Plant and brain cannabinoids: major players in physiology.
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Transcript of Plant and brain cannabinoids: major players in physiology.
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Plant and brain cannabinoids:major players in physiology.
Raphael Mechoulam
Beit Dagan, January 2007 LOH 2003
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Gan-zi-gun-nu – the drug that takes away the mindAzallu – hand of ghost, poison of all limbs (neurological diseases?)Qunnabu – used in religious rites
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Pliny, the Elder (79 AD): The roots boiled in water ease cramped joints, gout too and similar violent pain.
Dioscorides (90 AD): The sodden root when placed on inflammations sooths them, eliminates edema and disperses obdurate matter above inflammed joints.
LOH 2003
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For the relief of certain kinds of pain, I believe, there is no more useful medicinethan Cannabis within our reach.
J. Russell Reynolds, Archives of Medicine, Vol 2, 154, 1859
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-tetrahydrocannabinol (-THC) (Gaoni and Mechoulam, 1964)
CH3
O
OH
C5H11
cannabidiol (CBD)(Mechoulam and Shvo, 1963)
HO C5H11
OH
CH3
CH3
cannabigerol (CBG)(Gaoni and Mechoulam, 1964)
HO
OH
C5H11
cannabichromene (CBC) (Claussen et al., 1966;Mechoulam and Gaoni, 1966)
O C5H11
OH
Representative natural cannabinoids
CH3
cannabinol (CBN)(Adams et al., 1940)
O
OH
C5H11
O C5H11
OH
cannabicyclol (CBL)(Crombie et al., 1968)
LOH 2003
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Gaoni and Mechoulam: J.Amer.Chem.Soc. 86, 1646 (1964)
cannabidiol (CBD)
HO C5H11
OH
CH3
O
OH
CH 3
9-tetrahydrocannabinol (9-THC)
Mechoulam and Shvo: Tetrahedron 19,2073 (1963)
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Brain regions in which cannabinoid receptors are abundant
Reward pathwayNucleus accumbens
Link between cerebral hemispheresIntrabulbar anterior commissure
Higher cognitive functionCerebral cortex, especially cingulate, frontal, and parietal regions
Learning and memory, stressHippocampus
Body-movement coordinationCerebellum
Putamen
Globus pallidus
Enteropeduncular nucleus
Substantia nigra pars reticulata
Movement controlBasal ganglia
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LOH 2004
anandamide
-tetrahydrocannabinol
-THC)
O
OH
CH3
OC
O
OH
OH
2-arachidonoyl glycerol (2-AG)
N
OC
H
OH
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Binding to cannabinoid receptors
Ligand CB1
(nM)
CB2
(nM)
GPR55
EC50 (nM)
9-THC 6 0.4 8
cannabidiol > 30000 > 30000 445 *
anandamide 31 27 18
2-arachidonoylglycerol 519 618 3
palmitoylethanolamide > 30000 19800 4
HU-210 0.2 0.5 26
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G G
AC AC
Calciumentryblocked
[Ca2+]Decreasedrelease ofneurotransmitters
Cannabinoidreceptor
Agonists (e.g. THC,anandamide)
Ca2+
(-)(-)
K+
PotassiumPotassiumchannelschannelsopenopen
[cAMP]
(-)K+
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Science (STKE, 23 April, 2002)
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What do endocannabinoids do?
