User:Tkadm30/Notebook/Endocannabinoids: Difference between revisions

From OpenWetWare
Jump to navigationJump to search
(8 intermediate revisions by the same user not shown)
Line 4: Line 4:
The therapeutic effects of the marijuana plant are still subject of provocative debates. Hence, the delivery of
The therapeutic effects of the marijuana plant are still subject of provocative debates. Hence, the delivery of
cannabinoids drug (THC, CBD) to the brain and central nervous system (CNS) remains poorly understood. Moreover, the role of
cannabinoids drug (THC, CBD) to the brain and central nervous system (CNS) remains poorly understood. Moreover, the role of
marijuana may be a beneficial asset in the treatment of epilepsy and depression.
marijuana may be a beneficial asset in the treatment of epilepsy, Alzheimer, and depression.


== Synopsis ==
== Synopsis ==
Line 10: Line 10:
* Define a neurocognitive therapy through the stimulation of endocannabinoids with fatty acids derived phospholipids (DHA, EPA) to target [http://en.wikipedia.org/wiki/Major_depressive_disorder major depressive disorders] (MDD).
* Define a neurocognitive therapy through the stimulation of endocannabinoids with fatty acids derived phospholipids (DHA, EPA) to target [http://en.wikipedia.org/wiki/Major_depressive_disorder major depressive disorders] (MDD).
* Identify key evidences of endocannabinoid-dependent activity (LTP, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression.
* Identify key evidences of endocannabinoid-dependent activity (LTP, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression.
* Note the effects of Cannabis derived endogenous ligands on excitatory synapses and in particular astrocytes.
* Validate the effects of the CB1 receptor on excitatory (glutamatergic) synapses and in particular astrocytes.
 
* Elucidate the functions of a novel GPR120-CB1 heteromer with potent anti-inflammatory properties.
== Hypothesis  ==
 
=== Astrocytic activity promote persistent synaptic plasticity in the hippocampus. ===
 
DHA (docosahexaenoic acid) supplementation enhance synaptic plasticity and cognition by regulating BDNF expression and glutamate release from astrocytic metabotropic glutamate receptors. <cite>Wu-2008</cite> <cite>Martin-2011</cite>
 
Furthermore, BDNF expression may requires Adenosine receptors (A2a) activation to induce long-term potentiation (LTP). <cite>Duster-2014</cite>
 
Thus, BDNF-induced synaptogenesis is enhanced by DHA supplementation to neurons, while endogenous cannabinoids may
protect neurons from glutamate excitoxicity and inflammation. <cite>Kim-2013</cite> <cite>Kim-2011</cite>
 
=== Astrocytic promoters of synaptic plasticity ===
# DHA conjugate in the hippocampus is N-docosahexaenoyl ethanolamine (DHEA; synaptamide).
# DHA synthesis is produced by astrocytes from α-linolenic acid (ALA), a polyunsaturated (n-3) fatty acid precursor.
# DHEA subclass is N-acyl ethanolamines (NAE)
 
=== CB1 receptor: On-demand protection agaisnt excitatory neuronal activity. ===
# http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769341/
# http://www.ncbi.nlm.nih.gov/pubmed/14526074/
# [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687658/ DHEA bind and activate the CB1 receptor]
# neuroprotection
# promotes hippocampal development: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215906/
# synaptogenesis (synapse formation)
# neurite growth and neurons survival
# glutamatergic synaptic activity
# Fatty acid amide hydrolase (FAAH) hydrolysis of synaptamide?
# DHEA hydrolysis stimulate N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382453/
# endocannabinoids degradation (THC, DHEA)
# cannabidiol (CBD) and anandamide signaling
 
=== 2-AG as a novel gliotransmitter modulate astrocytes-mediated metaplasticity ===
# depolarization-induced suppression of inhibition  ('''DSI'''):
## dont forget depolarization-induced suppression of excitation (DSE)
## http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574086
## http://www.ncbi.nlm.nih.gov/pubmed/12080342
## http://www.ncbi.nlm.nih.gov/pubmed/17392410
## http://www.sciencedirect.com/science/article/pii/S0896627304005732
# endocannabinoids-mediated heterosynaptic '''metaplasticity''':
## http://www.ncbi.nlm.nih.gov/pubmed/15363397
## http://www.ncbi.nlm.nih.gov/pubmed/18523004
 
