-classical cannabinoids, the aminoalkylindoles,
the eicosanoids related to the endocannabinoids, quinolines
and arylsulphonamides (Woelkart et al. 2008;Console-Bram
et al. 2012), and additional compounds that do not fall into
these standard classes, but bind to cannabinoid receptors (CB).
Multifaceted effects of marijuana can be singled out aiming at
evaluation of the potential medical value of marijuana and
cannabinoids in specific human diseases, with minimal
undesired side effects.
Nomenclature of cannabinoid receptors (CB)
There are two well-characterized CB with distinctly different
physiological properties. The psychoactive effects of canna-
binoids are associated with the CB
1
receptor; the CB
2
receptor
mainly mediates anti-inflammatory and immunomodulatory
actions (Miller and Stella 2008).
CB
1
Cannabinoid receptor 1 (CB
1
) was disco vered by Devane et
al. 1988 (Devane et al. 1988). CB
1
cDNA was cloned by
Matsuda et al. ( 1990) from rats using a homology approach
to G-protein-coupled receptors (GPCR). Subsequently, CB
1
receptors have been found in other vertebrates as well. The
S. Rom (*)
:
Y. Persidsky (*)
Department of Pathology and Laboratory Medicine,
Temple University School of Medicine, 3401 N. Broad St.,
Philadelphia, PA 19140, USA
e-mail: srom@temple.edu
e-mail: yuri.persidsky@tuhs.temple.edu
J Neuroimmune Pharmacol
DOI 10.1007/s11481-013-9445-9
genes for mouse, rat and human CB
1
receptors (CNR1) are
located on chromosomes 4, 5 and 6, respectively. The CB
1
receptor is widely distributed throughout the brain regions,
especially the frontal cortex, the limbic system, including
the hippocampus and amygdala, sensory and motor areas,
hypothalamus, p ons and medulla (Ashton et al. 200 7;
Ashton and Moore 2011).
Human CB
1
shares 94 % amino acid sequence identity
with rodent CB
1
(Anday and Mercier 2005). In addition to
full-length CB
1
receptor, two splice variants, human CB
1
aand
human CB
1
b, have been described. Both splice variants have
altered ligand binding and activation properties compared to
full length CB
1
, and are expressed at very low levels in
different tissues (Ryberg et al. 2005). In contrast, another
group demonstrated no significant differences between the
three variants (full-length and two splice variants) in pharma-
cological characteristics, such as binding affinity, functional
potency, and efficacy of several CB
1
agonists (Xiao et al.
2008). The functional significance of different human canna-
binoid CB
1
receptor variants remains to be clarified.
The majority of high CB
1
-expressing cells are GABAergic
(gamma-aminobutyric acid) neurons belonging mainly to the
cholecystokinin-positive and parvalbumin-negative type of
interneurons (basket cells) and, to a less extent, to the mid-
proximal dendritic inhibitory interneurons. Only a fraction of
low CB
1
-expressing cells is GABAergic. In the hippocampus,
amygdala and entorhinal cortex areas, CB
1
mRNA is present
at low but significant levels in many non-GABAergic neuro-
nal cells (Marsicano and Lutz 1999).
CB
2
The second cannabinoid recept or (CB
2
) was isolated from
human myeloid cells in 1992 (Munro et al. 1993). Soon
afterwards, CB
2
was identified in other species, such as
mouse, rat, bovine and zebra fish. The CB
2
gene is located
on chromosome 1 and 4 in humans and mice, respectively.
Unlike the mouse CB
2
gene, which is intron-less, the human
gene has been reported to have two splice variants (Liu et al.
2009). The longer variant human CB
2
a, comprised of exon
1a, exon 1b and exon 3, is mostly expressed in testis (about
100-fold more compared to spleen or leukocytes). It is also
detected in various regions of the brain (Liu et al. 2009). The
shorter variant, human CB
2
b, consisting of exon 2 and exon
3, is expressed mostly in the spleen and leukocytes, 100-
and 30-fold higher, respectively, when compared to CB
2
b
expression in the brain (Liu et al. 2009). Immune cells express
high levels of CB
2
and there is a hierarchy of CB
2
expression
within the immune system (B cells > natural killer cells >
monocytes > neutrophils > CD8 lymphocytes > CD4 lympho-
cytes) (Nunez et al. 2004; Yao and Mackie 2009). The level of
expression is dependent on the activation state of the cell and
the type of stimuli. Stimulation of splenocytes with LPS leads
to CB
2
mRNA down-regulation, whereas CD40 co-
stimulation results in CB
2
mRNA up-regulation (Lee et al.
2001). CB
2
receptor sequences are less conserved throughout
evolution compared to CB
1
receptors. CB
2
and CB
1
receptors
share about 44 % identity in humans at the level of amino
acids (Liu et al. 2009;Console-Brametal.2012). Humans and
mice share about 82 % identity in amino acid sequence of CB
2
(Anday and Mercier 2005), whereas mice and rat share 93 %
identity. Human, rat and mouse sequences diverge at the C-
terminus. The mouse protein is 13 amino acids shorter, while
the rat protei n is 50 amino acids longer than th e human
(Console-Bram et al. 2012). Diversity in CB
2
sequences be-
tween species can possibly explain differential effects of CB
2
agonists in human and rodent models (Fig. 1).
