ABOUT OMICS GROUP
A
BOUT
OMICS G
ROUP
OMICS Group is an amalgamation of
and worldwide international science conferences
and events. Established in the year 2007 with the sole aim of
making the information on Sciences and technology ‘Open
Access’, OMICS Group publishes 500 online open access
in all aspects of Science, Engineering,
Management and Technology journals. OMICS Group has
been instrumental in taking the knowledge on Science &
technology to the doorsteps of ordinary men and women.
Research Scholars, Students, Libraries, Educational
Institutions, Research centers and the industry are main
stakeholders that benefitted greatly from this knowledge
dissemination. OMICS Group also organizes 500
annually across the globe, where
knowledge transfer takes place through debates, round table
discussions, poster presentations, workshops, symposia and
exhibitions.International conferencesscholarly journals PublicationsOpen Access
OMICS I
NTERNATIONAL
C
ONFERENCES
OMICS International is a pioneer and leading science
event organizer, which publishes around 500 open
access journals and conducts over 500 Medical, Clinical,
Engineering, Life Sciences, Pharma scientific
conferences all over the globe annually with the support
of more than 1000 scientific associations and 30,000
editorial board members and 3.5 million followers to its
credit.
OMICS Group has organized 500 conferences,
workshops and national symposiums across the major
cities including San Francisco, Las Vegas, San Antonio,
Omaha, Orlando, Raleigh, Santa Clara, Chicago,
Philadelphia, Baltimore, United Kingdom, Valencia,
Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.
A
NTI
-
INFLAMMATORY
EFFECTS
OF
CANNABINOID
2
RECEPTOR
AGONIST
, GW405833,
IN
A
MODEL
OF
CARRAGEENAN
-
INDUCED
ACUTE
INFLAMMATION
OF
THE
RAT
PAW
O
UR
WORKING
TEAM
A
NTI
-
INFLAMMATORY
EFFECTS
OF
CANNABINOID
2
RECEPTOR
AGONIST
, GW405833,
IN
A
MODEL
OF
CARRAGEENAN
-
INDUCED
ACUTE
INFLAMMATION
OF
THE
RAT
PAW
I
NTRODUCTION
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
C
ANNABIS
SATIVA
Cannabis sativa produces over 80 cannabinoids
Δ9-tetrahydrocannabinol (THC)
was identified
as
the main bioactive constituent of cannabis
,
the
main psychotropic
constituent of marijuana.
The psychological addiction resulting from the
abuse
of cannabis is the main concern limiting its
therapeutic use
.
N
onpsychoactive
compound;
cannabidiol (CBD) and
cannabinol (CBN)
T
HE
SYNTHETIC
CANNABINOIDS
Naphthoylindoles (e.g., JWH-018, JWH-073, JWH-398).
Naphthylmethylindoles. (e.g., JWH-175, JWH-195, JWH-197).
Naphthoylpyrroles.(e.g., JWH-030, JWH-156, JWH-243).
Naphthylmethylindenes (e.g., JWH-176).
Phenylacetylindoles (i.e., benzoylindoles, e.g., JWH-250, JWH-253,
JWH-313).
Cyclohexylphenols (e.g., CP 47,497 and homologs of CP 47,497).
Classical cannabinoids (e.g., HU-210).
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
I. T
HE
R
ECEPTORS
The cannabinoid receptors
were found and cloned in the early
1990s
The endogenous cannabinoid
(EC)
system
consists of
two
G-protein-coupled
cannabinoid i.e.
CB1
and
CB2
receptors
However
there are
maybe
additional receptors
And, some EC effects
result from the interaction with other
receptors, such as the
vanilloid
receptor
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
I. T
HE
R
ECEPTORS
The
cannabinoid CB1
receptors are preferentially
located on brain
and also
expressed in nerve
terminals of peripheral
tissues
including heart and
vessels.
The
cannabinoid CB2
receptors
are mainly
located on
peripheral non-neuronal cells
(
mostly
immune
system cells
)
which exert
a
broad range of
critical
effects
under physiological or pathological conditions
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
II. E
NDOCANNABINOID
LIGANDS
First endogenous
ligands turned out to be fatty acid-derived
molecules including
A
nandamide
(a
rachidonoyl ethanolamide
,
AEA
) and
2-arachidonoylglycerol
(
2-AG
)
AEA has more affinity to CB1 than CB2,
2-AG
shows similar affinity for CB1 and CB2
CB2 receptors may also bind other
endocannabinoid ligands;
however, the signalling consequences
of this binding is poorly
known
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
III.