=== Astrocytes mediate activity-dependent LTP via purinergic signaling receptors ===
# Adenosine and cannabinoids connection
## DHA modulation of ATP response is controlled via the (use-dependent) inhibition of '''ionotropic [http://www.ncbi.nlm.nih.gov/gene/5027 P2X7 receptors]''':
### http://www.ncbi.nlm.nih.gov/pubmed/17099292
### http://www.ncbi.nlm.nih.gov/pubmed/12351710
# Astrocytes mediated synaptic plasticity :
## http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279365/
## http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915348/
## http://www.nature.com/tp/journal/v3/n1/full/tp2012136a.html
# Exocytosis of ATP 
## Downregulation of glutamatergic synaptic transmission
## P2X7 receptor activation induce exocytosis of ATP <cite>Lalo-2014</cite>
## non-exocytotic glutamate release
## http://www.ncbi.nlm.nih.gov/pubmed/15371507


== Neuroprotective properties of endogenous cannabinoids/DHEA ligands ==
== Neuroprotective properties of endogenous cannabinoids/DHEA ligands ==
=== Reversible ('''competitive''') acetylcholinesterase inhibition mecanism of THC ===
=== Reversible, competitive acetylcholinesterase (AChE) inhibition mecanism of THC ===
* THC inhibit AChE-induced beta-amyloid aggregation in Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562334/
* THC inhibit AChE-induced beta-amyloid aggregation in Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562334/
* Anti-inflammatory activity of THC agaisnt organophosphate-induced neuroinflammation:  
* Anti-inflammatory activity of THC agaisnt organophosphate-induced neuroinflammation:  
Line 75: Line 20:
** https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366364/
** https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366364/
* Unlike THC, caffeine is a noncompetitive reversible inhibitor of AChE
* Unlike THC, caffeine is a noncompetitive reversible inhibitor of AChE
=== Docosanoids as neuroprotective lipid messengers ===
 
* Docosanoids (neuroprotectins and resolvins) are lipid signaling metabolites of DHA catalyzed by the 15-lipoxygenase enzyme. In addition, Neuroprotectin D1 (NPD1) exert anti-inflammatory and anti-apoptotic bioactivity on synapses.
=== 2-arachidonoylglycerol (2-AG) ===
=== 2-arachidonoylglycerol (2-AG) ===
* 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DAGL) and phospholipase C (PLC).
* 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DAGL) and phospholipase C (PLC).
Line 96: Line 40:
* See also http://en.wikipedia.org/wiki/Anandamide
* See also http://en.wikipedia.org/wiki/Anandamide


=== Δ9-THC ===
=== Δ9-tetrahydrocannabinol (Δ9-THC) ===
* Antidepressant effect of Δ9-tetrahydrocannabinol (Δ9-THC). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/
* Antidepressant effect of Δ9-tetrahydrocannabinol (Δ9-THC). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/
** Regulation of stress-induced neuroinflammation on selective (working) memory?  
** Regulation of stress-induced neuroinflammation on selective (working) memory?  
Line 121: Line 65:
#Duman-2012 pmid=22826346
#Duman-2012 pmid=22826346
#Monory-2006 pmid=16908411
#Monory-2006 pmid=16908411
#Pertwee-2010 pmid=21079038
</biblio>
</biblio>


== See also ==
== See also ==


* [[User:Etienne_Robillard/Notebook/Astrocytes|Astrocytes Notebook]]
* [[User:Etienne_Robillard/Notebook/Cannabidiol|Cannabidiol Notebook]]
* [[User:Etienne_Robillard/Notebook/Cannabidiol|Cannabidiol Notebook]]
* [[User:Etienne_Robillard/Notebook/EGFR|EGFR Notebook]]
* [[User:Etienne_Robillard/Notebook/Cannabidivarin|Cannabidivarin Notebook]]
* [[User:Etienne_Robillard/Notebook/GABA|GABA Notebook]]
* [[User:Etienne_Robillard/Notebook/Docosanoids|Docosanoids Notebook]]

Revision as of 10:30, 20 May 2015

Introduction

The therapeutic effects of the marijuana plant are still subject of provocative debates. Hence, the delivery of cannabinoids drug (THC, CBD) to the brain and central nervous system (CNS) remains poorly understood. Moreover, the role of marijuana may be a beneficial asset in the treatment of epilepsy, Alzheimer, and depression.