Structural similarities and differences of CB
2
and CB
1
Cannabinoid receptors are integral membrane proteins
whose amino acid sequences are characterized by seven
hydrophobic segments containing α-helical patterns. CBs
belong to a group of rhodopsin-like seven- transmembrane
(7TM) GPCRs (Palczewski et al. 2 000). CBs share the
structural characteristics of other GPCRs: an extracellular
N-terminus that is glycosylated, seven transmembrane α-
helixes with extracellular and intracellular loops, and an
intracellular C-terminus (Ahn et al. 2009). While CB
1
and
CB
2
are encoded by different genes, they exhibit 44 %
amino acid identity throughout the whole protein (Fig. 1).
Since CBs are intrinsic membrane proteins, they are difficult
to crystallize for X-ray study. Although their crystal struc-
tures are not available, homology models built by using
bovine rhodopsin as a template, along with reso lution
NMR and computer modeling, have revealed that the most
important differences between CB
1
and CB
2
with respect to
their interaction with the surrounding lipid environment are
located in the TM7 juxtamembrane domain (Dainese et al.
2008). CB
1
presents a hydrophobic surface at the helix I-
helix VII interface that is suitable for a specific interaction
with cholesterol and palmitic acid, whereas CB
2
displays a
negatively charged region within TM7, which is rather
unfavorable for any interaction with lipids. Arg302 in CB
2
TM7 (homologous to Arg401 in CB
1
) is not available for
any interaction with cholesterol or with G-proteins (Xie and
Chen 2005). Despite the ability to be activated by the same
endocannabinoids and trigger the same signaling pathways,
CB
2
is independent of membrane cholesterol content (Bari
et al. 2006).
In every TM domain, there are residues that have been
probed for their imp ortance in ligand binding or signal
transduction. CB
2
helix III is in contact with the other
helixes and plays an important role in the regulation of
cannabinoid activities (Xie et al. 2003). CB
2
Ser112 has
been shown to be crucial for recognition of several canna-
binoid ligands (based on mut agenesis studies) (Tao et al.
1999). The homologous residue in the CB
1
TM3 is Gly195
(Xie et al. 2003). Unlike the CB
1
receptor, in which Lys192
plays an important role for the binding of most cannabinoid
ligands, the homologous resi due Lys109 in CB
2
TM3 does
not appear to be a key residue (Tao et al. 1999; Xie et al.
2003). Mutagenesis studies indicate that the TM4 domain in
CB
2
plays a more important role for the recognition of the
cannabinoid ligand that in CB
1
. The CB
2
-selective antago-
nist, SR144528, completely fails to antagonize the CB
2
in
S161A or S165A mutants, which is explained by existence
of alanines in the homologous two sites of TM4 of the CB
1
Fig. 1 Multiple alignment and
homology of human and mouse
CB
1
and CB
2
receptors.
Sequence alignment was
performed using ClustalW tool
(http://www.ebi.ac.uk/Tools/
msa/clustalw2/). The following
symbols denote the degree of
conservation observed in each
column: * means that the
residues are identical in all
sequences, : means that
conserved substitutions have
been observed, and .
means that semi-conserved
substitutions are observed
receptor (Xie et a l. 2003). To date, studies of the CB
2
have
been limited by the lack of a three dimensional structure,
leaving many unanswered questions about inte ractions at
the molecular level with its ligands as well as the nature of
the receptor active site(s) (Xie and Chen 2005). Knowledge
of the three-dimensional structure of CB
2
should greatly aid
in the rational design of specific CB
2
ligands possessing
therapeutic activities, but devoid of undesirable side effects.
The dissimilarities between the two receptors could be
exploited to design CB
2
-specific ligands in the future.
Medical marijuana
Medical marijuana refers to the parts of the cannabis plant
used as a physician-recommended form of herbal therapy or
as medicine (synthetic analogs of cannabinoids). In the US
recently, use of medical marijuana has surged in the 18
states and the District of Colum bia that permit its use. The
cannabis plant has a long history of use as a medicine dating
back to 2737 B.C. (Ben Amar 2006). Cannabis sativa
contains over 80 different chemical constituents (Molina et
al. 2011; Console-Bram et al. 2012). There are three
phytocannabinoids (Fig. 2): THC, cannabidiol (CBD) and
cannabinol (CBN). THC is a primary component of canna-
bis, responsible for the psychoactive effects of the plant; it
has mild analgesic and antioxidant activities (Hampson et al.