E
NDOCANNABINOID
-
BIOSYNTHETIC
AND
CATABOLIC
ENZYMES
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
III.
E
NDOCANNABINOID
BIOSYNTHETIC
AND
CATABOLIC
ENZYMES
T
he biosynthesis of AEA
is
catalyzed by Ca2+-
dependent N-acyl-phosphatidylethanolamine–
hydrolyzing
phospholipase D
,
AEA can also be produced by other
routes
,
AEA is
hydrolyzed
mainly
by fatty acid amide
hydrolase (FAAH)
into
arachidonic acid
and
ethanolamine
.
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
III.
E
NDOCANNABINOID
BIOSYNTHETIC
AND
CATABOLIC
ENZYMES
2-AG is synthesized
from its phospholipid precursor
diacylglycerol
by
diacylglycerol lipases
.
Phospholipase
C-
β
releases diacylglycerol (DAG) from
phosphatidylinositol-4,5-bisphosphate, which in turn is
metabolized by
diacylglycerol lipases (DAGLs) – with
DAGL
α
and DAGL
β
having
prevalent roles in the
brain and in several peripheral tissues,
respectively –
to produce 2-AG
.
The major degradative
or inactivated
pathway
of 2-AG
is its hydrolysis to
arachidonic acid
and
glycerol
by
monoacylglycerol lipase
(MAGL)
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
III.
E
NDOCANNABINOID
BIOSYNTHETIC
AND
CATABOLIC
ENZYMES
Although the hydrolysis pathway seems
to be the
primary fate of AEA and 2-AG, they can also be
oxidized by
cyclooxygenase-2
and
lipoxygenase
isozymes,
thus
producing oxidized
endocannabinoids,
which are involved in regulating
brain
synaptic
transmission and other biological processes
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
T
HE
E
FFECTS
A
ccumulating evidence has indicated that EC and
their major receptors CB1 and CB2 play a major role
in the pathophysiology
of diseases
at a preclinical stage,
the selective CB2 molecules
are increased to
interest
as new targets in
drug discovery
Endocannabinoids can modulate levels of proinflammatory
mediators and immune cell migration. Exogenously administered
2-AG and anandamide
or
several selective agonists
to animal
models of inflammation have also
shown to be effective
.
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
T
HE
E
FFECTS
ECs
are provided by a series of
central and
peripheral effects
CB1 is more responsive
to psychoactive cannabinoids (eg, THC)
than to nonpsychoactive
cannabinoids (eg, cannabidiol)
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
T
HE
E
FFECTS
ECs
influence
analgesia and
motor function,
energy balance and food intake,
cardiovascular
function,
immune and inflammatory responses
, and
cell proliferation
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
A
ND
I
NFLAMMATION
the endocannabinoid system
has been found to be
involved in many inflammation-related
conditions, such as
M
ultiple sclerosis,
A
therosclerosis,
I
nflammatory
bowel disease,
RA,
Sepsis, and
A
llergic inflammation
I
NTRODUCTION
T
HE
C
ANNABINOID
ERGIC
SYSTEM
A
ND
I
NFLAMMATION
The
blockage of CB1 and activation of CB2 could inhibit
inflammation in various animal models
, mainly through
restraining the
activity of the immune system.
The
exogenous application of AEA and 2-AG exerts
anti-
inflammatory effects by decreasing the production of
inflammatory
mediators
.
The
exogenous application of
selective CB2 agonists
exerts
anti-inflammatory effects by decreasing the
production of inflammatory
mediators
.
Upregulating the level of endogenous
cannabinoids by
inhibiting their
common
metabolic enzyme, becomes an
important
strategy in the treatment process of
inflammation-related diseases
I
NTRODUCTION
I
N
OUR
PREVIOUS
STUDIES
We
had evaluated some effects of the cannabinoid
(CB)2 receptor activations’ during the
inflammatory processes of peripheral tissues after
intestinal ischemia/reperfusion .
I
NTRODUCTION
A
IM
OF
THIS
STUDY
This study was designed to investigate the anti-
inflammatory effects of
selective CB2 receptor agonist
,
GW405833
,
in the carrageenan paw oedema test of rats.
in the ca
psaicin
paw oedema test of rats.
M
ATERIALS
AND
M
ETHODS
A
NIMALS
AND
E
XPERIMENTAL
D
ESIGN
The subjects weighed between
200
and 25
0
g, and were housed
in a temperature (20–22 °C) in their home cages and were
maintained on a 12/12 h light/dark cycle
.
