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Cannabinoids, inflammation, and fibrosis

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Cannabinoids apparently act on inflammation through mechanisms different from those of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of the phytocannabinoids Δ(9)-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented. Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of 3 synthetic preparations-Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United Kingdom)-that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (CT-3, AJA; Resunab; Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a presentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special interest is their possible use for treatment of chronic inflammation, a major unmet medical need.-Zurier, R. B., Burstein, S. H. Cannabinoids, inflammation, and fibrosis.
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JOURNAL REVIEW www.fasebj.org
Cannabinoids, inflammation, and fibrosis
Robert B. Zurier,
1
and Sumner H. Burstein
Department of Medicine and Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School,
Worcester, Massachusetts USA
ABSTRACT: Cannabinoids apparently act on inflammation through mechanisms different from those of agents such
as nonsteroidal anti-inflammatory drugs (NSAIDs). As a class, the cannabinoids are generally free from the adverse
effects associated with NSAIDs. Their clinical development thus provides a new approach to treatment of diseases
characterized by acute and chronic inflammation and fibrosis. A concise survey of the anti-inflammatory actions of
the phytocannabinoids D
9
-tetrahydrocannabinol (THC), cannabidiol, cannabichromene, and cannabinol is presented.
Mention is also made of the noncannabinoid plant components and pyrolysis products, followed by a discussion of
3 synthetic preparationsCesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, USA), Marinol (dronabinol; THC;
AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge United
Kingdom)that have anti-inflammatory effects. A fourth synthetic cannabinoid, ajulemic acid (AJA; CT-3; Resunab;
Corbus Pharmaceuticals, Norwood, MA, USA), is discussed in greater detail because it represents the most recent
advance in this area and is currently undergoing 3 phase 2 clinical trials by Corbus Pharmaceuticals. The endogenous
cannabinoids, including the closely related lipoamino acids, are then discussed. The review concludes with a pre-
sentation of a possible mechanism for the anti-inflammatory and antifibrotic actions of these substances. Thus, several
cannabinoids may be considered candidates for development as anti-inflammatory and antifibrotic agents. Of special
interest is their possible use for treatment of chronic inflammation, a major unmet medical need.Zurier,R.B.,Burstein,
S. H. Cannabinoids, inflammation, and fibrosis. FASEB J. 30, 36823689 (2016). www.fasebj.org
KEY WORDS: endocannabinoids specialized proresolving mediators anti-inflammatory antifibrotic
Preparations derived from Cannabis have been the source
of medical therapies since the earliest records on phar-
macobotany (1). Many beneficial effects of Cannabis on
the human body, including those on rheumatismwere
noted 4000 yr ago in a work reported by Hui-Lin Li called
Pen-tsao (2). The term cannabinoid usually refers to com-
pounds that activate the G-protein-coupled cannabinoid
receptors 1 and 2 (CB1 and -2). CB1 receptors, located
mainly on neurons in the hippocampus and basal ganglia,
mediate the psychoactive actions of cannabinoids (3).
CB2 receptors are present mainly on tissue and circulating
cells of the immune system (4). However, many Cannabis
components that do not activate either receptor are
sometimes called cannabinoids. Given that the Cannabis
plant contains more than 60 cannabinoids and 200250
noncannabinoid constituents, it follows that the therapeu-
tic benefits of marijuana are related to some combination of
these compounds. We review the current knowledge of the
mechanisms whereby phytocannabinoids, noncannabinoid
plant components, and their pyrolysis products aid in the
control of inflammation and fibrosis. We also address the
development of synthetic cannabinoids as treatment for
patients with diseases characterized by chronic inflamma-
tion and subsequent fibrosis. The ability of some cannabi-
noids to facilitate the resolution of inflammation by
stimulating the action of several specialized proresolv-
ing mediators (SPMs), an important emerging concept, is
also discussed. The roles of endogenous cannabinoids
(endocannabinoids) and the closely related lipoamino
acids in control of inflammation are also discussed.
CANNABIS CONSTITUENTS
Experiments with D
9
-tetrahydrocannabinol (THC; Fig.1),
the main psychoactive cannabinoid in the plant, have been
helpful in understanding the anti-inflammatory actions of
the nonpsychoactive cannabinoids (5, 6). Although there is
rich documentation of the anti-inflammatory actions of
several of the nonpsychoactive constituents, that literature
ABBREVIATIONS: 2-AG, 2-arachidonoylglycerol; AJA, ajulemic acid; ARCI-
M, Addiction Research Center Inventory-Marijuana; CB1/2, cannabinoid
receptor 1/2; CBD, cannabidiol; COX, cyclooxygenase; DMH, dime-
thylheptyl; FAAH, fatty acid aminohydrolase; FDA, U.S. Food and Drug
Administration; LINGly, N-linoleoyl glycine; LX, liposin; Mcl-1, myeloid
cell leukemia 1; MOA, mechanism of action; NAGly, N-arachidonoyl
glycine; NLINgly, NSAID, nonsteroidal anti-inflammatory drug; PBM,
peripheral blood monocyte; PG, prostaglandin; PPAR-g, peroxisome
proliferator-activated receptor-g; RA, rheumatoid arthritis; SLE, systemic
lupus erythematosus; SPM, specializing proresolving mediators; THC, D
9
-
tetrahydrocannabinol
1
Correspondence: Department of Biochemistry and Molecular Pharma-
cology, University of Massachusetts Medical School, 364 Plantation St.,
Worcester, MA 01605, USA. E-mail: robert.zurier@umassmed.edu
doi: 10.1096/fj.201600646R
3682 0892-6638/16/0030-3682 © FASEB
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has been crowded out by discussions about psycho-
activity and legalization of marijuana. For example, the
noncannabinoid, prenylated flavone cannflavin is 30
times more potent as an inhibitor of cyclooxygenase
(COX) than the time-honored anti-inflammatory drug
aspirin. In addition, Sofia et al. (7, 8) demonstrated the
anti-inflammatory actions of a crude extract of THC and
of the nonpsychoactive Cannabis constituents cannabidiol
(CBD) and cannabinol in a carrageenan-induced paw
edema model of acute inflammation in rats. They showed
in the same model that THC is 80 times more potent than
aspirin and twice as potent as hydrocortisone and that
the nonpsychoactive constituent cannabichromene also
suppresses the induced inflammation (911). Moreover,
CBD reduced acute inflammation in a murine model of
collagen-induced arthritis (12). The precise mechanisms
whereby CBD reduces inflammation are not clear. CBD
does reduce production of the proinflammatory cytokine
TNF-aand induces reduction of fatty acid amino-
hydrolase (FAAH) activity, thereby increasing production
of anandamide, an anti-inflammatory endocannabinoid.