1998; Molina et al. 2010). CBD represents up to 40 % of the
extract of medicinal cannabis. It has been shown to relieve
cough, congestion and nausea, convulsion, inflammation
and anxiety, and has been shown to be effective in treating
multiple sclerosis (MS), anxiety attacks and schizophrenia
(Crippa and Zuardi 2006; Zuardi et al. 2006a, b; Kogan et
al. 2007; M echoulam et al. 2007; Lakhan and Rowland
2009). CBN is a breakdown product of THC and acts as a
weak agonist of CB
1
and CB
2
because of lower affinity than
THC toward receptors (Mahadevan et al. 2000).
There are several medications (plant extracts or synthetic
cannabinoid analogues of THC alone or in combination with
CBD) that have been approved for medicinal use. Nabilone®
was approved in the US and Canada in 1985 as an anti-nausea
treatment for patients undergoing cancer chemotherapy
(Todaro 2012). Sative was approved in Canada and the
UK for treatment of neuropathic pain in MS and pain associ-
ated with cancer (Russo et al. 2007; Sastre-Garriga et al. 2007).
Sativex® has been also approved for MS-associated spasticity
in many countries, such as New Zealand, UK, Austria, Czech
Republic, Denmark, Germany, Sweden, Israel, Italy and Spain
(Leussink et al. 2012). In the majority of cases, administration
of cannabinoids (natural or synthetic analogs) results in im-
provement of symptoms of MS, especially spasticity, muscle
pain, tremors and bladder control. However, there were differ-
ences in the actions of orally administered versus inhaled
cannabinoids, probably due to variable absorption of orally
administered cannabinoids (Maurer et al. 1990; Russo et al.
2007). Several studies have been done on the pharmacokinet-
ics of cannabinoids during different routes of drug administra-
tion. Smoking, the major route, provides a rapid and efficient
Fig. 2 Prototypical structures of natural and synthetic cannabinoids
method for drug delivery from the lungs to the brain, contrib-
uting to its abuse potential. The number, duration and spacing
of the puffs, as well as holding time and inhalation volumes,
greatly affect the degree of exposure (Heishman et al. 1989;
Azorlosa et al. 1992). Synthetic THC, Dronabinol (Marinol®),
is usually taken orally, but may also be administered rectally. In
addition, abuse is being common by the oral route. Absorption
is slower when cannabinoids are ingested, with lower and
delayed peak THC concentrations (Law et al. 1984; Huestis
2007). To prevent first-pass metabolism by the liver, Sativex®
is administered sublingually, via the oromucosal route. The
oromucosal form of administration has the advantage that the
first-pass effects are reduced and, compared to smoking, the
maximum plasma THC levels are lower and increase more
slowly (Karst et al. 2010;Leussinketal.2012). Because MS is
considered to be a relapsing chronic inflammatory disease of
the CNS, beneficial anti-inflammatory effects of cannabinoids
would provide much needed MS symptom relief. Clinical
benefits for the use of cannabinoids in MS patients were also
supported by studies in animal models of MS (Baker et al.
2001; Pryce and Baker 2005;Mestreetal.2009).
CB
1
antagonists (AM251 and SR141716A) lead to
changes in efflux of noradrenaline and dopamine in various
brain regions, leading to antidepressant effects (Tzavara et
al. 2003;Witkinetal.2005). These studies suggest the
possibility of use of cannabinoids in the treatment of mood
disorders, such as depression, anxiety, manic depression and
posttraumatic stress (Ashton and Moore 2011).
Marinol® (Dronabinol) was approved by the US and
Canada in 1985 for patients undergoing cancer chemotherapy
to relieve nausea associated with treatment. In 1992, it was
approved for treatment of anorexia associated with AIDS-
related weight loss (Dejesus et al. 2007; Todaro 2012).
Cannabinoids are increasingly being used for treatment of
migraine headaches in patients that are not responding to the
serotonin 1D agonist , sumatripan (Kry mchan towski and
Jevoux Cda 2007). Dronabinol has been shown to inhibit the
5-HT3 receptor involved in emetic and pain responses (Fan
1995). A patent has been filed for the use of Dronabiniol for
treatment of migraines (Barbato 2007). Canasol® is used for
reduction of intraocular pressure in glaucoma (Crandall et al.
2007). Cannabinoid compounds applied topically show hypo-
tensive and neur oprotective effects in mice and monkeys
(Williams et al. 200 7; Yazulla 2008). In 1992, the FDA
approved the use of Dronabinol to stimulate appetite in
AIDS patients suffering from wasting syndrome. This trig-
gered further interest in the development of cannabinoid an-
tagonists that would reduce appetite. Rimonabant has been
shown to suppress appetite, producing reduction in body
weight (Pi-Sunyer et al. 2006). Dronabinol has been shown
to be a potent drug for treatment of HIV-associated sensory
neuropathy, the most common peripheral nerve disorder com-
plicating HIV-1 infection (Abrams et al. 2007).
Synthetic cannabinoid agonists
Synthetic cannabinoids are functionally similar to THC, the
active part of cannabis. Like THC, they bind to the same
cannabinoid receptors in the brain and other organs as the
endogenous ligands, anandamide and 2-arachidonylglycerol,
which interact with both CB
1
and CB
2
receptors. More cor-
rectly designated as cannabinoid receptor agonists, synthetic
cannabinoid agonists were developed over the past 40 years as
therapeutic agents, often for the treatment of pain. However, it
proved difficult to separate their desired properties from
unwanted psychoactive effects.