All rats were given standard rat chow and water ad libitum
The sample size for
each treatment group was 6 to
8
mice/group
All animal protocols were approved by the
Institutional Animal
Care and Use Committee and were in accordance with the
National
Institutes of Health
G
uide for the care and use of
Laboratory animals.
After testing was completed, all mice were humanely
euthanized via CO2 asphyxia, followed by rapid cervical
dislocation.
M
ATERIALS
AND
M
ETHODS
I
NFLAMMATION
TYPE
Carrageenan-induced paw edema -
Mix type
of
inflammation
were induced by giving an intraplantar injection of
carrageneen (50 µl, 1%) or
Capsaicin-induced paw edema -
N
eurogenic
type
of
inflammation
were induced by giving an intraplantar injection of
capsaicin (50 µl, 0.1%) into the paw
M
ATERIALS
AND
M
ETHODS
I
NFLAMMATION
TYPE
P
AW
EDEMA
Edema was expressed as the increase in
paw thickness
(mm) after
carrageenan
injection relative to the pre-
injection value
for each animal.
Paw thickness was
measured with electronic
digital calipers, prior to
and
1 or 4
h following
capsaicin or
carrageenan administration
respectively
, which corresponds to peak edema
time.
M
ATERIALS
AND
M
ETHODS
A
NIMALS
AND
E
XPERIMENTAL
D
ESIGN
In the first group,
P
lasma extravasations
were measured via Evans
blue dye method.
The dye was injected in the tail vein 15 min before
the end of the experiments.
The anaesthetized animals were sacrificed by
decapitation, and hind paws were incubated with
formamide, and then the extracted dye was
measured by spectrophotometry at 620 nm.
M
ATERIALS
AND
M
ETHODS
A
NIMALS
AND
E
XPERIMENTAL
D
ESIGN
In the second group
,
paw thickness
was measured with electronic digital
callipers, prior to and 4 h following carrageenan or 1 h
following capsaicin administration, which corresponds
to peak oedema.
This procedure has been used
previously by
studies.
The anti-oedematous effects of GW405833 (3 mg/kg,
i.v.) were compared to diclo
f
enac (10 mg/kg, i.v.), a
nonselective cyclooxygenase inhibitor, 15 min before
these intraplantar injections of inflammatory agents.
CB receptor involvement in the anti-inflammatory
effects of GW405833 was evaluated by administration
of the CB2 receptor antagonist, AM630 (1 mg/kg, i.v.,
5 min before CB2 agonist injection).
M
ATERIALS
AND
M
ETHODS
S
TATISTICAL
D
ATA
A
NALYSIS
All statistical analyses were carried out using GraphPad
statistical software.
All data were presented as mean ± standard error mean.
Difference between groups was compared using
student
t
test or
one-way ANOVA followed by
Tukey
's Multiple Comparison.
P
<0.05 was considered significant.
R
ESULTS
I.
The
carrageenan-induced paw oedema
Administrate of carrageenan caused clear edema in paw
tissue (P < 0.001)
Pretreatment of rats with both GW405833
(P < 0.05) and
diclofenac
(P < 0.0
01
) significantly attenuated
carrageenan-induced paw oedema compared to vehicle-
treated group.
CB2 receptor antagonist, AM630, significantly reversed
th
e
effect
of CB2 agonist
(P < 0.01)
*
***
F
i
g
u
r
e
1
.
T
h
e
c
a
r
r
a
g
e
e
n
a
n
-
i
n
d
u
c
e
d
p
a
w
o
e
d
e
m
a
a
n
d
t
h
e
e
f
f
e
c
t
o
f
C
B
2
a
g
o
n
i
s
t
R
ESULTS
II.
The
c
apsaicin
-induced paw oedema
Administrate of capsaicin caused clear edema in paw
tissue (P < 0.001)
Pretreatment of rats with GW405833
(P < 0.
0
0
1
)
significantly attenuated ca
psaicin
-induced paw
oedema compared to vehicle-treated group.
CB2 receptor antagonist, AM630, significantly
reversed that effect (P < 0.001)
***
F
i
g
u
r
e
2
.
T
h
e
c
a
p
s
a
i
c
i
n
-
i
n
d
u
c
e
d
p
a
w
o
e
d
e
m
a
a
n
d
t
h
e
e
f
f
e
c
t
o
f
C
B
2
a
g
o
n
i
s
t
R
ESULTS
III.