Volatile oil components of Cannabis sativa suppress COX1
activity (13, 14), and pyrolysis products of CBD exhibit
activity in COX-1-suppression assays (15). Several of the
most abundant cannabinoid and noncannabinoid con-
stituents of the plant are not psychoactive (16). Thus, it
is clear that cannabinoid and noncannabinoid constitu-
ents of Cannabis are potential nonpsychoactive anti-
inflammatory agents.
As the most abundant nonpsychoactive cannabinoid
in Cannabis, CBD has been studied extensively for its
anti-inflammatory properties. As noted, it is active in a
murine model of collagen-induced arthritis. In addition,
CBD reduces carrageenan-induced paw edema in rats (17)
and intestinal inflammation in mice (18). CBD also coun-
ters psychoactivity, sedation, and tachycardia induced by
THC (19).
SYNTHETIC CANNABINOIDS
Synthetic cannabinoids are being developed in an effort to
separate psychoactivity from their analgesic and anti-
inflammatory actions. The dimethylheptyl-11-oic-acid
analog of CBD (DMH-CBD-11-oic acid; Fig. 1) reduces
joint inflammation and tissue injury (cartilage degradation
and bone erosion) in collagen-induced arthritis in mice
(20). Hydrogenation of DMH-CBD-11-oic acid yields 4
distinct epimers (21). Hydrogenation at different double
bonds leads to compounds with different bioactivities,
none of which depend on CB1 activation. Thus, several
potential therapeutic agents devoid of psychotropic ac-
tivity may eventually be derived from this one phyto-
cannabinoid. Three cannabinoidsCesamet (nabilone;
Meda Pharmaceuticals, Somerset, NJ, USA), Marinol
(dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA),
and Sativex (Cannabis extract; GW Pharmaceuticals,
Cambridge, United Kingdom)which activate both the
CB1 and -2 receptors have been approved by the U.S.
Food and Drug Administration (FDA) for clinical use.
Nabilone (Fig.1), a dimethylheptyl analog of THC, is
approved in many countries, including the United States,
Figure 1. Structures of compounds discussed in this review.
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for treatment of the severe nausea and vomiting associ-
ated with chemotherapy. It is also used for the manage-
ment of neuropathic pain and pain associated with cancer
and fibromyalgia (22). It is used most commonly as an
adjunctive therapy and as such results in small but sig-
nificant reductions in pain.
Dronabinol, THC, was approved by the FDA in 1985
for treatment of nausea and vomiting in patients receiving
cancer chemotherapy who failed to respond to conven-
tional antiemetics. It is administered in capsule form.
Dronabinol has also been used as an appetite stimulant
for patients with wasting diseases such as cancer and
HIV/AIDS (23).
THC with CBD (Sativex) is approved in 24 countries for
the treatment of muscle spasticity associated with mul-
tiple sclerosis. Sativex was granted fast track designation
by the FDA in 2014. Administered as a mint-flavored
oral spray, it is now in phase 3 clinical trials in the United
States for treatment of cancer-related pain. Similar to
nabilone and dronabinol, Sativex treatment has the same
potential adverse effects as marijuana (24). In a double-
blind placebo-controlled 5 wk study of 58 patients with
rheumatoid arthritis (RA) who received Sativex by oral
spray (25), pain at rest, pain on movement, sleep quality,
and clinical responses (disease activity score 28) were
improved significantly by Sativex.
Ajulemic acid (AJA; CT-3; Resunab; Corbus Pharma-
ceuticals, Norwood, MA, USA)is a synthetic cannabinoid
derived from a modification of THC-11-oic acid, the major
metabolite of THC.Extension of the pentyl side chain from
5 to 7 carbons, addition of 2 methyl groups to increase
receptor affinity, and a carboxylic acid at the 9 position
to reduce bloodbrain barrier penetration, results in the
formation of AJA (19,19-dimethylheptyl-THC-11-oic acid;
Fig. 1 (26). AJA, administered by mouth, is 50100 times
more potent than THC as an analgesic (27). The recently
developed preparation of AJA has 12 times greater affinity
for CB2 than for CB1, which renders it nonpsychoactive at
therapeutic doses (28). The anti-inflammatory and anti-
fibrotic actions of AJA have been demonstrated in several
in vitro systems and in animal models. Anti-inflammatory
effects were first demonstrated in arachidonic acid
induced rodent paw edema (26). In an adjuvant-induced
arthritis model, rats treated with 0.1 mg/kg AJA 33/wk
for 5 wk did not display evidence of active synovitis or
cartilage or bone damage, whereas control animals had
cartilage degradation and bone erosion that resembled RA
(29). In other experiments, rats treated with AJAat up to 30
mg/kg/d for 5 d, did not show signs of physical de-
pendence on the drug (30).
In studies designed to explore mechanisms of AJA ac-
tion, it was found that addition of AJA to human periph-
eral blood and synovial fluid monocytes in vitro reduces
production of the proinflammatory, bone-degrading cy-
tokine IL-1b(31).ItisofinterestthatAJAdidnotreduce
production of TNFain these studies, given the finding that
clinical trials of TNFainhibitors in patients with systemic
lupus erythematosus (SLE) have been limited by toxicity
and increases in disease activity (32, 33).We have observed
(unpublished data) that oral administration of single doses
of 310 mg AJA to healthy volunteers reduced pro-IL-1b
gene expression in and secretion of IL-1bfrom LPS-
stimulated peripheral blood monocytes (PBMs) (Table 1;
Zurier RB, Rossetti RG, Burstein SH, et al., unpublished
data). In contrast, AJA had no appreciable effect on TNFa
mRNA levels or TNFasecretion. Maximum serum con-
centration of AJA reached 0.15 mM at 5 h after a dose of 10
mg AJA (Corbus Pharmaceuticals, unpublished data).
No marijuana-like CNS effects were noted in the vol-
unteers, as assessed by the Addiction Research Center
Inventory-Marijuana (ARCI-M; developed in conjunction
with the Addiction Research Center of the National In-
stitute on Drug Abuse (National Institutes of Health,
Bethesda, MD, USA) scale (34) (Table 2; Corbus Phar-
maceuticals, unpublished data). Overall, the ARCI-M
scores for treated subjects were not different from baseline
scores or from placebo-treated subjects. The largest mean
number of items positively responded to by subjects given
AJA was 0.5 and occurred when the inventory was given
at the second hour after administration. The largest mean
number of positive responses among placebo-treated
subjects was 0.375 and occurred before administration.