Although often referred to simply as synthetic cannabi-
noids, many of the substances are not structurally related to
the so-called classical cannabinoids, i.e., compounds like
THC, based on dibenzopy ran. The cannabinoid receptor
agonists form a diverse group, but most are lipid-soluble,
non-polar, and consist of 22 to 26 carbon atoms; they would
therefore be expected to volatilize readily when smoked. A
common structural feature is a side-chain, where optimal
activity requires more than four and up to nine saturated
carbon atoms. The first figure shows the structure of THC,
while the others show examples of synthetic cannabinoid
receptor agonists, all of which have been found in Spice
or other smoking mixtures. The synthetic cannabinoids fall
into seven major structural groups (Fig. 2):
1. Naphthoylindoles (e.g., JWH-018, JWH-073, JWH-398).
2. Naphthylmethylindoles (e.g., JWH-175, JWH-195,
JWH-197).
3. Naphthoylpyrroles (e.g., JWH-030, JWH-156, JWH-243).
4. Naphthylmethylindenes (e.g., JWH-176).
5. Phenylacetylindoles (i.e., benzoy lindoles, e.g., JWH-
250, JWH-253, JWH-313).
6. Cyclohexylphenols (e.g., CP 47,497 and homologs of
CP 47,497).
7. Classical cannabinoids (e.g., HU-210).
Compounds in groups 15 (JWH compounds) were largely
synthesized by Huffman et al. over the past 15 years (Huffman
et al. 1996; Wiley et al. 1998; Huffman et al. 2000; Huffman et
al. 2003; Huffman et al. 2005; Huffman et al. 2006; Huffman
et al. 2010). The sixth group, cyclohexylphenols, were devel-
oped by Pfizer during the 1970s and 1980s (Carissimi et al.
1976). The classical cannabinoids (seventh group) is the
oldest; synthesis began in the 1960s following the identifica-
tion of the chemical structure of THC (Mechoulam and Gaoni
1965, 1967; Gaoni and Mechoulam 1971). In general, the
agonists show little selectivity between CB
1
and CB
2
,while
antagonist compounds are highly selective (>1000 fold selec-
tive for CB
1
vs. CB
2
and vice versa with nanomolar affinity at
the relevant receptor) (Console-Bram et al. 2012). The selec-
tivity of these antagonists allows the discrimination of CB
1
-
vs. CB
2
-mediated effects in vitro and in vivo. Despite the
existence of numerous non-selective agonists, there are some
that exhibit selectivity. For example, HU-308 is a highly
selective CB
2
agonist with nanomolar affinity at CB
2
and
>1000 fold selectivity for CB
2
vs. CB
1
. If a compound shows
>100 fold selectivity, it is classified as a selective agonist
(Console-Bram et al. 2012).
CB signalingCB-ligand interactions
CB
2
, as with the rest of the GPCRs, signals through the three
main components of the MAPK pathway, namely, ERK,
JNK and p38 (Howlett et al. 2002). However, activation of
CB receptor coupling to MAPKs is dependen t on cellular
content. A wide range of activation and inhibition has been
observed dependent on cell type, cell differentiation status
and co-modulators of MAPK cascades (Howlett 2005). CB
2
agonism decreased CXCR4-activation mediated G-protein
activity and MAPK phosphorylation. Furthermore, CB
2
ag-
onists altered cytoskeletal reorganization, by decreasing F-
actin levels, impairing productive infection (Costantino et al.
2012). Signaling events associated with inflammatory re-
sponses in e ndothelial cells and monocytes are complex;
few studies have addressed potential mechanisms of anti-
inflammatory CB
2
stimulation. Gertsch et al. investigated
intracellular signaling pathways triggered in monoc ytes by
LPS-triggered TNFα and IL-1β production that w ere
suppressed by CB
2
agonist. LPS treatment of human mono-
cytes led to a rapid phosphorylation of p38 and JNK1/2
(Gertsch et al. 2008) and CB
2
agonist reduced Erk1/2 and
JNK1/2 activation (phosphorylation) (Gertsch et al. 2008).
Whether or not CB
2
modulates ion channels has been contro-
versial. Felder and colleagues (Felder et al. 1995)suggested
that CB
2
does not modulate potassium or high-voltage calci-
um channels. More recent work indicates that CB
2
agonists do
modulate these channels and earlier results were due to func-
tional selectivity of the ligands used (Atwood et al. 2012).
CB
2
affects additional signaling pathways, including activa-
tion of phospholipase C, leading to release of calcium
(Shoemaker et al. 2005), regulation of small G proteins (such
as Rho, Rac and cdc42) (Kurihara et al. 2006), and activation
of JNK via the phosphatidyl inositol 3 kinase (PI3K)/Akt
pathway (Viscomi et al. 2009; Atwood et al. 2012). In human
umbilical vein endothelial cells, cannabidiol could evoke
phosphorylation of p44/42 MAPK and PKB/Akt via PI3K
pathway (Offertaler et al. 2003).