The effect of CB2 agonist on
plasma
extravasation in
carrageenan-induced paw
oedema
The
GW405833
significantly
inhibited
plasma
extravasation in
carrageenan-induced paw oedema
(P < 0.0
01
) .
D
iclofenac
inhibited also plasma
extravasation, but has effect as more week (P < 0.05)
CB2 receptor antagonist, AM630, significantly
reversed th
e
effect
of CB2 agonist
(P < 0.01)
a***
b*
b***
F
i
g
u
r
e
3
.
T
h
e
c
a
r
r
a
g
e
e
n
a
n
-
i
n
d
u
c
e
d
i
n
f
l
a
m
m
a
t
i
o
n
i
n
p
a
w
t
i
s
s
u
e
a
n
d
t
h
e
e
f
f
e
c
t
o
f
C
B
2
a
g
o
n
i
s
t
o
n
p
l
a
s
m
a
e
x
t
r
a
v
a
s
a
t
i
o
n
c**
R
ESULTS
IV.
The effect of CB2 agonist on
plasma
extravasation in
ca
psaicin
-induced paw
inflammation
The
GW405833
s
trongly
inhibited
plasma
extravasation in
ca
psaicin
-induced
the
neurogenic
inflammation in paw tissue
(P < 0.0
01
).
D
iclofenac
not inhibited plasma extravasation (P >
0.05)
CB2 receptor antagonist, AM630, significantly
reversed th
e
effect
of CB2 agonist
(P < 0.0
0
1)
a***
b***
F
i
g
u
r
e
4
.
T
h
e
c
a
p
s
a
i
c
i
n
-
i
n
d
u
c
e
d
n
e
u
r
o
g
e
n
i
c
i
n
f
l
a
m
m
a
t
i
o
n
a
n
d
t
h
e
e
f
f
e
c
t
o
f
C
B
2
a
g
o
n
i
s
t
o
n
p
l
a
s
m
a
e
x
t
r
a
v
a
s
a
t
i
o
n
c***
b
ns
D
ISCUSSION
GW405833 significantly decreased the plasma extravasations
in both carrageenan-induced mix type inflammation and
capsaicin-induced neurogenic inflammation of rat paw.
The pretreatment with AM630 clearly reversed the effects of
GW405833, which suggests a significant interaction between
GW405833 and AM630.
So
CB2 receptors mediate the anti-oedematous and anti-
plasma extravasations effects of GW405833.
D
ISCUSSION
The present study
increases the understanding that
pharmacological level of CB2 agonist
plays on
anti-
inflammatory effects
by demonstrating
that
GW405833
reduces
capsaicin or
carrageenan-induced paw edema.
These effects were similar in magnitude to those produced
by the
CB2 agonist
GW405833
,
as well as the nonselective
COX inhibitor diclofenac
.
The anti-edematous effects of
GW405833
were
mediated through CB2 receptors
.
CB2 antagonist,
AM630
, reversed these anti-
edema effects.
These results suggest that the GW405833 reduces
inflammation through the activation of CB2 receptors
when administered after carrageenan, and that effect
seems to be related to the suppression of neurogenic
inflammation.
F
INALLY
The stimulation of CB2 receptors
induces anti-
inflammatory effects in
several experimental
conditions
Our experimental studies provide evidence that
supports the hypothesis for
the
activation of
CB2 receptors
may
have beneficial
effect
s
against
inflammatory processes, maybe via and
related the control of neurogenic inflammation
R
EFERENCES
R
ECENT
P
APERS
Huan Gui, Qiang Tong , Wenchun Quc, Chen-Mei Mao, Sheng-Ming Dai.
The endocannabinoid system and its therapeutic implications in
rheumatoid arthritis. International Immunopharmacology 26 (2015) 86–
91.
Mireille Alhouayek, Julien Masquelier and Giulio G. Muccioli.
Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory
strategy
.
Drug Discovery Today Volume 19, Number 3 March 2014
.
Sudeshna Ghosha, Laura E. Wisea, Yugang Chenb, Ramesh Gujjarb,
Anu Mahadevanb,
Benjamin F. Cravattc, and Aron H. Lichtmana,
The
monoacylglycerol lipase inhibitor JZL184 suppresses
inflammatory pain
in the mouse carrageenan model
.
Life Sci. 2013 March 19; 92(0): 498–
505.
Renger Witkamp and Jocelijn Meijerink.