The mean response rate of placebo-treated subjects at h 2
was 0:25. These numbers are relatively small compared to
those from experienced marijuana smokers. Subjects
smoking marijuana report mean scores of 5.2 and, under
placebo or presmoking conditions, 0.71.0. The relatively
few positive responses obtained in this study were not
dose related. These results suggest that AJA is not psy-
choactive at the doses tested.
Addition of AJA (330 mM) to human monocyte-
derived macrophages reduces steady-state levels of IL-6
mRNA and the subsequent secretion of IL-6 from LPS-
stimulated cells (35). IL-6 is a multifunctional cytokine that
contributes to inflammation and tissue injury in several
diseases. It has been identified in kidney biopsy tissue
from patients with SLE with active glomerulonephritis
(36). Skin biopsies from patients with SLE have exhibited
increased expression of IL-6 in active sites (37), and plasma
levels of IL-6 have correlated with lupus arthritis (38). In
addition, higher levels of IL-6 in synovial fluid increase the
risk of joint destruction in patients with RA (39). Because
activation of osteoclasts is central to the pathogenesis of
bone erosion in patients with RA, the influence of AJA on
osteoclast differentiation and survival was investigated (40).
TABLE 1. IL-1bsecretion from stimulated PBMs from healthy
volunteers administered AJA orally in capsules
Dose (mg)
Reduction of IL-1b
secretion 5 h after AJA (%)
3 14.6
6 35.6
10 47.4
Results are presented as percentage reduction in 3 subjects. PBMs
were isolated from peripheral blood of healthy male volunteers by
Ficoll-Hypaque separation. Rested cells were stimulated or not with 10 ng/ml
LPS 18 h for IL-1bsecretion (cytokine ELISA) in supernatants. Oral
administration of safower oil (AJA control) did not inuence IL-1b
secretion from stimulated PBMs. IL-1bsecretion from a 49-yr-old man
before and 5 and 24 h after oral administration of safower oil in
placebo capsules was 390410 pg/ml.
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Addition of AJA to cell cultures suppressed development of
multinucleated osteoclasts (osteoclastogenesis), and pre-
vented further osteoclast formation in cultures in which
osteoclastogenesis had already begun. Addition of AJA to
fibroblastlike synovial cells also reduces production of ma-
trix metalloproteinases, enzymes that facilitate cartilage and
bone destruction (41).
In addition to its capacity to bind to CB2, AJA binds to
and activates peroxisome proliferatoractivated receptor
(PPAR)-g(42). PPARgreceptors are members of a family
of nuclear receptors that modify the transcription of target
genes in response to a variety of signaling proteins. They
are expressed on immune cells, such as monocytes and
macrophages and regulate inflammatory responses
through inhibitory effects on expression of proin-
flammatory cytokines and eicosanoids (43). AJA binds
directly to a second site in the PPARgreceptor that is
separate from that utilized by other partial agonists, such
as the thiazolidinediones (44). Thus, the problems of
weight gain, fluid retention, and heart failure caused by
the thiazolidinediones, have not been seen in animals or
humans given AJA. Activation of PPARgby AJA
suppresses IL-8 promoter activity. IL-8 is a chemo-
attractant cytokine with specificity for the neutrophil,
the major cell involved in acute inflammation. Thus,
suppression of neutrophil migration and reduction of
enzyme release from neutrophil granules limits acute
inflammation and tissue injury. The loss of PPARg
in fibrotic tissues results in enhanced signaling by
TGFb, a major fibrogenic cytokine, and compounds
that activate PPARgreduce fibrosis in a murine model
of scleroderma (45). AJA exhibits antifibrotic effects in
murine models of systemic sclerosis (46) and reduces
collagen synthesis in dermal fibroblasts of patients
with scleroderma (47).
The discovery of SPMs (48) has broadened our un-
derstanding of how inflammation is controlled: not simply
by passive cessation of proinflammatory mediators, but
also by an increase in programmed cell death (apoptosis)
of immune-inflammatory cells and by activation of stop
signals that lead to resolution of inflammation. It is the lack
of resolution of inflammation that is in large part respon-
sible for the signs and symptoms of diseases character-
ized by chronic inflammation, tissue injury, and fibrosis.
Novel actions of AJA include its capacity to induce apo-
ptosis in human T lymphocytes (49) and to increase pro-
duction of 2 proresolving eicosanoidsprostaglandin
(PG)J
2
and LXA
4
(Fig. 1)that facilitate the resolution of
inflammation (50, 51).
In a phase 2 proof-of-principal trial, 21 patients with
neuropathic pain received twice daily doses of 20 mg AJA
in a double-blind, placebo-controlled manner for 7 d (52).
No clinically significant adverse events were noted. A
significant reduction in neuropathic pain was noted in 30%
of patients.
ENDOGENOUS CANNABINOIDS
Endocannabinoids are groups of naturally occurring
members of the eicosanoid superfamily that can activate
cannabinoid receptors and are derivatives of long-chain
fatty acids, primarily arachidonic acid. They are produced
rapidly from lipid precursors, are released from neurons by
neurotransmitters or from immune cells by inflammatory
agents, and can subsequently activate cannabinoid recep-
tors on the same or on adjacent cells. Some are metabolized
rapidly by the serine hydrolase FAAH to release the free
fatty acid.
Anandamide (Fig. 1), the amide conjugate of arachi-
donic acid and ethanolamine, is one of the most important
of the endocannabinoids andis well named. Ananda,from
the Sanskrit word for bliss, alludes to the capacity of
anandamide to increase motivation and pleasure (53).