GPCRs are regulated at many levels. In general, once
they are activated by ligand binding, their signaling is at-
tenuated by a desensitization process, followed by internal-
ization. Desensitization involves G protein receptor kinase-
mediated phosphorylation of multiple serine or threonine
residues of GPCR, followed by binding of the β-ares tins.
This protein complex is usually localized to clathrin-coated
pits or caveoli where it is internalized. The internalized
receptor might be transported to endosomes for dephosphor-
ylation and returned to the plasma membrane for the next
signaling event or directed to lysosomes for degradation
(Atwood et al. 2012). Little is known about the processes
involved in CB
2
adaption to chronic activation. Most of the
knowledge comes primarily from cell lines over-expressing
CB
2
. Although the levels of expression in those systems
significantly exceed in vivo CB
2
levels, the use of expres-
sion systems provides very valuable information (Atwood et
al. 2012).
CB
2
receptor expression in immune and neuroimmune
cells
Anti-inflammatory effects of cannabinoids
The two well-characterized CBs possess different physiolog-
ical properties. The psychoactive effects of cannabinoids are
associated with CB
1
;CB
2
mainly mediates anti-inflammatory
and immunomodulatory actions (Miller and Stella 2008).
Identification of CB
1
and CB
2
resulted in the recognition of
endogenous cannabinoids (endocannabinoids) (Pacher et al.
2006). Tw o endocannabinoid metabolizing enzymes
were identified: fatty acid amine hydrolase (FAAH) and
monoacylglycerol lipase. CB
1
agonists possess neuroprotective
properties via diminishing excitotoxicity in postsynaptic neu-
rons (Marsicano et al. 2003), enhancing vasodilation through
CB
1
in vascular smooth muscle and the inhibition of
endothelin-1 (Ronco et al. 2007), and decreasing the release
of pro-inflammatory mediators including nitric oxide (NO) and
tumor necrosis factor (TNFα) in the acute phase of injury
(Fernandez-Lopez et al. 2006; Panikashvili et al. 2006).
Besides their involvement in controlling excitotoxicity and
inflammation, compelling evidence shows that CB
1
recep-
tors in the CNS play an important role in neuroprotection
(Sanchez and Garcia-Merino 2011). CB
1
-deficient mice
were more susceptible to experimental autoimmune enceph-
alomyelitis (EAE), had more neurodegeneration and had
worse recovery, compared to wild type mice (Maresz et
al. 2007). The presence of CB
1
in neurons, but not in T-
cells, wa s an essential requisite for cannabinoid-mediated
neuroprotection in EAE. The therapeutic limitations of CB
1
agonists are related to the very short window of their
beneficial actions and psychoactiv e effects at effective
doses. CB
2
agonists are devoid of psychoactive activities.
Because neuroinflammation plays a significant role in essen-
tially all neurodegenerative processes, CB
2
stimulation be-
came an attractive target for development of neuroprotective
therapies. CB
2
is expressed in different types of leukocytes
mediating cannabinoid anti-inflammatory effects and
immunomodulation (McKallip et al. 2002a, b).
Cannabinoid induced immunomodulation
The mechanism of cannabinoid-induced immunomodulation
has been studied in both in vitro and in vivo systems; however,
still many questions remain unanswered. It is known that
cannabinoids bind to CB
1
and CB
2
inhibiting adenylate cy-
clase activity and preventing forskolin-stimulated cAMP acti-
vation. This process leads to decreased activity of protein
kinase A and subsequently lesser binding of transcription
factors to CRE consensus sequences (Condie et al. 1996;
Rieder et al. 2010). Cannabinoids clearly modulate immune
responses during inflammatory processes and their immuno-
modulatory effects have been studied in many disease models
such as MS, diabetes, septic shock, rheumatoid arthritis,
and others (Tables 1 and 2). Results of animal studies
show that cannabinoids exert their immunomod ulatory
properties in four ways: i) induction of apoptosis, ii)
suppression of cell proliferation, iii) inhibition of pro-
inflammatory cytokine/chemokine production and increase
in anti-inflammatory cytokines, and iv) induction of regulatory
T cells (Rieder et al. 2010). It has been shown that THC
inhibits proliferation of human lymphocytes in culture
(Schwarz et al. 1994) and leads to apoptosis of murine macro-
phages and T cells (Zhu et al. 1998). McKallip and colleagues
showed that THC affects naïve lymphocytes to a greater degree
than activated lymphocytes (McKallip et al. 2002b). It was also
noted that activated lymphocytes had less expression of
CB
2
, thereby explaining the decreased sensitivity of acti-
vated lymphocytes to THC (McKallip et al. 2002b). JWH-
015, a CB
2
synthetic agonist, inhibited proliferation in T and B
cells in a dose-dependent manner and induced apoptosis in
splenocytes and thymocytes (Lombard et al. 2007;Riederet
al. 2010). Derocq and colleagues (Derocq et al. 1995)dem-
onstrated that the activity of cannabinoids is not restricted to
immunomodulation, and in nanomolar concentrations of syn-
thetic (CP55,940 and WIN55212-2) and natural (THC) can-
nabinoids increase proliferation of B cells co-stimulated with
anti-CD40-antibodies, while at micromolar range (1100 μM)
the same cannabinoids inhibited proliferation (Derocq et al.