The endocannabinoid system:
an emerging key
player in inflammation.
Curr Opin Clin Nutr Metab
Care 2014, 17:130–138
.
Slava Rom and Yuri Persidsky
.
Cannabinoid receptor 2: Potential role
in immunomodulation
and neuroinflammation Review.
Neuroimmune
Pharmacol. 2013 June ; 8(3): 608–620.
L
ET
US
MEET
AGAIN
..
We welcome you all to our future conferences of OMICS
International
3
rd
World Congress on Pharmacology
On
August 08-10, 2016
at
Birmingham, UK
http://pharmacology.pharmaceuticalconferences.com//
OMICS Group, established in 2007, focuses on Open Access science and technology dissemination through 500 journals and 500 worldwide conferences annually. Benefiting research scholars, students, institutions, and the industry, OMICS Group facilitates knowledge transfer through debates, workshops, and exhibitions. Explore innovative research in various aspects of Science, Engineering, Management, and Technology with OMICS Group.
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Presentation Transcript
ABOUT OMICS GROUP OMICS Publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology Open Access , OMICS Group publishes 500 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions. Group is an amalgamation of Open Access Libraries, Educational also organizes 500
OMICS INTERNATIONAL CONFERENCES OMICS International is a pioneer and leading science event organizer, which publishes around 500 open access journals and conducts over 500 Medical, Clinical, Engineering, Life Sciences, conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. Pharma scientific OMICS workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai. Group has organized 500 conferences, Santa Clara, Chicago,
ANTI- INFLAMMATORY EFFECTS OF CANNABINOID 2 RECEPTOR AGONIST, GW405833, IN A MODEL OF CARRAGEENAN-INDUCED ACUTE INFLAMMATION OF THE RAT PAW Seyfullah Oktay Arslan, PhD Department of Pharmacology Yildirim Beyazit University, Faculty of Medicine From Ankara, T RK YE
OUR WORKNG TEAM Seyfullah Oktay Arslan, Yildirim Beyazit University Ali Parlar, Adiyaman University Muhammet Fatih Do an Yildirim Beyazit University Alper Yal n, Adiyaman University Mehmet Kaya zer Adiyaman Beyazit University
ANTI- INFLAMMATORYEFFECTSOFCANNABINOID 2 RECEPTOR AGONIST, GW405833, INAMODELOF CARRAGEENAN- INDUCED ACUTEINFLAMMATIONOFTHERATPAW Introduction Materials and Methods Results Discussion References
INTRODUCTON Cannabis sativa Synthetic Cannabinoids The receptors The ligands The enzymes The effect mechanism Endocanna binoidergic system (ECS) ECs and their effects Central Pheripferal ECs and Inflammation
INTRODUCTON THE CANNABINOIDERG CSYSTEM CANNAB S SAT VA Cannabis sativa produces over 80 cannabinoids 9-tetrahydrocannabinol (THC) was identified as the main bioactive constituent of cannabis, the main psychotropic constituent of marijuana. The psychological addiction resulting from the abuse of cannabis is the main concern limiting its therapeutic use. Nonpsychoactive compound; cannabidiol (CBD) and cannabinol (CBN)
THESYNTHETICCANNABINOIDS Naphthoylindoles (e.g., JWH-018, JWH-073, JWH-398). Naphthylmethylindoles. (e.g., JWH-175, JWH-195, JWH-197). Naphthoylpyrroles.(e.g., JWH-030, JWH-156, JWH-243). Naphthylmethylindenes (e.g., JWH-176). Phenylacetylindoles (i.e., benzoylindoles, e.g., JWH-250, JWH-253, JWH-313). Cyclohexylphenols (e.g., CP 47,497 and homologs of CP 47,497). Classical cannabinoids (e.g., HU-210).