“Relax, eat, sleep, forget and protect”
Di Marzo, 1998
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Physiological systems and conditions affected by endocannabinds (a partial list)
Anxiety Inflammation
Appetite/feeding Memory Blood pressure Mood
Bone formation Movement Cerebral blood flow Neuroprotection Digestive system Pain Emesis and nausea Reproduction Immune system Stress
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Neuroprotection
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control 15 min 1 h 4 h 8 h 24 h 0
10
20
30
40
50
60
70
80
90
100
110
120
Levels of 2-AG in mouse brain after CHI
Anova with Tukey post-test:P<0.0001, F=36.01
-P<0.01 vs. control
-P<0.05 vs. control
Time after CHI
con
cen
trat
ion
of
2-A
G(n
M/g
r)
-P<0.001 vs. control
Nature 413, 527 (2001)
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sham CHI 0.1 5 10 (mg/kg)
76.5
77.5
78.5
79.5
80.5
81.5
Effect of exogenous 2-AG on edema after CHI
-P<0.05 vs.CHI
0.0
0.5
1.0
1.5
2.0
2.5
3.0
NS
S (
imp
rove
men
t)
CHI 0.1 5 10 (mg/kg)
Effect of exogenous 2-AG on recovery after CHI
w
ate
r
*
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2-AG Reduces Infarct Volume 24 h After CHI2-AG Reduces Infarct Volume 24 h After CHI
control 2-AG (5 mg/kg)0.0
2.5
5.0
7.5
10.0
12.5
15.0control2-AG 5 mg/kg
*
n=9 n=7
unpaired t-test, P=0.0 3
infa
rct
vo
lum
e(%
)
2-AG
control
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glutamatecytokines, ROS
cerebralischemia
neuronal & glial cell death
Brain injury
Vasoconstrictors(e.g. ET-1, Thromboxane)
2-AG
cerebroprotection
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Regulation of vasodilation
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Corticosteroids
Androgens
Estrogens
AldosteroneProgesteron
Costicosteroids
Digitalis
HO
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Plasma MembranePlasma Membrane
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CO
O
CO
O
OP
O O
ONH2-
phosphatidylethanolamine
R1
R2
CO
O
CO
O
OP
O O
ON-
N-arachidonoylphosphatidylethanolamine
R1
R2
CO
H
HON
CO
H
anandamide
CO
O
CO
O
OP
O O
ONH2-
R1
R2
COOH
phosphatidylserine
CO
O
CO
O
OP
O O
ON-
N-arachidonoylphosphatidylserine
R1
R2
CO
H
HON
CO
H
arachidonoylserine
COOH
COOH
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CN
OHHO
CN
OH
O HCOOH
anandamide
arachidonoyl-serine
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anandamide
OC
O
OH
OH
2-arachidonoyl glycerol (2-AG)
N
OC
H
OH
HO
COOH
N
OC
H
arachidonoyl serine
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Inflammation
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0 0.05 0.1 1 5 10 50
0
50
100
150
200T
NF
pro
du
cti
on
(S
50
un
its
)
Inhibition of TNF production by 2-AGIn vitro
2-AG (mg/ml) LOH 2004
Eur.J.Pharmacol. 406, R5-R7 (2000)
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0
500
1000
1500
2000
LPS LPS + 2-AG LPS + 2-AG + +2-LG + 2-PG
TN
F
in
ser
um
(S
50 u
nit
s)Inhibition of TNF production by 2-AG in mice
In vivo
LOH 2004
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0 2 4 60
100
200
300
400
500
CBD (g/ml)(macrophages)
TN
F
tite
r (S
50)
0 2 4 60
1
2
3
4
5
6
CBD (g/ml)(macrophages)
NO
(n
M)
0
500
1000
1500
2000
zymosan zymosan +CBD
zymosan+ CBD (- 1 h)
ROI(granulocytes)
chem
ilum
inis
cenc
e pe
ak
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Synovium is the most critical site of cytokineproduction in arthritis. Synovial cells from arthritic mice spontaneously produce large amounts of TNF when cultured in vitro. Cells from arthritic mice which had been treated with CBD produced significantly less (50%) TNF.
LOH 2003
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Cannabidiol (i.p.), acute
0 1 3 5 7 9 110
1
2
3
4
5
control2.5 mg/kg5 mg/kg10 mg/kg20 mg/kg
Days after onset of arthritis
Cli
nic
al s
core
LOH 2003
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Appetite and feeding
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0 14 28 42
-0.4
-0.3
-0.2
-0.1
-0.0
0.1
0.2
0.3
Day
Mea
n w
eig
ht
chan
ge
(kg
)
Dronabinol
Placebo
Mean change in weight from baseline in patients with AIDS treated with dronabinol (THC) and placebo (Beal et al., 1995)
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0 1 2 3 4 5 6 7 83
4
5
6
7
anandamide (0.001 mg/kg i.p.)vehicle
Days
gram
/mou
se/d
ay
Effect of anandamide on food intake (16 mouse in each group).
