Transcript Diapositiva 1

LA CANAPA E LO STIMOLO
DELLA FAME:
STORIA DI AGONISMI
ED ANTAGONISMI
Dr. Uberto Pagotto
Unità Operativa di Endocrinologia
Dip. Medicina Int. e Gastroenterologia
Ospedale S.Orsola-Malpighi
Bologna
UNIVERSITA'
di
BOLOGNA
S. ORSOLA
MALPIGHI
The first written evidence of medical use of cannabis
sativa comes from China some 5000 years ago
The drug was introduced in
Europe by Napoleon
Bonaparte’s troops when
returning from Egypt
Nowadays marijuana and its
derivatives have become the
most widely consumed illegal
drugs in western countries
1964
1990
isolation of 9-THC (Gaoni and Mechoulam)
cloning of cannabinoid
receptor 1 (Cb1) (Matsuda et al.)
1993
cloning of a second cannabinoid
Both receptors belong to
the G protein coupled
receptor superfamily
receptor (Cb2) (Munro et al.)
Ion channels
Intracellular signalregulated kinases
Adenylate-cyclase
1992
purification of anandamide,
the first endogenous cannabinoid (Devane et al.)
The discovery of Cb receptors and their endogenous ligands
suggested the existence of an
Endogenous Cannabinoid System
Cb1 ligands
Classical
cannabinoids
9-THC
8-THC
Cannabinol
Cannabidiol
HU 210
Non classical
cannabinoids
CP-55,940
Aminoalkylindols
Endocannabinoids
Cb1 selective
antagonists
WIN-55,212
Anandamide
2-Arachidonylglycerol
SR 141716A
AM 630
1964
1992
1990
OH
O
NH
CB1
OH
O
D9-Tetrahydrocannabinol
Feeding
Sleep
Anandamide
Hormones modulation
Learning & Memory
Rewarding
Pain perception
Antitumoral activity
Blood pressure
Neuroprotection
Locomotion
Thermoregulation
Orexigenic peptides
Anorexigenic peptides
• Neuropeptide Y (NPY)
• Agouti-related protein (AgRP)
• Corticotrophin-releasing hormone (CRH)
• Melanin-concentrating hormone (MCH) • -melanocyte-stimulating hormone (-MSH)
• Orexins (Hypocretins)
• Ghrelin
• Cocaine-and amphetamine regulated
transcripts (CART)
Role of Reward System in
feeding behavior in the
mesocorticolimbic pathaways
Substantia
Nigra
Amygdala
Hippocampus
GABA
D2-R
DOPA
DOPA
Reward
enkephalin
GABA
enkephalin
5-HT
DOPA
DOPA
Reward
D2-R
Hypothalamus
Ventral tegmental
region
Blue: excitatory neurons
Nucleus Accumbens
Red: inhibitory neurons
IN 1985, THE USE OF 9-THC (DRONABINOL) WAS
APPROVED BY FDA FOR TREATMENT OF
CANCER-CHEMOTHERAPY INDUCED NAUSEA
AND VOMITING REFRACTORY TO OTHER
AGENTS
Average weight loss or gain during placebo and treatment periods
with 9-THC (2.5 mg or 5.0 mg per os, twice per day, for 2 weeks)
Number of
subjects
Average gain
during Marijuana
week
Average loss
during Placebo
week
8 Marijuanaplacebo
0.69
2.10
9 Placebomarijuana
0.39
1.11
Regelson et al.
Dronabinol
0.3
0.2
Mean Weight change (Kg)
Mean Weight change (Kg)
IN 1992, DRONABINOL WAS THE FIRST DRUG APPROVED
BY FDA FOR THE TREATMENT OF ANOREXIA AND
WEIGHT LOSS IN AIDS PATIENTS...
Placebo
0.1
0.0
-0.1
-0.2
-0.3
-0.4
-0.5
Day 0
Day 14
Day 28
Day 42
Mean change in weight from baseline,
evaluable AIDS patients
Dronabinol
1.5
Placebo
1.0
0.5
0.0
-0.5
Day 0
Day 14
Day 28
Day 42
Mean change in weight from baseline,
evaluable AIDS patients. Excludes
patients with moderate, severe, or lifethreatening drug- nonrelated adverse
events
Beal et al, 1995
STUDIES SUPPORT LONG-TERM,
SAFE USE OF DRONABINOL FOR
ANOREXIA AND CACHEXIA IN AIDS
PATIENTS
% patients with at least 2Kg
BW gain
(Beal et al., 1997)
40
*
30
20
10
Dronabinol 2.5mg os
Placebo
1
6
month
12
DRONABINOL WAS TESTED
ALSO IN ALZHEIMER PATIENTS
15 PATIENTS WERE TREATED FOR 6 WEEKS
WITH PLACEBO AND 6 WEEKS WITH DRONABINOL
THE RESULTS WERE…..
”BODY WEIGHT OF STUDY SUBJECTS
INCREASED MORE DURING
THE DRONABINOL TREATMENT
THAN DURING THE PLACEBO PERIODS..”
