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The Endocannabinoid System

Overview of current ECS understanding and its known contributions to understanding disease pathophysiology. (Use left and right arrow keys to navigate preset path)
by

Paul Wackerow, M.D.

on 26 May 2014

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Transcript of The Endocannabinoid System

Paul Wackerow, M.D.
ENDOCANNABINOID
Works Cited

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El-Remessy, Azza B., Mohamed Al-Shabrawey, Yousuf Khalifa, Nai-Tse Tsai, Ruth B. Caldwell, and Gregory I. Liou. "Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes." The American Journal of Pathology 168.1 (2006): 235-44. Web.

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Mechoulam, Raphael, and Linda A. Parker. "The Endocannabinoid System and the Brain." Annual Review of Psychology 64.1 (2013): 21-47. Web.

Muccioli, Giulio G., Damien Naslain, Fredrik Bäckhed, Christopher S. Reigstad, Didier M. Lambert, Nathalie M. Delzenne, and Patrice D. Cani. "The Endocannabinoid System Links Gut Microbiota to Adipogenesis." Molecular Systems Biology 6 (2010): n. pag. Web.

Pacher, Pál, and George Kunos. "Modulating the Endocannabinoid System in Human Health and Disease - Successes and Failures." FEBS Journal 280.9 (2013): 1918-943. Web.

Pisani, Valerio, Graziella Madeo, Annalisa Tassone, Giuseppe Sciamanna, Mauro Maccarrone, Paolo Stanzione, and Antonio Pisani. "Homeostatic Changes of the Endocannabinoid System in Parkinson's Disease." Movement Disorders 26.2 (2011): 216-22. Web.

Rajesh, Mohanraj, Et Al. "Cannabidiol Attenuates High Glucose-induced Endothelial Cell Inflammatory Response and Barrier Disruption." American Journal of Physiology. Heart and Circulatory Physiology 293.1 (2007): H610.

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Ryan, D., A. J. Drysdale, C. Lafourcade, R. G. Pertwee, and B. Platt. "Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2 Levels." Journal of Neuroscience 29.7 (2009): 2053-063. Web.

Teixeira-Clerc, Fatima, Boris Julien, Pascale Grenard, Jeanne Tran Van Nhieu, Vanessa Deveaux, Liying Li, Valérie Serriere-Lanneau, Catherine Ledent, Ariane Mallat, and Sophie Lotersztajn. "CB1 Cannabinoid Receptor Antagonism: A New Strategy for the Treatment of Liver Fibrosis." Nature Medicine 12.6 (2006): 671-76. Web.

Thomas, A., G. L. Baillie, A. M. Phillips, R. K. Razdan, R. A. Ross, and R. G. Pertwee. "Cannabidiol Displays Unexpectedly High Potency as an Antagonist of CB1 and CB2 Receptor Agonists in Vitro." British Journal of Pharmacology 150.5 (2007): 613-23. Web.

Varma, Namita, Et Al. "Metabotropic Glutamate Receptors Drive the Endocannabinoid System in Hippocampus." The Journal of Neuroscience: the Official Journal of the Society for Neuroscience 21.24 (2001): RC188-RC188.

Wikipedia Commons. http://en.wikipedia.org. 2014.
SYSTEM
THE
Today's Discussion:
History of discovery and naming
The Endocannabinoid System (ECS)
Systems affected by ECS
Disease pathology
Psychiatric disorders
Neurodegenerative disorders
What's next??
...Some time for questions
As we go forward...
...try to imagine the possible therapeutic benefits of targeting the ECS.
History
∂9-Tetrahydrocannabinol (THC) first discovered from the
Cannabis sativa
plant
This led to the search for its receptor, leading to the discovery of...
Cannabinoid Receptors 1 and 2
(CB1, CB2)
These were named as such because it was discovered through the
Cannabis
plant
This fueled the search for an endogenous ligand of these receptors...
....for which we have now found many.
Anandamide (arachidonylethanolamide, AEA)
2-Arachidonylglycerol (2-AG)
These have been termed "
endocannabinoids
," as they were originally discovered as endogenous ligands of the cannabinoid receptor.
So...

What are the components of the "Endocannabinoid SYSTEM"??
ECS = Ligands + Receptors + Enzymes
- Arachidonic Acid (
AA
)
- Anandamide (arachidonylethanolamide,
AEA
)
- 2-Arachidonylglycerol (
2-AG
)
- Cannabinoid Receptors (CB1, CB2)
- Transient Receptor Protein Family (TRPV1, etc)
- G-Protein Receptor 55 (GPR55)
- Peroxisome proliferator-activated receptor (PPAR-alpha, -beta, -gamma)
- Lipoxygenase (LOX)
- Glycine Receptor
- Abnormal-Cannabidiol receptor
- 5-HT1A Receptor
- Adenosine A1a reuptake
Synthesis:
- Phospholipase C (PLC)
- Diacylglycerol lipase (DAGL)

