Endocannabinoids Flashcards

1
Q

eCBs vs phyto/synthetic compounds - 2 e.g.’s + sim/diff (4)

A

-anandamide or AEA – partial agonist

-2-AG – full agonist

diff:
-derived from fatty acids
- can exist in aq better

similar:
-both like lipids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Biosynthesis of eCBs - EAE + 2AG

A

AEA:
-produced by our body
-produced by enzymatic reactions
-derived from rare fatty acid
-use N-acyl transferase + Phospholipase D

2-AG:
-produced by our body
-produced by enzymatic reactions
-derived from fatty acid
- use DGL

both enzymes sensitive to calcium levels
= difficult to control 2AG conc in body
( some GCPRs might inc ca2+ = 2AG + CB1r activation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Production of eCBs - not stored (4)

A

produced due to stimuli for de novo synthesis:
* From phospholipid-derived precursors
* Activation of GPCRs, PLC, inc.[Ca2+]i, (depolarization)

Produced from:
* Neurons, cardiac myocytes, astrocytes, microglia, blood cells, vascular wall, gut etc

Target tissues:
* Neurons, cardiac myocytes, astrocytes, microglia, blood cells, vascular wall, gut etc

(prod + target = same because like autocrine/paracrine system - local (not like hormone))

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How to carry out Liquid chromatography-mass spectrometry
(LC-MS/MS) (5)

A

to measure a lipid conc - diffi. to do

1) break down tissues/ cells = release of whatever is inside (in alc (inorganic solvent)

2) feed through chromatography column - separates chemicals

3) funnelled to MS = bombard each chemical w/ high energy= break it up

4) detector: gives chemical + precise level of each found in sample

control vs test = how much CB present in sample

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Tissue content of eCBs (2)

A

range of conc. - maybe down to tissue type

net result - not how much is being produced etc

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

eCBs degradation - EAE + 2-AG:

A

Know they are taken up by cells - dk if by produce cells or other nearby cells

ACA- FAAH: fatty acid amide hydrolase: will be hydrolysed back to original fatty acid - then poten fed into COX system (=PGs?)

2-AG- MGL: monoacyl glycerol lipase: back to same acid ^ + glycerol = ten poten fed into COX system (=PGs?)
these degr. enxymes =inside cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Proof of FAAH - rats studies

A

FAAH: 1) inject FAAH inhib invo in rats
= accum of AEA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Depression resistance effect of AEA - role of FAAH (4)

A

if it acts as a brake for dev depression after activation of signalling r = anxiolytic effect

= if inhib degradation = reduce anxiety + resist. to depression

studies: K/O of FAAH gene

1)massive accum of AEA
2) measured pain, anxiety etc
= more tolerant to pain = anxiolytic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

The endocannabinoid system - future research

A

idea:
1) production of eCBs
2) = they can activate CB1/CB2 r’s
3)= modulate tissue function

how?
- key degradation enzyme in both = simpler pathway = target enzymes = alter levels of eCB’s

  • drug that stim. eCBs prod - more complicated + not as efficacious
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Retrograde signalling via eCBs (5)

A
  • eCBs not considered neurotransmitters because they’re not even stored in vesicles

-they’re modulatory (-ve feedback: reduced the release of neurotransmitters)

  • eCB’s produced by post-synap neurones
  • eCB’s travel up (opposite) from post-synp to Pre: they activate CB1 in pre

Fine tuning of neuronal excitability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Hippocampus - CB1 (2)

A
  • CB1 antagonists block depolarization =induced suppression of inhibition (DSI)
  • CB1 ↓ spontaneous IPSP of GABAergic interneurons
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

The eCBs system at synapses (3)

A

Complementary localization of eCB components:

NAPE-PLD and FAAH in postsynaptic neurons

CB1 receptors in presynaptic terminals of interneurons

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

AEA vs 2-AG in synaptic plasticity

A

AEA: for glutanergic transmission

2AG: GABAergic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Neuronal functions of eCB-CB1 signalling (3)

A
  • Fine tuning neurotransmission and synaptic plasticity
  • A local endocannabinoid system vs global CB1 activation?
  • What happens when eCB signalling goes wrong? Dysregulation in pathological conditions?
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Therapeutic potentials of eCBs (5)

A

-MS - pain control
-Depression + obesity
-Painkiller
-Anti-nauseant or anti-emetic
-CB1 antagonist for addiction?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Periphery- some cell types in which eCB’s or CB1/2r expressed

A
  • Blood vessels – endothelial cells, smooth muscle cells
  • Heart
  • Blood cells – platelets, monocytes, macrophages
  • Adipocytes
  • Liver
  • Pancreas
  • Gut
  • Skeletal muscle
  • Ovaries, placenta
  • Testes, sperms
17
Q

How to modulate eCBs signalling? - all 3 points (3)

A

CB1 and CB2 receptors
* Selective antagonists
* Non-selective antagonists
* Allosteric modulators

eCB degradation
* Selective FAAH/MGL inhibitors
* Non-selective FAAH/MGL inhibitors
* Other combined inhibitors

eCB synthesis
* Synthetic enzyme inhibitors? - potential/ trickier to target due to loads of enzymes - not just one

18
Q

behavioural effects produced by CB1 agonists vs the genetic (KO) or chemical (inhibitor) inactivation of FAAH (6)

A

CB1 agonist : analgesia, anxiolytic, MS, anti-emesis, decrease IOP (glaucoma)

FAAH k/o: analgesia, unknown anxiolytic, unknown MS, anti-unknown emesis, unknown IOP (glaucoma)

FAAH inhib: analgesia, anxiolytic, unknown MS, unknown anti-emesis, unknown IOP (glaucoma)

side-effects: CB1 agonist: Hypomotility, hypothermia + catalepsy (may be down to selectivity)

19
Q

Or design a drug that acts just in the periphery - idea + pain study

A

if you know the therapeutic application requires cb1r (e.g= better than brain in which it causes bad side effects - fewer side effects )+ better for patients w/o getting them high

pain control - liver = successful

20
Q

Alternative targets of eCBs (4)

A

Transient Receptor Potential Vanilloid receptor (TRPV1)
* Sensory neurons, brain, epithelium

Peroxisome proliferator-activated receptor (PPAR)
* Adipocytes, macrophages, blood vessels, neurons

K+ channels
* KCa, Kv, TASK1

Ca2+ channels
* T-type Ca2+ channels

21
Q

Non-CB1/ CB2
targets

A

not just CB1r

e.g. FAAH inhibitors also increase levels of other

FAAH substrates eg PEA and OEA

22
Q

Summary (5)

A
  • AEA & 2-AG are major endogenous CB1/2 agonists
  • AEA & 2-AG modulate synaptic plasticity via CB1-mediated retrograde signalling
  • Modulation of eCB signalling has therapeutic potentials
  • FAAH inhibitors increase effects of AEA and probably structurally similar eCBs-like lipids
  • eCBs can act on non-CB1/CB2 receptors and ion channels