INTRODUCTON THE CANNABINOIDERG CSYSTEM I. THE RECEPTORS The cannabinoid receptors were found and cloned in the early 1990s The endogenous cannabinoid (EC) system consists of two G-protein-coupled cannabinoid i.e. CB1 and CB2 receptors However there are maybe additional receptors And, some EC effects result from the interaction with other receptors, such as the vanilloid receptor
INTRODUCTON THE CANNABINOIDERG CSYSTEM I. THE RECEPTORS The cannabinoid CB1 receptors are preferentially located on brain and also expressed in nerve terminals of peripheral tissues including heart and vessels. The cannabinoid CB2 receptors are mainly located on peripheral non-neuronal cells (mostly immune system cells) which exert a broad range of critical effects under physiological or pathological conditions
INTRODUCTON THE CANNABINOIDERG CSYSTEM II. ENDOCANNAB NO D L GANDS First endogenous ligands turned out to be fatty acid-derived molecules including Anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoylglycerol (2-AG) AEA has more affinity to CB1 than CB2, 2-AG shows similar affinity for CB1 and CB2 CB2 receptors may also bind other endocannabinoid ligands; however, the signalling consequences of this binding is poorly known
INTRODUCTON THE CANNABINOIDERG CSYSTEM III. ENDOCANNABINOID-B OSYNTHET C AND CATABOL CENZYMES Ca2+-dependent N-acyltranferase N-acylphosphatidylethanolamine- hydrolyzing phospholipase D AEA Fatty acid amide hydrolase (FAAH) diacylglycerol lipase phospholipase C 2-AG Monoacylglycerol lipase (MAGL)
INTRODUCTON THE CANNABINOIDERG CSYSTEM III. ENDOCANNABINOIDBIOSYNTHETICANDCATABOLICENZYMES The biosynthesis of AEA is catalyzed by Ca2+- dependent N-acyl-phosphatidylethanolamine hydrolyzing phospholipase D, AEA can also be produced by other routes, AEA is hydrolyzed mainly by fatty acid amide hydrolase (FAAH) into arachidonic acid and ethanolamine .
INTRODUCTON THE CANNABINOIDERG CSYSTEM III. ENDOCANNABINOIDBIOSYNTHETICANDCATABOLICENZYMES 2-AG is synthesized from its phospholipid precursor diacylglycerol by diacylglycerol lipases. Phospholipase C- releases diacylglycerol (DAG) from phosphatidylinositol-4,5-bisphosphate, which in turn is metabolized by diacylglycerol lipases (DAGLs) with DAGL and DAGL having prevalent roles in the brain and in several peripheral tissues, respectively to produce 2-AG. The major degradative or inactivated pathway of 2-AG is its hydrolysis to arachidonic acid and glycerol by monoacylglycerol lipase (MAGL)
INTRODUCTON THE CANNABINOIDERG CSYSTEM III. ENDOCANNABINOIDBIOSYNTHETICANDCATABOLICENZYMES Although the hydrolysis pathway seems to be the primary fate of AEA and 2-AG, they can also be oxidized by cyclooxygenase-2 and lipoxygenase isozymes, thus producing oxidized endocannabinoids, which are involved in regulating brain synaptic transmission and other biological processes
INTRODUCTON THE CANNABINOIDERG CSYSTEM THE EFFECTS Accumulating evidence has indicated that EC and their major receptors CB1 and CB2 play a major role in the pathophysiology of diseases at a preclinical stage, the selective CB2 molecules are increased to interest as new targets in drug discovery Endocannabinoids can modulate levels of proinflammatory mediators and immune cell migration. Exogenously administered 2-AG and anandamide or several selective agonists to animal models of inflammation have also shown to be effective.
INTRODUCTON THE CANNABINOIDERG CSYSTEM THE EFFECTS ECs are provided by a series of central and peripheral effects CB1 is more responsive to psychoactive cannabinoids (eg, THC) than to nonpsychoactive cannabinoids (eg, cannabidiol)
INTRODUCTON THE CANNABINOIDERG CSYSTEM THE EFFECTS ECs influence analgesia and motor function, energy balance and food intake, cardiovascular function, immune and inflammatory responses, and cell proliferation
INTRODUCTON THE CANNABINOIDERG CSYSTEM AND INFLAMMAT ON the endocannabinoid system has been found to be involved in many inflammation-related conditions, such as Multiple sclerosis, Atherosclerosis, Inflammatory bowel disease, RA, Sepsis, and Allergic inflammation
INTRODUCTON THE CANNABINOIDERG CSYSTEM AND INFLAMMAT ON The blockage of CB1 and activation of CB2 could inhibit inflammation in various animal models, mainly through restraining the activity of the immune system. The exogenous application of AEA and 2-AG exerts anti- inflammatory effects by decreasing the production of inflammatory mediators. The exogenous application of selective CB2 agonists exerts anti-inflammatory effects by decreasing the production of inflammatory mediators. Upregulating the level of endogenous cannabinoids by inhibiting their common metabolic enzyme, becomes an important strategy in the treatment process of inflammation-related diseases
INTRODUCTON INOURPREVIOUSSTUDIES We had evaluated some effects of the cannabinoid (CB)2 receptor activations during the inflammatory processes of peripheral tissues after intestinal ischemia/reperfusion .