1995). Interestingly, cannabinol and THC protected human B
lymphoblastoid cell line from serum-deprived cell-death and
oxidative stress in sub-micromolar concentrations (Chen and
Buck 2000). The fact that activation of CB
2
triggers apoptosis
in immune cells suggests that targeting CB
2
may be a novel
approach to the treatment of inflammatory and autoimmune
diseases.
CB
2
expression in CNS and its mediated
anti-neuroinflammatory responses
CB
2
expression has been detected in microglia. Carlisle et al.
(Carlisle et al. 2002)foundCB
1
and CB
2
mRNA in brain
tissue and in primary rat microglia cultures. CB
2
expression in
microglia is up-regulated during activation. Neuroprotective
effects of CB
2
agonists are associated with suppression of
microglia activation (Klegeris et al. 2003; Eljaschewitsch et
al. 2006) via inhibiting the release of neurotoxic factors and by
decreasing neurona l cell damage in cell or tissue culture
models.
Increased expression of CB
2
under neuroinflammatory
conditions was found in human brain (Benito et al. 2008).
Prominent CB
2
upregulation was reported in brain tissues
affected by MS, amyotrophic lateral sclerosis (ALS), Down
syndrome and Alzheimers disease (AD) (Benito et al. 2005,
Table 1 Anti-inflammatory effects of CB
2
activation on immune and neuroimmune cells
Cell type Effect of CB
2
activation Reference
Immune cells
Macrophages diminished release of NO, IL-12p40 and TNFα (Chuchawankul et al. 2004)
Macrophages prevented ROS production and secretion of TNFα and CCL2 (Han et al. 2009)
B and T cells affected B and T cell differentiation, and the
balance of pro-inflammatory to anti-inflammatory cytokines
(Ziring et al. 2006)
Macrophages increased secretion of the anti-inflammatory cytokine, IL-10 (Correa et al. 2009)
Macrophages (Kupffer cells) inhibited LPS-induced NF-kB activation (Louvet et al. 2011)
Neuroimmune
Microglia diminished levels of IL-1β, IL-6 and TNFα (Puffenbarger et al. 2000)
Microglia inhibited release of TNFα (Facchinetti et al. 2003;
Ramirez et al. 2005)
Microglia diminished expression of CD40 (Engelhardt and Ransohoff 2005)
Glia enhanced release of the anti-inflammatory factors, IL-4 and IL-10 (Molina-Holgado et al. 1998)
Microglia inhibited TNFα production, p38 MAPK activation
and NADPH oxidase (NOX) activation
(El-Remessy et al. 2008)
Microglia interfered with expression of CCR2 and iNOS (Racz et al. 2008)
Microglia inhibited migration of microglial cells to HIV Tat protein (Fraga et al. 2011)
2007, 2008; Yiangou et al. 2006; Solas et al. 2012). Enhanced
CB
2
expression was detected on microglia, perivascular mac-
rophages and T cells in simian immunodeficiency virus en-
cephalitis, a model of HIV-1 infection that paralleled FAAH
over-expression in astrocytes (Benito et al. 2005). Increased
expression of CB
2
on microglia/perivascular macrophages
and brain microvascular endothelial cells were found in
HIV-1 encephalitis, brain endothelium in HIV
+
cases (without
encephalitis) and very little in non-infected control human
brains (Persidsky et al. 2011). CB
2
agonist prevented neuronal
injury during neuroinflammation via upregulation of mitogen-
activated protein kinase phosphatase-1 that resulted in Erk1/2
inhibition (Eljaschewitsch et al. 2006). CB
2
stimulation spe-
cifically reduced iNOS production via inhibition of ERK-1/2
phosphorylation in microglia during CNS inflammation
(Merighi et al. 2011). These findings have relevance to
anti-inflammatory effects of CB
2
stimulation i n brain.
CB
2
-mediated regulation of this pathway could be very
important for cannabinoid regulation of neuroinflammation.
Anti-inflammatory and neuroprotective effects of cannabinoids
have been confirmed in animal models for MS, A D,
stroke, ALS, and other animal models of diverse inflam-
matory diseases (summarized in Table 2). In summary,
cannabinoids can be neuroprotective via their immuno-
modulatory properties, which have been mainly attributed to
CB
2
receptors.
CB receptors in leukocytes and endothelium: relevance
to HIV infection
Cannabinoids can affect different pro-inflammatory events
associated with HIV infection, such as: i) chemotaxis of
immune cells, ii) activation of endothelium and leukocyte
infiltration into tissues, iii) injury of endothelial barriers, like
the blood brain barrier (BBB), and iv) HIV-1 infection of
susceptible cells.