Volicer L et al. 1997
Hyperphagia in pre-fed rats following
oral 9-THC
8
*
2-hours food intake (g)
*
*
6
4
9-THC mg/Kg
2
1
0.5
0.25
0.125
0.063
2
0
2-hours food intake (g)
(Williams et al, 1998)
Reversal of 9-THC
hyperphagia in pre-fed rats by
CB1 selective antagonist SR141716
(Williams et al, 2002)
SR141716
9-THC +SR
10
8
†††
*
6
***
4
***
***
2
0
0.05 0.1
0.5
SR141716 mg/Kg s.c.
1
The selective Cb1 antagonist, SR 141716A, reduces dosedependently sucrose and ethanol intake in rodents
SR 141716
Sucrose
pellets
Sucrose
solution
Ethanol
solution
28.3  5.0
NPYinduced
sucrose
drinking
(rats)
8.1  1.7
(rats)
(rats)
vehicle
3.1  0.4
0.3 mg/Kg
2.1  0.2
16.1  3.9
3.6  1.2 †
1.3  0.2
1 mg/Kg
1.6  0.2**
7.4  2.8**
1.2  0.4 ††
1.1  0.2**
3 mg/Kg
1.0  0.4**
8.6  2.9**
n.d.
1.0  0.2**
(mice)
1.9  0.1
Arnone et al, 1997
If you want a knockout...
The conditional mutagenesis
CRE/lox P system
Gene targeting
Breeding
CB1 Nullmutation
Feeding
behavior
CB1-/- mice show decreased body
weight and reduced fat mass
CB1+/+
CB1-/-
body weight (g)
30
25
* *
*
*
*
*
*
*
T
B
*
20
15
10
*
CB1+/+
5
2
4
6
8 10 12 14
Age (week)
16
T
CB1+/+
15
10
CB1-/**
5
Fat mass
% of body weight
% of body weight
T
75
B
T
*
70
65
60
CB1-/Lean mass
Cota D. et al., J Clin Invest 2003
CB1 transcripts are co-localized with mRNAs of hypothalamic neuropeptides
a
b
*
CRH/PVN
c
CART/PVN
d
*
Pre-pro-orexin/LHA
MCH/LHA
Cota D. et al., J Clin Invest 2003
Caloric intake (kcal/day)
CB1+/+ Young
CB1-/-
15
10
5
3
Body weight (g)
25
4
CB1+/+
CB1-/CB1+/+ pair-fed
20
15
5
Age (week)
*
**
*
*
*
** † †
*
**
††
25
20
15
10
5
6
20
21
22
Age (week)
45
*
** *
** * * *
††
†
††
†† †
10
5 3
CB1+/+ Adult
CB1-/-
30
†
Body weight (g)
Caloric intake (kcal/day)
CB1-/- lean phenotype is principally related to the decreased caloric intake
40
* **
* * * ** **** ** **
**
35
30
25
20
4
5
Age (week)
6
15 20
21
22
Age (week)
Cota D. et al., J Clin Invest 2003
M
1.0
0.5
CB1
 Actin
LPL activity
(% of control)
400
*
300
200
100
0
CT
WIN WIN+SR SR
Cota D. et al., J Clin Invest 2003
White adipose tissue may represent
a novel peripheral target for
cannabinoid action
We confirm that the cannabinoid system is
strongly involved in the body weight regulation
I conclusions
• CB1ko mice are lighter and leaner than their wt
controls
• Pairfeeding studies using young animals indicate a
main role of central orexigenic drive in body weight
regulation, however in adults also a food-intakeindependent mechanism contributes to the lean
phenotype
• CB1ko mice are not different in energy expenditure,
body temperature and locomotor activity from their
wt controls
We confirm that the cannabinoid system is
strongly involved in the body weight regulation
II conclusions
•CRH, CART, Pre-pro-orexin, MCH co-expression and CB1
have been found in hypothalamus of wt fed ad libitum
•Higher expression of CRH mRNA in PVN of CB1ko mice
fed ad libitum,lower expression of CART mRNA
in LHA and DMN of CB1ko mice fed ad libitum
• CB1 is expressed in adipose tissue
and stimulates lipogenesis
Hypothalamic action
of CB1 antagonists
may modulate
neuropeptide network
controlling food intake
CB1 antagonists
acting in the limbic
system may decrease
the rewarding
property of food
Endogenous Cannabinoid System seems to be an ideal target for
the treatment of eating disorders and obesity
Blockade of
gastroenteric CB1
might contribute to
the therapy by
modulating feedingrelated peripheral
signals
Anti-obesity action
of CB1 antagonists
could involve
metabolic processes
and directly target
adipose tissue
The cannabinoid system is involved in
several physiological functions and
might be related to a general stress-recovery
system.
Such a variety of effects was concisely
summarized by a recent statement by Di Marzo:
“…..FEEL LESS PAIN,
CONTROL YOUR MOVEMENT,
RELAX, EAT, FORGET,
SLEEP AND PROTECT.”
Di Marzo et al. Trends Neurosc, 1998