Other endocannabinoids include 2-arachidonylglycerol
(2-AG), and virodhamine. Enzymes known to hydrolyze
endocannabinoids include FAAH, monoglyceride li-
pase, and N-acetylethanolamine. Endocannabinoids
TABLE 2. ARCI-M scores for AJA given orally in capsules
Hour
Dose (mg) n0 1 2 4 8 12 24 Overall mean
1 6 0.5 0.167 0.0 0.0 0.0 0.0 0.0 0.095
3 6 0.0 1.25 1.67 1.25 0.167 0.0 0.0 0.619
6 6 0.5 0.167 0.33 0.0 0.5 0.167 0.167 0.262
10 6 0.33 0.0 0.0 0.0 0.0 0.0 0.0 0.047
All active 24 0.33 0.42 0.5 0.33 0.167 0.04 0.04 0.262
All placebo 8 0.375 0.125 0.25 0.25 0 0.0 0.0 0.143
This was a single-center, phase 1, double-blind, randomized, placebo-controlled study to assess 4 single
increasing oral doses of AJA (1, 3, 6, and 10 mg) in 4 groups of 8 healthy male adult subjects. Thirty-two
eligible consenting subjects were randomized to 1 of the 4 groups and within each group of 8 subjects, 2
were randomized to receive placebo, and 6 subjects were randomized to receive AJA. Plasma concentrations
of AJA were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic
parameters were calculated by noncompartmental methods. Monitoring for the occurrence of adverse
events, changes in physical examination, vital signs (blood pressure, pulse rate, respiration), electrocardio-
grams, rating scales (mood scale and ARCI-M) and clinical laboratory tests (biochemistry, hematology,
urinalysis) were performed before and after administration of the study drug to assess safety, tolerability, and
psychoactivity. The Addiction Research Center Inventory-Marijuana (ARCI-M) scale was used to identify
possible marijuana-like effects of AJA. This 12-item questionnaire was developed to represent the
perceptions and feelings experienced by subjects when smoking marijuana.
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act to regulate inflammation and immune responses (54).
Anandamide reduces mitogen-induced T- and B-
lymphocyte proliferation, probably because of increased
apoptosis (55). Anandamide concentrations are increased
in cerebrospinal fluid and in circulating lymphocytes of
patients with multiple sclerosis (56), perhaps as an attempt
at regulation of the neuroinflammation characteristic of
the disease. In a murine model of colitis, CB1-knockout
(CB1
2/2
) mice exhibited far more inflammation than
animals with intact CB1 receptors (57). CB1 and -2 are up-
regulated on gingival fibroblasts of patients with perio-
dontitis. Anandamide reduces production of Porphyr-
omonas gingivalis LPS-induced IL-6, IL-8, and monocyte
chemoattractant protein-1 by these cells. Anandamide
also blocks LPS-triggered activation of NFkB, a protein
complex that controls transcription of DNA, cytokine
production, and cell survival (58). Anandamide also sup-
presses TNFa-induced NFkB activation by direct inhibi-
tion of I-kB kinase, the enzyme responsible for NFkB
activation (59). Of interest is the observation that the in-
hibitory activity was independent of CB1 and -2 activa-
tion. Another endocannabinoid, 2-AG, appears to inhibit
COX-2 via the CB1 receptor andcause down-regulation of
the MAPK/NFkB signaling systems (60). Thus, further
investigation and a better understanding of the regulation
of endocannabinoid production and metabolism may lead
to new therapy for diseases characterized by chronic in-
flammation and fibrosis.
LIPOAMINO ACIDS
An endogenous subfamily of eicosanoids, the lip-
oamino acids, are structurally and metabolically related
to the endocannabinoids and also exhibit analgesic,
anti-inflammatory, and proinflammatory resolving
properties (61). The best-studied member of this family
is N-arachidonoyl glycine (NAgly), which is similar in
structure to anandamide (Fig. 1). Indeed, oxidation of the
hydroxyl group of anandamide leads to NAgly, and
NAgly inhibits the FAAH-mediated metabolism of anan-
damide with moderate potency. There is evidence to sug-
gest that rather than acting through the CB1 or -2 receptors,
NAgly binds and activates an orphan G- protein-coupled
receptor GPR18 (62). In addition, GPR18, expressed on
human leukocytes, binds directly to resolvin D2 (RvD2), an
immunoresolvent synthesized during the resolution phase
of inflammation. In studies with mice, GPR18, bound to
RvD2, stimulated macrophage phagocytosis of bacteria
(Escherichia coli and Staphylococcus)andapoptosisof
PMNs, thereby enhancing clearance of bacteria, limiting
PMN infiltration, accelerating resolution, and reducing
tissue injury. These protective actions were substantially
reduced in GPR18-deficient mice (63).
It has long been thought that acute inflammation, a
primitive, protective response, simply resolvesor
noton its own, spontaneously. It is now clear that just as
mediators of inflammation initiate and sustain the in-
flammatory response, so also do lipid mediators, includ-
ing LXs, resolvins, protectins, and maresins, together
called SPMs, facilitate an active process of resolution of
inflammation, a series of events that prevent chronic in-
flammation, tissue injury, and fibrosis, and promote a
return of tissue to physiologic homeostasis (64). As ex-
emplified by the animal study cited above, a deficiency of
SPM impairs resolution of inflammation, just as an abun-
dance of inflammation mediators increases the intensity of
inflammation. As noted, select cannabinoids, such as AJA
and NAgly, stimulate particular SPMs. In an effort to
identify the precise proresolving actions of SPMs, a set of
quantitative resolution indices designed to determine the
active components (inflammatory and resolving) of a
particular resolution process were introduced (65). In ad-
dition, the impact of a known therapeutic agent on the
resolution process can be determined. For example, down-
regulation of the intracellular protein myeloid cell leuke-
mia 1 (Mcl-1) induces apoptosis of human PMNs but does
not impair their phagocytosis by macrophages, a series of
actions crucial to resolution. In a murine model of bacteria-
induced (E. coli) lung inflammation, down-regulation of
inflammatory cell Mcl-1 accelerated resolution time,
maintained appropriate lung function, and enhanced
bacterial clearance (66). These results may in future be
applied directly to treatment of patients with cystic fibrosis
who experience ongoing pulmonary inflammation, even
though their lung bacterial infections are cleared by
antibiotics.
Just as different prostaglandins derive from different
fatty acids (proinflammatory PGE
2
from arachidonic acid,
anti-inflammatory PGE
1
from linoleic acid) so, too,
do lipoamino acids derive from different fatty acids. N-
linoleoyl glycine (LINgly), for example, at doses as low as
0.3 mg/kg, reduced leukocyte migration into an area of
inflammation in a murine model of peritonitis (67). In
addition, LINgly treatment increases production by cells
in the peritoneum of the proresolving eicosanoid 15-
deoxy-D
13,14
-PGJ
2
(Fig. 1). A small group of N-linoleoyl
analogs have been studied for their ability to stimulate
PGJ
2
production in mouse macrophage RAW cells. The
D-alanine derivative was the most active, whereas the
D-phenylalanine showed almost no response. A high de-
gree of stereo specificity was observed when comparing
the D- and L-alanine isomers, the latter being the less active,
a finding that suggests the response is receptor mediated.