Degradation:
- Monoacylglycerol lipase(MAGL)
- Fatty-acid-amide hydrolase

Rx example: Lipase blockers can enhance or diminish the ECS
Synthesis and Degradation Pathways:
Gq
AEA (Anandamide):
1. Ca++-dependent N-AcylTranferase (NAT)
yields...
2. N-AcylPhosphatidylEthanolamine (NAPE)
which is hydrolyzed by...
3. Phospholipase D (PLD)
yielding...
4. Arachidonylethanolamine (
AEA
)
which is hydrolyzed by...
5. Fatty-acid-amide Hydrolase (FAAH)
yielding...
6. Ethanolamine and Arachidonic acid

2-AG (2-Acylglycerol)
1. G-protein coupled activation of Phospholipase C (PLC)
yields...
2. Diacylglycerol (DAG)
which is hydrolyzed by...
3. Diacylglycerol lipase (DAGL)
yielding...
4. 2-Arachidonylglycerol (
2-AG
)
which is hydrolyzed by
5. Monoacylglycerol lipase (MAGL)
yielding...
6. Glycerol and Arachidonic acid
Extensiveness of the ECS
- Obesity/metabolic syndrome
- Diabetes and diabetic complications
- Neurodegenerative disease
- Inflammatory disease
- Cardiovascular disease
- Liver disease
- Gastrointestinal disease
- Skin diseases
- Pain
- Psychiatric disorders
- Cancer, cachexia and chemotherapy-induced nausea and vomiting
Studies show involvement in wide range of disease pathophysiology:
Complexity of the ECS
- Centrally and peripherally acting
- Overlap between endocannabinoid signalling and eicosanoid signalling
- Often opposing effects mediated by CB1 and CB2 receptors in animal disease models
- Intrinsic activity of the ECS allows for inverse-agonism at receptor sites.
- Each ligand at each receptor in each environment (tissue) has a unique set of affinity / efficacy
Early understanding
Receptor locations:
CB1 —> Central Nervous System
CB2 —> Immune System

BOTH noted to be lacking in brainstem
(respiratory center of the medulla)
CB1:
- Most abundant G-protein-coupled receptor (GPR) in mammalian brain
- Located in
CNS/PNS
, and
almost all peripheral tissue

CB2:
- Largely restricted to
immune
and
haematopoetic cells
- Also found in myocardium, gut, endothelium, vascular smooth muscle and Kupffer cells, exocrine and endocrine pancreas, bone, reproductive tissues
- Also found in various tumor cells.

ECS is involved in regulation of the inflammatory process by involvement with: PPARs, LOX, GlyR, TNFa, NF-KB, iCAM/vCAM
Current Understanding
Synthesized on demand and not stored
Gq
PRIMARY FUNCTION OF CB1??

Retrograde neuronal signaling
: CB1 pre-synaptic roll in receiving retrograde ECS signals to inhibit membrane depolarization, leading to diminished neurotransmitter release with time
Involvement in Disease Pathophysiology:
- Anxiety
- PTSD
- Depression
- Alzheimer's Disease
- Cardiovascular Disease
Anxiety
- Clinically manifested by frequent worrying, hyperarousal, autonomic hyperactivity and motor tension.
- GAD incidence ~5-11% in United States

Rimonabant
: Synthetic CB1 Inverse-Agonist
- Originally designed as a treatment for obesity. Despite weight lose seen among trial participants, rimonabant was eventually pulled due to adverse effects of anxiety and suicidal tendencies. This provided evidence toward an association between the CB1 receptor and anxiety.

Methanandamide
:

AEA analogue (CB1 agonist) administered in escalating dosage to rat PFC
- First anxio
lytic
at low doses
- Then anxio
genic
as higher doses due to TRPV1 stimulation at higher concentrations

URB597
: FAAH Blocker, increases levels of systemic AEA
- Increased levels of AEA were shown to reduce anxiety
- Rimonabant reverses anxiolytic effects, therefore indicating that
AEA is CB1-dependent.

JZL184
: MAGL Blocker, increases levels of systemic 2-AG
- Increased levels of 2-AG were shown to reduce anxiety
- Rimonabant unable to reverse anxiolytic effects, therefore 2-AG is CB1-INdependent.
- CB2 -/- KO mice do not display anxiolytic effects of JZL184, indicating
2-AG is CB2-dependent
.