INTRODUCTON A M OF TH S STUDY This study was designed to investigate the anti- inflammatory effects of selective CB2 receptor agonist, GW405833, in the carrageenan paw oedema test of rats. in the capsaicin paw oedema test of rats.
MATERALS AND METHODS AN MALS AND EXPER MENTAL DES GN The subjects weighed between 200 and 250g, and were housed in a temperature (20 22 C) in their home cages and were maintained on a 12/12 h light/dark cycle. All rats were given standard rat chow and water ad libitum The sample size for each treatment group was 6 to 8 mice/group All animal protocols were approved by the Institutional Animal Care and Use Committee and were in accordance with the National Institutes of Health Guide for the care and use of Laboratory animals. After testing was completed, all mice were humanely euthanized via CO2 asphyxia, followed by rapid cervical dislocation.
MATERALS AND METHODS INFLAMMATION TYPE Carrageenan-induced paw edema - Mix type of inflammation were induced by giving an intraplantar injection of carrageneen (50 l, 1%) or Capsaicin-induced paw edema - Neurogenic type of inflammation were induced by giving an intraplantar injection of capsaicin (50 l, 0.1%) into the paw
MATERALS AND METHODS INFLAMMATION TYPE PAW EDEMA Edema was expressed as the increase in paw thickness (mm) after carrageenan injection relative to the pre- injection value for each animal. Paw thickness was measured with electronic digital calipers, prior to and 1 or 4 h following capsaicin or carrageenan administration respectively, which corresponds to peak edema time.
MATERALS AND METHODS AN MALS AND EXPER MENTAL DES GN In the first group, Plasma extravasations were measured via Evans blue dye method. The dye was injected in the tail vein 15 min before the end of the experiments. The anaesthetized animals were sacrificed by decapitation, and hind paws were incubated with formamide, and then the extracted dye was measured by spectrophotometry at 620 nm.
MATERALS AND METHODS AN MALS AND EXPER MENTAL DES GN In the second group, paw thickness was measured with electronic digital callipers, prior to and 4 h following carrageenan or 1 h following capsaicin administration, which corresponds to peak oedema.This procedure has been used previously by studies. The anti-oedematous effects of GW405833 (3 mg/kg, i.v.) were compared to diclofenac (10 mg/kg, i.v.), a nonselective cyclooxygenase inhibitor, 15 min before these intraplantar injections of inflammatory agents. CB receptor involvement in the anti-inflammatory effects of GW405833 was evaluated by administration of the CB2 receptor antagonist, AM630 (1 mg/kg, i.v., 5 min before CB2 agonist injection).
MATERALS AND METHODS STAT ST CAL DATA ANALYS S All statistical analyses were carried out using GraphPad statistical software. All data were presented as mean standard error mean. Difference between groups was compared using student t test or one-way ANOVA followed by Tukey's Multiple Comparison. P <0.05 was considered significant.
RESULTS I. The carrageenan-induced paw oedema Administrate of carrageenan caused clear edema in paw tissue (P < 0.001) Pretreatment of rats with both GW405833 (P < 0.05) and diclofenac (P < 0.001) significantly attenuated carrageenan-induced paw oedema compared to vehicle- treated group. CB2 receptor antagonist, AM630, significantly reversed the effect of CB2 agonist (P < 0.01)
Figure 1. The carrageenan-induced paw oedema and the effect of CB2 agonist C ontrol C a rre +D iclo 9 C arre+C B 2 A g C arre+C B 2 A nta 8 C arre+D M S O 7 **** C a rre C arre+C B 2 A g+A nta P aw Thickness (m m ) 6 5 4 3 2 1 0 -1 0 1 2 3 4 5 T im e (h )
RESULTS II. The capsaicin-induced paw oedema Administrate of capsaicin caused clear edema in paw tissue (P < 0.001) Pretreatment of rats with GW405833 (P < 0.001) significantly attenuated capsaicin-induced paw oedema compared to vehicle-treated group. CB2 receptor antagonist, AM630, significantly reversed that effect (P < 0.001)
Figure 2. The capsaicin-induced paw oedema and the effect of CB2 agonist C ontrol C apsaicin+D iclo 9 C apsaicin+C B 2 A g C apsaicin+C B 2 A nta 8 C apsaicin+V ehicle 7 C apsaicin *** C apsaic+C B 2 A g+A nta P a w Th ickn ess (m m ) 6 5 4 3 2 1 0 -1 0 1 2 T im e (h )