McHugh et al. (6870) found that recruitment of BV-2
microglia by NAgly resultsin anti-inflammatory actionsin
the brain. They reported that NAgly potently acts on
GPR18 to produce directed migration, cell proliferation,
and perhaps other MAPK-dependent actions. These re-
sults advance our understanding of the lipid-based sig-
naling mechanisms used in the CNS to actively recruit
microglia to sites of injury. The NAgly-GPR18 pathway
offers a novel approach to development of therapeutic
agents to elicit a population of regenerative microglia, or
alternatively, to prevent the accumulation of misdirected,
proinflammatory microglia that contribute to and in-
tensify neurodegenerative disease. These effects on
microglia may also apply to inflammation in the periph-
ery. The concept of an inflammatory reflex (71), a reflex
circuit that maintains immunologic homeostasis mediated
by the vagus nerve, is pertinent to a discussion of CNS
regulation of inflammation. The CNS receives input from
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the peripheral immune system via inflammatory cytokines
and chemokines that inform resident microglia and neu-
rons, which in turn act to reduce further production of the
cytokines. The result is that, for example, patients with RA
who receive anti-TNFatreatment develop changes in
brain activity before resolution of inflammation (redness,
swelling, heat, and pain) in the affected joints and before
reduction in C-reactive protein, a circulating marker of
inflammation. It appears that the nervous system is
hardwired to monitor the presence of cytokines and mo-
lecular products of invaders. It may well be that the lip-
oamino acids promote resolution of inflammation through
the inflammatory reflex. Thus, the lipoamino acids, in-
cluding the cannabinoids and endocannabinoids, contain
a multitude of compounds to investigate as potential new,
effective, and safe treatments for diseases characterized by
chronic inflammation, tissue injury, and fibrosis.
CONCLUSIONS
From the reports presented in this review, it may be con-
cluded that several cannabinoids can be considered
candidates for development as anti-inflammatory agents
(Table 3). These compounds are generally free from the
adverse effects associated with drugs now in clinical use.
In addition, cannabinoids apparently act on inflammation
through mechanisms that are different from those of other
agents such as NSAIDs. A putative mechanism of action
(MOA) of cannabinoids on inflammation is shown in Fig.
2, in which 2 well-studied examples, AJA and NAgly, are
illustrated. The initial event is the binding to and activation
ofCB2(forAJA)andGPR18(forNAgly)atlowdosesin
cells that are part of the immune system. In both cases an
increase in release of free arachidonic acid leads to the
increased production and release of proresolving eico-
sanoidssuchasPGJ
2
and LXA
4
. Ultimately, this process
results in an increase in the rate of resolution of chronic
inflammation. These released eicosanoids may also act
locally on fibroblast-like cells to reduce TGFbproduction
and signaling, resulting in turn, in a decrease in collagen
synthesis and subsequent fibrosis. At high doses, AJA can
activate PPARg, which may also result in a reduction of
fibrosis. As is true of all MOAs, this one will probably be
modified as more data are reported. Regardless of the
MOA, it appears likely that some of the cannabinoids
TABLE 3. Summary of the targets and anti-inammatory actions of substances discussed in this review
Substance Target proteins Response
Anandamide CB1/CB2 T- and B-lymphocyte proliferation reduced
NAGLY GPR-18 Recruitment of microglia stimulates PGJ
2
THC CB1/CB2 Antiedema activity; adjuvant induced arthritis
CBD PPARgReduces collagen-induced arthritis; increases anandamide
FAAH
CBN - Reduces collagen-induced arthritis
CBCr - Reduces collagen-induced arthritis
Dimethylheptylcannabidiol-11-oic acid - Reduces collagen-induced arthritis
Nabilone CB1/CB2 Chronic pain management and antiemetic
AJA CB2/ PPARgStimulates PGJ
2
and LXA
4
Cannavin COX-1/COX-2 Inhibits PGE
2
synthesis
LPXA
4
ALXR Inhibits NF-kB
PGJ
2
PPARgInhibits NF-kB
Figure 2. A proposed mechanism for the anti-inammatory and antibrotic actions of selected cannabinoids is presented. Two
examples are shown; the synthetic cannabinoid AJA and the endocannabinoid NAgly. The former activates the CB2 receptor, and
the latter activates the orphan receptor GPR-18. In cells of the immune system, this results in increased levels of the proresolving
eicosanoids PGJ
2
and LXA
4
. Ultimately, this process produces an increase in the rate of resolution of chronic inammation. A
second outcome is the action on broblast cells, resulting in decreased collagen production and reduced brosis.
CANNABINOIDS FOR INFLAMMATION AND FIBROSIS 3687
Vol.30, No.11 , pp:3682-3689, December, 2016The FASEB Journal. 146.189.156.77 to IP www.fasebj.orgDownloaded from
will be developed into safe and effective anti-inflammatory
drugs.
ACKNOWLEDGMENTS
The authors thank Corbus Pharmaceuticals, Inc. for pro-
viding unpublished ndings and Grant Kaufman for help in
preparing Fig. 1. The authors declare no conicts of interest.
AUTHOR CONTRIBUTIONS
R. B. Zurier and S. H. Burstein conceived of the content of
the article and wrote the manuscript.
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Received for publication June 4, 2016.
Accepted for publication July 11, 2016.
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2016 30: 3682-3689 originally published online July 19, 2016FASEB J
Robert B. Zurier and Sumner H. Burstein
Cannabinoids, inflammation, and fibrosis
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... Similarly, Wang S et al. recently demonstrated that specific deletion of CB 1 R in hepatic stellate cells did not protect mice from fibrosis (Wang et al., 2021). Instead, cannabinoids, such as Δ 9 -tetrahydrocannabinol (THC), cannabidiol, cannabichromene, cannabinol, Cesamet (nabilone; Meda Pharmaceuticals, Somerset, NJ, United States), Marinol (dronabinol; THC; AbbVie, Inc., North Chicago, IL, USA), and Sativex (Cannabis extract; GW Pharmaceuticals, Cambridge, USA) were considered useful for the treatment of chronic inflammation and fibrosis (Zurier and Burstein, 2016). Therefore, the role of CB1 signaling in the development of fibrosis, including IPF, has not yet been identified. ...