CB
2
appears to play a major role in leukocyte migration.
Human monocytes treated with the synthetic CB
2
agonist,
JWH-015, showed diminished migration in response to the
chemokines, CCL2 and CCL3, via down-regulation of their
receptors and inhibition of IFNγ-induced ICAM-1 expres-
sion. Leukocyte migration mediated by RhoA activation
was inhibited by CB
2
agonists (Kurihara et al. 2006).
Cannabinoids could reduce inflammation by interfering
with the action of other chemoattractants (Mont ecucco et
al. 2008 ). Cannabinoids have been reported to inhibit
chemokine-induced chemotaxis of various cell types includ-
ing neutrophils, lymphocytes, macrophages, monocytes and
microglia (Miller and Stella 2008). Recently, it has been
shown that CB
2
agonist affected dendritic cell migration in
vitro and in vivo, primarily throu gh the inhibition of matrix
metalloproteinase-9 expression (Adhikary et al. 2012).
In addition to putative effects o n leukocytes, anti-
inflammatory properties of CB agonists may be related to
their actions on the endothelium. CB
2
has been found in
brain endothelium (Golech et al. 2004; Lu et al. 2008) and in
endothelial ce lls from other organs (Rajesh et al. 2007).
Synthetic CB
2
agonists (JWH-133, HU-308) reduced
TNFα-induced activation of human coronary artery endo-
thelial cells in vitro. CB
2
agonists reduced secretion of
MCP-1 and attenuated monocyte transendothelial migration
(Rajesh et al. 2007). Those results are relevant to CB
2
anti-
inflammatory effects.
Lu and colleagues (Lu et al. 2008)demonstratedthatHIV-1
gp120 caused secretion of substance P and dysfunction of
brain endothelial cells (Ca
2+
influx, decreased barrier tight-
ness, decrease in tigh t junction (TJ) expression) that was
prevented by non-selective CB
1
/CB
2
or CB
1
agonists. These
compounds diminished monocyte migration across endothe-
lial monolayers pretreated with gp120. The molecular mech-
anism underlying the beneficial effects of CB agonists was not
investigated. Because CB
2
agonists modulate immune cell
migration, they represent a promising pharmacological ap-
proach for development of anti-inflammatory therapeutics.
Fraga a nd colleagues (Fraga et al. 2011) found that CB
2
inhibited migration of microglial cells toward HIV Tat protein
in a mouse BV-2 microglia-like cell model. In addition, the
level of the β-chemokine receptor CCR3 was reduced and its
localization was altered.
Our group investigated the effects of CB
2
receptor
agonists (JWH133 and O1966) on leukocyte-brain endo-
thelial cell interactions. Using primary human brain mi-
crovascular endothelial cells and human monocytes, we
showed diminished adhesion of leukocytes to activated
endothelium and down-regulation of adhesion molecules.
In an animal model of systemic inflammation, leukocyte
adhesion was signific antly attenuated in postcapillary
Table 2 Anti-inflammatory effects of CB
2
activation in animal models
Animal model for disease Reference
Inflammatory pain
and ischemic stroke
(Yu et al. 2010; Pini et al. 2012)
Alzheimers disease (AD) (Martin-Moreno et al. 2012)
Colitis (Storr et al. 2009)
Acute hind paw inflammation (Berdyshev et al. 1998)
Acute lung injury (Conti et al. 2002)
Sepsis (Tschop et al. 2009)
Ischemic injury (Fernandez-Lopez et al. 2006)
ALS (Kim et al. 2006)
Viral MS model (Mestre et al. 2009)
Stroke (ischemia and reperfusion) (Zhang et al. 2007, 2009;
Murikinati et al. 2010;
Tuma and Steffens 2012)
EAE (Docagne et al. 2007)
Alcoholic liver disease (Louvet et al. 2011)
venules in animals treated with CB
2
agonists. BBB injury
and increased permeability were prevented (Ramirez et
al. 2012).
The CB
2
agonist, JWH133, was shown to inhibit HIV-1
infection in primary CD4+ T lymphocytes by altering T cell
actin dynamics via inactivation of the actin-modulat ing pro-
tein, cofilin. Actin rearrangements are essential for produc-
tive infection. CB
2
agonist did not alter CXCR4 expression,
T cell activation or viral fusion (Costa ntino et al. 2012 ). We
showed that CB
2
agonists diminished HIV replication and
HIV LTR activation in m onocyte-deriv ed macrophag es
(personal communication). Cannabim imeti c drugs are of
particular relevance to HIV-1 associated neurocognitive dis-
orders (HAND) because of their clinical and illicit use in
patients with AIDS. The cannabinoid receptor agonist,
Win55,212-2, inhibited HIV-1 gp120-induced IL-1β pro-
duction and synapse loss in a manner reversed by CB
2
receptor antagonist. In contrast, Win55,212-2 did not inhibit
synapse loss elicited by exposure to the HIV-1 protein Tat.