These studies show that there is an
essential role of CB1 and CB2 in anxiogenesis and anxiolysis
response.
Gq
A common theme...
Disturbance of homeostasis --> ECS tone increases --> Protective effect observed
[Acute Stressor]
—> Stimulation of HPA
—> Inc GC in adrenals
—> Inc ECS
—> Inc Excitability of prelimbic mPFC neurons
—> Inc inhibition of HPA
—> GC levels stabilize
—> ECS tone stabilizes

• ECS supports frontal lobe inhibition making stressors less effective at boosting cortisol levels.
[Chronic Stressors]
—> HIGH ECS tone over time
—> ECS receptor down regulation
—> Dec mPFC excitability
—> Poorly suppressible HPA
—> Chronic high levels of GC
—> (Chronic Anxiety/Depression)

PTSD
Extinguished Fear Response
: (
test group 1: CB1 KO mice
,
test group 2: wt mice given Rimonabant
, control: wt
)
- Experiment derived to study roll of CB1 in extinguishing a fear response
- Auditory stimuli (buzzer) --> followed by a painful shock --> fear response (anxious behavior) observed in all test groups over a series of repeated periodic buzzer/shock cycles
- The shocking was then terminated in all groups, while maintaining periodic auditory stimuli

While the wt control mice were able to gradually return to baseline, CB1 KO and rimonabant test groups both showed a sustained fear response, despite the termination of the painful stimuli.


Morris Water Maze Task
: (
test group: CB1 KO mice
,
control: wt
)
- Experiment derived to study roll of CB1 in long-term depression of neurons
- CB1 -/- KO mice: KO and wt mice learn original location of platform in a water maze
- The platform is then relocated to the opposite side of the maze

While the wt control mice were able to adjust their behavior to find the new location, CB1 KO mice appeared unable to suppress the previously learned behavior and continued to venture toward the old platform location.
Depression
Neurogenesis theory
: A leading etiological hypothesis that depression is rooted in impaired/inadequate neurogenesis

What we know about the
ECS and neurogenesis
:
1. CB1 mRNA is expressed throughout developing brain
2. CB1 activation required for axonal growth
3. CB2 activation induces neural progenitor cell proliferation
4. Exogenous cannabinoids shown to promote neurogenesis

ECS roll in neurogenesis:
DAGL, 2AG
,
MGL
-
2-AG
, produced by
DAGL
and broken down by
MAGL
, is shown to be
essential to neuronal development
.
- It has been shown that at the neurite tip, not only are sufficient levels of DAGL required, but MAGL must be missing to sustain the necessary levels of 2-AG.
MAGL must be spatially and temporally restricted from the neurite tip for proper neurogenesis.

The Onaivi Group reported that in Japanese depressed subjects there is high incidence of a certain polymorphism in the CB2 gene.
- Therefore: CB2 hypo functioning —> Inc depressive symptoms
- Whereas: CB2 over expression —> Dec depressive symptom
Alzheimer's Disease
Multiple theories on etiology and pathophysiology of AD progression
ie. Genetic,
cholinergic
,
amyloid
and
tau

theories

Latest understanding of the ECS offers a multi-faceted approach for the treatment of AD

ECS stimulation shown to (in AD mouse-model):
-
Reduce Aβ-mediated lysosomal destabilization related to apoptosis
Neuroprotection against Aβ, partially mediated by reduction of oxidative stress
- Reduces neuroinflammation
-
Reduces tau phosphorylation
- Augment neurotrophin expression
-
Some ECS ligands shown to inhibit acetylcholinesterase activity, increasing available ACh

(EC therapy accompanied by cognitive improvement and reduction of several degenerative markers in two different animal models of AD)
Cardiovascular Disease
CB1 receptors have been found in
1. Myocardium
2. Coronary Vasculature
3. PNS/ANS Neurons

Acute Coronary Syndrome: Oddly hitting young, without CV dz
-- Simply put,
activation of CB1 = Bad for CVS
,
activation of CB2 = Good for CVS
- CB1 Agonism: Shown to increase ACS mortality by 29%
- Reversible with Surinabant (CB1 inverse agonist)
- Biomarker for coronary dysfunction?
Study of obese patients: high plasma [AEA] and [2-AG]
associated
with increased coronary dysfunction
- Possible therapeutic options:
CB2 Agonism
shown to
oppose effects of CB1 activation
- Evidence cautions use of pure CB1 agonists
This is commonly the mechanism of synthetic street cannabinoids (K2, spice…)
WHAT'S NEXT??
Pharmacologic therapies aimed at this system:
- Synthetic mono/poly-cannabinoid therapy
- Use of tailored phytocannabinoids
- Personalized nucleotide drug therapy targetting ECS SNPs

Furthered understanding of all disease processes
- Research in this field is expanding, and new links to disease etiology and pathophysiology are likely to continue to be discovered

The
Cannabis
plant genus offers diverse set of ligands to our ECS, all of which have
varying affinities
for these receptors and
varying efficacies
in producing the wide range of tissue-dependent intracellular cascades that can take place.
CANNABIDIOL
(HPA "hypothalamic-pituitary-adrenal axis", GC "glucocorticoids", mPFC "medial prefrontal cortex")
Recap
Discovered secondary to Cannabis plant, thus naming
ECS = Ligands + Receptors + Enzymes
CB1 and CB2 ubiquitous throughout central and peripheral tissues
Contribution to disease understanding
Where we’re heading

CB1 Activation
Smooth muscle relaxation
Baroreceptor response to drop in vascular tone
Tachycardia
?
THANK YOU!
Revised: Friday, May 9, 2014
Full transcript