... Although the overactivity of CB 1 R was found contributing to the pathogenesis of pulmonary fibrosis, the pharmaceutical development of CB 1 R antagonist and their potential therapeutic uses in fibrosis was halted (Cinar et al., 2016). On the other hand, the phytocannabinoids (THC, cannabidiol, cannabichromene, and cannabinol) and synthetic preparations (Cesamet, Marinol, and Sativex) are candidates for development as anti-inflammatory and antifibrotic agents (Zurier and Burstein, 2016). In the present study, we found that CB 1 R expression dramatically increased in lung tissues and fibroblasts in response to experimental pulmonary fibrosis, but showed that its selective agonist ACPA exhibited marked antifibrotic effect both in vitro and in vivo models of pulmonary fibrosis, which was inconsistent with CB 1 R inhibition that ameliorated fibrosis (Bronova et al., 2015;Cinar et al., 2017;Correia-Sá et al., 2021). ...
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Pulmonary fibrosis is a group of life-threatening diseases with limited therapeutic options. The involvement of cannabinoid type 1 receptors (CB 1 R) has been indicated in fibrotic diseases, but whether or not the activation of CB 1 R can be a benefit for fibrosis treatment is controversial. In this study, we investigated the effects of arachidonoylcyclopropylamide (ACPA), as a selective CB 1 R agonist, on bleomycin (BLM)-induced pulmonary fibrosis. We showed that ACPA treatment significantly improved the survival rate of BLM-treated mice, alleviated BLM-induced pulmonary fibrosis, and inhibited the expressions of extracellular matrix (ECM) markers, such as collagen, fibronectin, and α-SMA. The enhanced expressions of ECM markers in transforming growth factor-beta (TGF-β)-challenged primary lung fibroblasts isolated from mouse lung tissues were inhibited by ACPA treatment in a dose-dependent manner, and the fibroblast migration triggered by TGF-β was dose-dependently diminished after ACPA administration. Moreover, the increased mRNA levels of CB 1 R were observed in both lung fibroblasts of BLM-induced fibrotic mice in vivo and TGF-β-challenged primary lung fibroblasts in vitro . CB 1 R-specific agonist ACPA significantly diminished the activation of TGF-β–Smad2/3 signaling, i.e., the levels of p-Smad2 and p-Smad3, and decreased the expressions of downstream effector proteins including slug and snail, which regulate ECM production, in TGF-β-challenged primary lung fibroblasts. Collectively, these findings demonstrated that CB 1 R-specific agonist ACPA exhibited antifibrotic efficacy in both in vitro and in vivo models of pulmonary fibrosis, revealing a novel anti-fibrosis approach to fibroblast-selective inhibition of TGF-β-Smad2/3 signaling by targeting CB 1 R.
... 1 As a class, the cannabinoids are also considered to be generally free from the adverse effects associated with nonsteroidal anti-inflammatory drugs. 8 Therefore, the clinical development of cannabinoids provides a potential new approach for treatment of diseases characterized by acute or chronic inflammation. 8,9 In spite of the paucity of published, controlled studies in veterinary species, some animal owners had been treating their dogs, cats, and horses with cannabinoid products before the legalization of medical marijuana in some states in 1996. ...
... 8 Therefore, the clinical development of cannabinoids provides a potential new approach for treatment of diseases characterized by acute or chronic inflammation. 8,9 In spite of the paucity of published, controlled studies in veterinary species, some animal owners had been treating their dogs, cats, and horses with cannabinoid products before the legalization of medical marijuana in some states in 1996. Benefits of cannabinoids purportedly include the reduction of anxiety, relief of pain, improvement of mobility in animals with osteoarthritis, reduction in tumor size, increased appetite, and improved control of type 2 diabetes, inflammatory conditions, digestive issues, and epileptic seizures. ...
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The purpose of this study was to determine the pharmacokinetics of cannabidiol (CBD), a potential treatment option that may alleviate pain in companion animals and humans, in the Hispaniolan Amazon parrot (Amazona ventralis). A pilot study administered a single oral dose of CBD in hemp oil at 10 mg/kg to 2 birds and 20 mg/kg to 2 birds. Because the maximum serum concentrations (Cmax) for these doses were 5.5 and 13 ng/mL, respectively, and the serum half-life was 2 hours for both groups, the doses were considered too low for clinical use in this species. Therefore, a study was designed in which 14 healthy 1214-year-old parrots of both sexes and weighing 0.240.35 kg (mean, 0.28 kg) were enrolled. Seven birds were administered 60 mg/kg CBD PO, and 7 birds were administered 120 mg/kg CBD PO. Blood samples were obtained at time 0, and at 0.5, 1, 2, 3, 4, 6, and 10 hours posttreatment in a balanced incomplete block design. Quantification of plasma CBD concentrations was determined by use of a validated liquid chromatographymass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis. The areas under the curve (hng/mL) were 518 and 1863, Cmax (ng/ mL) were 213 and 562, and times to achieve Cmax (hours) were 0.5 and 4 for the 60 and 120 mg/kg doses, respectively. The serum half-life could not be determined in the 60 mg/kg treatment, but was 1.28 hours at 120 mg/kg. Adverse effects were not observed in any bird. The highly variable results and short half-life of the drug in Hispaniolan Amazon parrots, even at high doses, suggests that this drug formulation was inconsistent in achieving targeted concentrations as reported in other animal species.
... Reducing immune activation and inflammation levels may be a potential therapeutic target. Cannabis has anti-inflammatory and anti-fibrotic properties and could be a valid method to reduce immune activation and improve the immune profile [124]. Cannabinoids, present in the hemp plant Cannabis sativa, have been recognized for centuries for their analgesic, anticonvulsant, bronchodilator, sedative, hypnotic, and antispasmodic properties [125,126]. ...
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Medical case reports suggest that cannabinoids extracted from Cannabis sativa have therapeutic effects; however, the therapeutic employment is limited due to the psychotropic effect of its major component, Δ9-tetrahydrocannabinol (THC). The new scientific discoveries related to the endocannabinoid system, including new receptors, ligands, and mediators, allowed the development of new therapeutic targets for the treatment of several pathological disorders minimizing the undesirable psychotropic effects of some constituents of this plant. Today, FDA-approved drugs, such as nabiximols (a mixture of THC and non-psychoactive cannabidiol (CBD)), are employed in alleviating pain and spasticity in multiple sclerosis. Dronabinol and nabilone are used for the treatment of chemotherapy-induced nausea and vomiting in cancer patients. Dronabinol was approved for the treatment of anorexia in patients with AIDS (acquired immune deficiency syndrome). In this review, we highlighted the potential therapeutic efficacy of natural and synthetic cannabinoids and their clinical relevance in cancer, neurodegenerative and dermatological diseases, and viral infections.