RESULTS III. The effect of CB2 agonist on plasma extravasation in carrageenan-induced paw oedema The GW405833 significantly inhibited plasma extravasation in carrageenan-induced paw oedema (P < 0.001) . Diclofenac inhibited also plasma extravasation, but has effect as more week (P < 0.05) CB2 receptor antagonist, AM630, significantly reversed the effect of CB2 agonist (P < 0.01)
Figure 3. The carrageenan-induced inflammation in paw tissue and the effect of CB2 agonist on plasma extravasation a*** c** 15 C ontrol E B g /g in dry tissue b* C arre C arre+D iclo 10 C arre+C B 2 A g b*** C arre+C B 2 A nta C arre+C B 2 A g+A nta 5 C arre+D M SO 0 C ontrol C arre+C B 2 A g C arre+C B 2 A nta C arre+C B 2 A g+A nta C arre+D iclo C arre C arre+D M S O
RESULTS IV. The effect of CB2 agonist on plasma extravasation in capsaicin-induced paw inflammation The GW405833 strongly inhibited plasma extravasation in capsaicin-induced the neurogenic inflammation in paw tissue (P < 0.001). Diclofenac not inhibited plasma extravasation (P > 0.05) CB2 receptor antagonist, AM630, significantly reversed the effect of CB2 agonist (P < 0.001)
Figure 4. The capsaicin-induced neurogenic inflammation and the effect of CB2 agonist on plasma extravasation 20 a*** C ontrol E B g /g in dry tissue c*** bns C apsaicin C apsaicin+D iclo C apsaicin+C B 2 A g 10 b*** C apsaicin+C B 2 A nta C apsaic+C B 2 A g+A nta C apsaicin+V ehicle 0 C ontrol C apsaicin+C B 2 A nta C apsaicin+V ehicle C apsaicin+C B 2 A g C apsaic+C B 2 A g+A nta C apsaicin+D iclo C apsaicin
DSCUSSON GW405833 significantly decreased the plasma extravasations in both carrageenan-induced mix type inflammation and capsaicin-induced neurogenic inflammation of rat paw. The pretreatment with AM630 clearly reversed the effects of GW405833, which suggests a significant interaction between GW405833 and AM630. So CB2 receptors mediate the anti-oedematous and anti- plasma extravasations effects of GW405833.
DSCUSSON The present study increases the understanding that pharmacological level of CB2 agonist plays on anti- inflammatory effects by demonstrating that GW405833 reduces capsaicin or carrageenan-induced paw edema. These effects were similar in magnitude to those produced by the CB2 agonist GW405833, as well as the nonselective COX inhibitor diclofenac.
The anti-edematous effects of GW405833 were mediated through CB2 receptors. CB2 antagonist, AM630, reversed these anti- edema effects.
These results suggest that the GW405833 reduces inflammation through the activation of CB2 receptors when administered after carrageenan, and that effect seems to be related to the suppression of neurogenic inflammation.
FINALLY The stimulation of CB2 receptors induces anti- inflammatory effects in several experimental conditions Our experimental studies provide evidence that supports the hypothesis for the activation of CB2 receptors may have beneficial effects against inflammatory processes, maybe via and related the control of neurogenic inflammation
REFERENCES RECENT PAPERS Huan Gui, Qiang Tong , Wenchun Quc, Chen-Mei Mao, Sheng-Ming Dai. The endocannabinoid system and its therapeutic implications in rheumatoid arthritis. International Immunopharmacology 26 (2015) 86 91. Mireille Alhouayek, Julien Masquelier and Giulio G. Muccioli. Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy. Drug Discovery Today Volume 19, Number 3 March 2014 . Sudeshna Ghosha, Laura E. Wisea, Yugang Chenb, Ramesh Gujjarb, Anu Mahadevanb, Benjamin F. Cravattc, and Aron H. Lichtmana, The monoacylglycerol lipase inhibitor JZL184 suppresses inflammatory pain in the mouse carrageenan model. Life Sci. 2013 March 19; 92(0): 498 505. Renger Witkamp and Jocelijn Meijerink. The endocannabinoid system: an emerging key player in inflammation. Curr Opin Clin Nutr Metab Care 2014, 17:130 138. Slava Rom and Yuri Persidsky. Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review. Neuroimmune Pharmacol. 2013 June ; 8(3): 608 620.
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