These results indicate that cannabinoids prevent the impair-
ment of network function produced by gp120 and, thus,
might have therapeutic potential in HAND (Kim et al.
2011). Molina and colleagues (Molina et al. 2010; Molina
et al. 2011) demonstrated that that chronic Δ
9
-THC treat-
ment decreased plasma and cerebrospinal fluid (CSF) viral
load and tissue inflammation significantly reducing morbid-
ity and mortality of simian immunodeficiency virus-infected
macaques. THC treatment led to better maintenance of body
weight without any alterations in immune responses
(Molina et al. 2010). Win55,212-2 has been shown to inhibit
HIV-1 expression in CD4
+
lymphocytes and microglial cell
cultures in a time- and dose-dependant manner (Peterson et
al. 2004). Taken together, these studies point to potential
therapeutic benefits of CB stimulation in treatment of HIV-1
infection.
Summary
The full potential of CB
2
agonists as therapeutic agents remains
to be realized. Despite some inadequacies of preclinical models
to predict clinical ef ficacy in humans and dif ferences between
the signaling of human and rodent CB
2
receptors, the develop-
ment of selective CB
2
agonists may open new avenues in
therapeutic intervention. Such interventions would aim at re-
ducing the release of pro-inflammatory mediators particularly
in chronic neuropathologic conditions such as HAND or MS.
Further studies are needed to delineate the therapeutic effects of
CB
2
agonists in current efforts to legalize the use of marijuana
for medical purposes.
Acknowledgements This work was supported in part by NIH Grants
AA017398, MH065151, DA025566, and AA015913 (Y.P.). The
authors express their grateful acknowledgement for proofreading
and editing to Nancy L. Reichenbach.
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    • "In one recent study, among HIV-seropositive (HIV?) persons who inject drugs and who recently seroconverted, heavy cannabis use was associated with lower plasma viral load levels [12]. The therapeutic effects of marijuana are proposed to be mediated via the actions of active cannabinoid chemicals in marijuana—cannabidiol—at specific receptor sites: cannabinoid receptors (CB2) located mainly on cells and tissues of the immune system [13, 14]. In contrast the primary psychoactive cannabinoid in marijuana: tetrahydrocannabidiol (THC) binds to and activates another receptor site: cannabinoid receptor (CB1) located mainly in areas of the brain [15] to produce the euphoric and cognitive impairing effects of marijuana [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: To construct longitudinal trajectories of marijuana use in a sample of men who have sex with men living with or at-risk for HIV infection. We determined factors associated with distinct trajectories of use as well as those that serve to modify the course of the trajectory. Data were from 3658 [1439 HIV-seropositive (HIV+) and 2219 HIV-seronegative (HIV−)] participants of the Multicenter AIDS Cohort Study. Frequency of marijuana use was obtained semiannually over a 29-year period (1984–2013). Group-based trajectory models were used to identify the trajectories and to determine predictors and modifiers of the trajectories over time. Four distinct trajectories of marijuana use were identified: abstainer/infrequent (65 %), decreaser (13 %), increaser (12 %) and chronic high (10 %) use groups. HIV+ status was significantly associated with increased odds of membership in the decreaser, increaser and chronic high use groups. Alcohol, smoking, stimulant and other recreational drug use were associated with increasing marijuana use across all four trajectory groups. Antiretroviral therapy use over time was associated with decreasing marijuana use in the abstainer/infrequent and increaser trajectory groups. Having a detectable HIV viral load was associated with increasing marijuana use in the increaser group only. Future investigations are needed to determine whether long-term patterns of use are associated with adverse consequences especially among HIV+ persons.
    Full-text · Article · Jun 2016
    • "Various studies have demonstrated that the CB 2 receptors are primarily found in immune cells and participate in immune regula- tion [16, 17, 23, 24]. Thus, interactions of alkylamides with CB 2 receptors can be demonstrated by immunomodulatory effect of Echinacea preparations [21, 25, 26] . "
    [Show abstract] [Hide abstract] ABSTRACT: The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB 1 and CB 2 ) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ 9 -tetrahydrocannabinol mediates its action through CB 1 /CB 2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis . Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.
    Full-text · Article · Dec 2015
    • "Therefore, CB 1 receptor activation promotes neuronal differentiation and maturation and protects neurons from brain injury (Parmentier-Batteur et al., 2002; Marsicano et al., 2003; Fowler et al., 2010; Compagnucci et al., 2013). Selective CB 2 receptor stimulation prevents deficits in neurogenesis, microglial activation and cognitive impairment, including the undesired psychoactive effects of neuronal CB 1 receptor activation (Ashton and Glass, 2007; Goncalves et al., 2008; Stella, 2010; Palazuelos et al., 2012; Rom and Persidsky, 2013; Avraham et al., 2014). Most studies suggested reduced brain cannabinoid activity during alcohol consumption, likely from the low expression levels of the CB 1 and CB 2 receptors (Basavarajappa, 2007; Ishiguro et al., 2007; Serrano et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence.
    Full-text · Article · Sep 2015
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