... While CBD, THC and their precursors, cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA-A), respectively, are the major cannabinoids present in most cultivars, the minor cannabinoids have also been shown to have pharmacological benefits for various medical conditions [4,5]. Cannabinol (CBN), cannabigerol (CBG) and cannabichromene (CBC) have been shown to exhibit anti-inflammatory properties for various medical conditions, including irritable bowel syndrome [6][7][8][9][10]. There is also evidence to suggest that cannabigerolic acid (CBGA) and cannabidivarin (CBDV) have anticonvulsant properties and they may be useful in the treatment of epilepsy in conjunction with CBD [10,11]. ...
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The high-throughput quantitation of cannabinoids is important for the cannabis industry. As medicinal products increase, and research into compounds that have pharmacological benefits increase, and the need to quantitate more than just the main cannabinoids becomes more important. This study aims to provide a rapid, high-throughput method for cannabinoid quantitation using a liquid chromatography triple-quadrupole mass spectrometer (LC-QQQ-MS) with an ultraviolet diode array detector (UV-DAD) for 16 cannabinoids: CBDVA, CBDV, CBDA, CBGA, CBG, CBD, THCV, THCVA, CBN, CBNA, THC, Δ8-THC, CBL, CBC, THCA-A and CBCA. Linearity, limit of detection (LOD), limit of quantitation (LOQ), accuracy, precision, recovery and matrix effect were all evaluated. The validated method was used to determine the cannabinoid concentration of four different Cannabis sativa strains and a low THC strain, all of which have different cannabinoid profiles. All cannabinoids eluted within five minutes with a total analysis time of eight minutes, including column re-equilibration. This was twice as fast as published LC-QQQ-MS methods mentioned in the literature, whilst also covering a wide range of cannabinoid compounds.
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Obesity and nonalcoholic fatty liver disease (NAFLD) constitute global and growing epidemics that result in therapeutic dead ends. There is an urgent need for new and accessible treatments to improve and widen both preventive and curative approaches against NAFLD. The endocannabinoid system (ECS) is recognized as a complex signaling apparatus closely related to metabolic disorders and is a key target for treating NAFLD. Despite a lack of conclusive clinical trials, observational and pre-clinical studies highlight putative benefits of phytocannabinoids on liver steatosis through multiple pathways. Owing to both its safety profile and its diversity of active compounds acting primarily (although not exclusively) on the ECS-and its expanded version, the endocannabinoidome, the Cannabis plant should be considered a major prospect in the treatment of NAFLD. However, seizing this opportunity, and intensifying clinical research in this direction, will require overcoming both scientific and nonscientific barriers.
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: High-risk neuroblastoma is an aggressive pediatric tumor. Despite great advances in neuro-blastoma therapy and supportive care protocols, no curative treatment is available for most pa-tients with this disease. Here, we uncover that CBN attenuated the cell proliferation, invasion, and angiogenesis of neuroblastoma cell lines in a dose-dependent manner via the inhibition of the AKT pathway and the upregulation of miR-34a that targets E2F1. Both miR-34a and a 31-nt tRNAiMet fragment (tRiMetF31) derived from miR-34a-guided cleavage were downregulated in 4 examined neuroblastoma cell lines inversely correlated with the levels of its direct target, the PFKFB3 protein. Moreover, ectopic tRiMetF31 suppressed proliferation, migration, and angio-genesis in the studied neuroblastoma cell lines. Conversely, tRiMetF31 knockdown promoted PFKFB3 expression, resulting in enhanced angiogenesis. Our findings reveal a suppressive role of CBN in neuroblastoma tumorigenesis, highlighting a novel and crucial miR-34a tumor sup-pressor network in CBN’s antineuroblastoma actions.
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High-risk neuroblastoma is an aggressive pediatric tumor. Despite great advances in neuroblastoma therapy and supportive care protocols, no curative treatment is available for most patients with this disease. Here, we uncover that CBN attenuated the cell proliferation, invasion, and angiogenesis of neuroblastoma cell lines in a dose-dependent manner via the inhibition of the AKT pathway and the upregulation of miR-34a that targets E2F1. Both miR-34a and a 31-nt tRNAiMet fragment (tRiMetF31) derived from miR-34a-guided cleavage were downregulated in 4 examined neuroblastoma cell lines inversely correlated with the levels of its direct target, the PFKFB3 protein. Moreover, ectopic tRiMetF31 suppressed proliferation, migration, and angiogenesis in the studied neuroblastoma cell lines. Conversely, tRiMetF31 knockdown promoted PFKFB3 expression, resulting in enhanced angiogenesis. Our findings reveal a suppressive role of CBN in neuroblastoma tumorigenesis, highlighting a novel and crucial miR-34a tumor suppressor network in CBN’s antineuroblastoma actions.
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Background Cannabis use has been linked to lower systemic inflammation, but the pathways connecting cannabis use and systemic inflammation are unclear. Here we investigate whether body mass index (BMI) accounts for the association between cannabis use and systemic inflammation in a cohort of sexual and gender minority youth assigned male at birth (n = 712). Methods Substance use was assessed across six biannual visits. Cannabis use was measured using the Cannabis Use Disorders Identification Test-Revised (CUDIT-R) and urine screening for tetrahydrocannabinol (THC). At the final visit, BMI was measured, and a plasma sample was collected to measure biomarkers of systemic inflammation: C-reactive protein (CRP), interleukin-6, interleukin-1β, and tumor necrosis factor-α. Inflammatory markers were log2-transformed. Age, gender, race/ethnicity, education, HIV status, cigarette use, alcohol use, and polydrug use were included as covariates. Results In models including all covariates except BMI, greater cumulative CUDIT-R score was associated with lower CRP (β = −0.14; 95% CI: −0.22,−0.05) and lower interleukin-6 (β = −0.12; 95% CI: −0.21,−0.04). These associations were attenuated when BMI was added to the model. Mediation analyses revealed an indirect effect of cumulative CUDIT-R score on CRP (β = −0.08; 95% CI: −0.12,−0.05) and interleukin-6 (β = −0.08; 95% CI: −0.12,−0.05), mediated by BMI. Models using urine THC or self-reported frequency to operationalize cannabis use produced similar results. We found no clear evidence that HIV status moderates these associations. Conclusions These results suggest that BMI may partially account for the apparent anti-inflammatory effects of cannabis use. Research on the mechanisms linking cannabis use, adiposity, and inflammation may uncover promising intervention targets.
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Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.