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LOH 2004
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LOH 2004
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Cl
NN
N N
O
Cl
Cl
H
SR141716A
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Memory extinction
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d1 d2 d3 d60
10
20
30
40
50P
er c
ent
free
zin
g
(60
s t
one)
CS CS CS CSCo
Experimental day
*****
***
………
……
LOH 2004
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The endogenous cannabinoid system could represent a therapeutic target for the treatment of diseases associated with inappropriate retention of aversivememories or inadequate responses to aversive situations, such as post-traumaticstress disorders, phobias, and certainforms of chronic pain.
LOH 2004
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Cannabinoids and anxiety.
1. In animal models as well as in limited clinical trials cannabidiol has been shown to lower anxiety. Mechanism unknown. 2. Blocking of anandamide hydrolysis in vivo (rats) enhances anandamide levels in brain and lowers anxiety. This effect is blocked by endocannabinoid antagonists.
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Cannabinoids and schizophrenia.
1. Large doses of cannabis (particularly if they lack cannabidiol) may cause a psychotic state resembling psychosis. 2. In schizophrenic patients cannabis use may worsen positive symptoms. 3. Heavy use of cannabis may precipitate schizophrenia in susceptible individuals. Frequent cannabis use was associated with 6 fold increase of in high risk individuals (family history). 4. Increase in density of CB1 receptors in several brain areas in postmortem schizophrenic brains. Two fold increase of anandamide levels in CSF of patients.
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Cannabidiol treatment of positive schizophrenia.
High doses of the non psychoactive Cannabis constituent cannabidiol have shown effectiveness in the treatment of schizophrenics (lowering of positive effects). Mechanism – unknown.
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Endocannabinoids and depression.
Although at low doses cannabis may enhance mood it is not antidepressive.
A selective inhibitor of the enzyme which causes endocannabinoid hydrolysis (in vivo) exerts potent anti-depressant effects in the rat forced swim test.
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Hepatic encephalopathy.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome due to liver disease. It is the feature that defines prognosis in acute liver injury.
1. In a mouse model of HE (produced by the toxin thioacetamide) 2-AG levels are enhanced in the brain. 2. Administration of either 2-AG or the specific CB2 agonist HU-308 improves a neurological score, activity, cognitive function. 3. A specific CB2 receptor antagonist blocks these effects.
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Alzheimer’s disease
Compared to currently approved drugs prescribed for the treatment of Alzheimer’s disease, THC is considerably superior inhibitor of A aggregation and thus cannabinoid molecules may directly impact the progression of this debilitating disease.(Eubanks et al., Mol. Pharmac. 2006)
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Collaboration in Israel
Jerusalem
Prof. L. HanušProf. E. FrideDr. W. A. DevaneDr. A. BreuerDr. S. Ben-ShabatD. PanikashviliG. Milman N. KoganY. Maor
Jerusalem
Prof. E. ShohamiProf. R. GallilyProf. E. BerryProf. M. SchlesingerDr. Y. Avraham
Haifa
Prof. A. Mandelbaum
Rehovot
Prof. Z. Vogel
Tel Hashomer
Dr. S. AlmogDr. A. Gopher
LOH 2003
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Collaboration abroad
AberdeenR. Pertwee
BonnM. KarsakA. Zimmer
BrnoA. Šulcová
GreeceC. Simeonidou
RichmondB. MartinA. H. Lichtman
CanadaL. A. Parker
BethesdaG. KunosM. Spatz
NapoliV. Di Marzo
RomeM. Maccarrone
SiberiaL. Maslov
LondonM. FeldmannA. M. MalfaitP. F. Sumariwalla LOH 2003