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Background: Ajulemic acid (AjA) is a synthetic analogue of tetrahydrocannabinol that can prevent and limit progression of skin fibrosis in experimental systemic sclerosis. In this study we investigated whether AjA also prevents and modulates lung fibrosis induced by bleomycin (BLM) when administered in mice during the inflammatory or the fibrogenic phase of the model. Methods: The anti-inflammatory and antifibrotic efficacy of AjA was evaluated in DBA/2 mice treated orally once a day starting either at day 0 (preventive treatment) or at day 8 (therapeutic treatment) after a single intratracheal instillation of BLM. AjA was given at a dose of 1 mg/kg or 5 mg/kg. Mice were sacrificed at day 8, 14 and 21 after BLM and lungs were processed for histology and morphometry, and examined for HO-proline content and for the expression of transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2/3 (pSMAD2/3), connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and peroxisome proliferator-activated receptor-gamma (PPAR-γ). Results: In the 1st week after BLM challenge, an acute inflammation characterized by neutrophil and macrophage accumulation was the main change present in lung parenchyma. The "switch" between inflammation and fibrosis occurs between day 8 and 14 after BLM instillation and involves the bronchi and vasculature. In the subsequent week (at day 21 after BLM instillation) bronchiolocentric fibrosis with significant increase of tissue collagen develops. The fibrotic response evaluated by morphometry and quantified as HO-proline in lung tissue at day 21 after BLM treatment was significantly reduced in mice receiving either AjA in the inflammatory or in early fibrogenic phase. AjA induces marked change in the expression pattern of products implicated in fibrogenesis, such as TGF-β1, pSMAD2/3, CTGF and α-SMA. In addition, AjA increases significantly the number of PPAR-γ positive cells and its nuclear localization. Conclusions: AjA treatment, starting either at day 0 or at day 8 after BLM challenge, counteracts the progression of pulmonary fibrosis. The anti-fibrotic effectiveness of AjA is irrespective of timing of compound administration. Further clinical studies are necessary to establish whether AjA may represent a new therapeutic option for treating fibrotic lung diseases.
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Since the beginning of the HIV/AIDS epidemic, weight loss has been a common complaint for patients. The use of various definitions defining HIV wasting syndrome has made it difficult to determine its actual prevalence. Despite the use of highly active antiretroviral therapy, it is estimated that the prevalence of HIV wasting syndrome is between 14% and 38%. HIV wasting syndrome may stem from conditions affecting chewing, swallowing, or gastrointestinal motility, neurologic disease affecting food intake or the perception of hunger or ability to eat, psychiatric illness, food insecurity generated from psychosocial or economic concerns, or anorexia due to medications, malabsorption, infections, or tumors. Treatment of HIV wasting syndrome may be managed with appetite stimulants (megestrol acetate or dronabinol), anabolic agents (testosterone, testosterone analogs, or recombinant human growth hormone), or, rarely, cytokine production modulators (thalidomide). The goal of this review is to provide an in-depth evaluation based on existing clinical trials on the clinical utility of dronabinol in the treatment of weight loss associated with HIV/AIDS. Although total body weight gain varies with dronabinol use (-2.0 to 3.2 kg), dronabinol is a well-tolerated option to promote appetite stimulation. Further studies are needed with standardized definitions of HIV-associated weight loss and clinical outcomes, robust sample sizes, safety and efficacy data on chronic use of dronabinol beyond 52 weeks, and associated virologic and immunologic outcomes.
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A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy subjects and AN patients was observed for food-intake-induced changes in oleoylethanolamide concentrations. These data confirm that endocannabinoids and endocannabinoid-related compounds are involved in food-related reward and suggest a dysregulation of their physiology in AN. This trial was registered at ISRCTN.org as ISRCTN64683774. © 2015 American Society for Nutrition.
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Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.
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Nabilone, a synthetic cannabinoid, is approved in many countries including, but not limited to, Canada, the United States, Mexico, and the United Kingdom for the treatment of severe nausea and vomiting associated with chemotherapy. Clinical evidence is emerging for its use in managing pain conditions with different etiologies. We review the efficacy and safety of nabilone for various types of pain as well as its abuse potential, precautions and contraindications, and drug interactions; summarize pertinent clinical practice guidelines; and provide recommendations for dosing, monitoring, and patient education. Citations involving nabilone were identified through systematic reviews evaluating cannabinoids for pain. A systematic search (updated July 23, 2015) of the Ovid MEDLINE, EMBASE, PubMed, and Cochrane Library databases was performed. Eight randomized controlled trials, two prospective cohort trials, and one retrospective chart review were retrieved. Cancer pain, chronic noncancer pain, neuropathic pain, fibromyalgia, and pain associated with spasticity were the pain conditions evaluated. Nabilone was most commonly used as adjunctive therapy and led to small but significant reductions in pain. The most common adverse drug reactions included euphoria, drowsiness, and dizziness. Nabilone was rarely associated with severe adverse drug reactions requiring drug discontinuation, and the likelihood of abuse was thought to be low. Although the optimal role of nabilone in the management of pain is yet to be determined, certain clinical practice guidelines consider nabilone as a third-line agent.
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Setting: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. Subjects and methods: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. Results: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. Conclusions: Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.
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Endogenous mechanisms that orchestrate resolution of acute inflammation are essential in host defense and the return to homeostasis. Resolvin (Rv)D2 is a potent immunoresolvent biosynthesized during active resolution that stereoselectively stimulates resolution of acute inflammation. Here, using an unbiased G protein-coupled receptor-β-arrestin-based screening and functional sensing systems, we identified a receptor for RvD2, namely GPR18, that is expressed on human leukocytes, including polymorphonuclear neutrophils (PMN), monocytes, and macrophages (MΦ). In human MΦ, RvD2-stimulated intracellular cyclic AMP was dependent on GPR18. RvD2-stimulated phagocytosis of Escherichia coli and apoptotic PMN (efferocytosis) were enhanced with GPR18 overexpression and significantly reduced by shRNA knockdown. Specific binding of RvD2 to recombinant GPR18 was confirmed using a synthetic (3)H-labeled-RvD2. Scatchard analysis gave a Kd of ∼10 nM consistent with RvD2 bioactive concentration range. In both E. coli and Staphylococcus aureus infections, RvD2 limited PMN infiltration, enhanced phagocyte clearance of bacteria, and accelerated resolution. These actions were lost in GPR18-deficient mice. During PMN-mediated second organ injury, RvD2's protective actions were also significantly diminished in GPR18-deficient mice. Together, these results provide evidence for a novel RvD2-GPR18 resolution axis that stimulates human and mouse phagocyte functions to control bacterial infections and promote organ protection. © 2015 Chiang et al.