Synopsis

  • Define a neurocognitive therapy through the stimulation of endocannabinoids with fatty acids derived phospholipids (DHA, EPA) to target major depressive disorders (MDD).
  • Identify key evidences of endocannabinoid-dependent activity (LTP, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression.
  • Validate the effects of the CB1 receptor on excitatory (glutamatergic) synapses and in particular astrocytes.
  • Elucidate the functions of a novel GPR120-CB1 heteromer with potent anti-inflammatory properties.

Neuroprotective properties of endogenous cannabinoids/DHEA ligands

Reversible, competitive acetylcholinesterase (AChE) inhibition mecanism of THC

2-arachidonoylglycerol (2-AG)

anandamide (N-arachidonoylethanolamine)

Δ9-tetrahydrocannabinol (Δ9-THC)

Conclusion

DHA is an effective promoter of long-term potentiation and its effects on neuronal plasticity are well documented. Moreover, THC may exert a synergistic effect on DHA uptake, glutamate transport, and synaptic plasticity through retrograde signaling. Thus, the combination of THC with DHA is a potent activator of astrocytic channel transporter and exert the modulation of GABA through astrocytes. In addition, endocannabinoids may protect neurons from excitoxicity and neuroinflammation upon exposure to stress. Finally, endocannabinoids represent a family of lipid signaling molecules with potent anti-inflammatory (neuroprotective) bioactivity and promising therapeutic strategies to treat major neurological disorders (Depression, Alzheimer's disease) efficiently.

Keywords

endocannabinoids, hippocampus, anandamide, FAAH, DHA, DHEA, THC, neurogenesis, synaptogenesis, GABA, synaptamide, BDNF, LTP, ATP, purinergic signaling, adenosine, acetylcholine, synaptic plasticity, heterosynaptic plasticity, astrocytes, cytokines, neuroinflammation, Alzheimer

References

  1. Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, and Kim HY. Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem. 2009 Oct;111(2):510-21. DOI:10.1111/j.1471-4159.2009.06335.x | PubMed ID:19682204 | HubMed [ref1]
  2. Gaiarsa JL and Porcher C. Emerging neurotrophic role of GABAB receptors in neuronal circuit development. Front Cell Neurosci. 2013;7:206. DOI:10.3389/fncel.2013.00206 | PubMed ID:24282395 | HubMed [GABA-2013]
  3. Kim HY, Spector AA, and Xiong ZM. A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):114-20. DOI:10.1016/j.prostaglandins.2011.07.002 | PubMed ID:21810478 | HubMed [Kim-2011]
  4. Wu A, Ying Z, and Gomez-Pinilla F. Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neuroscience. 2008 Aug 26;155(3):751-9. DOI:10.1016/j.neuroscience.2008.05.061 | PubMed ID:18620024 | HubMed [Wu-2008]
  5. Lalo U, Palygin O, Rasooli-Nejad S, Andrew J, Haydon PG, and Pankratov Y. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 2014 Jan;12(1):e1001747. DOI:10.1371/journal.pbio.1001747 | PubMed ID:24409095 | HubMed [Lalo-2014]
  6. Martin JL and Finsterwald C. Cooperation between BDNF and glutamate in the regulation of synaptic transmission and neuronal development. Commun Integr Biol. 2011 Jan;4(1):14-6. DOI:10.4161/cib.4.1.13761 | PubMed ID:21509169 | HubMed [Martin-2011]
  7. Düster R, Prickaerts J, and Blokland A. Purinergic signaling and hippocampal long-term potentiation. Curr Neuropharmacol. 2014 Jan;12(1):37-43. DOI:10.2174/1570159X113119990045 | PubMed ID:24533014 | HubMed [Duster-2014]
  8. Kim HY and Spector AA. Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function. Prostaglandins Leukot Essent Fatty Acids. 2013 Jan;88(1):121-5. DOI:10.1016/j.plefa.2012.08.002 | PubMed ID:22959887 | HubMed [Kim-2013]
  9. Duman RS and Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2475-84. DOI:10.1098/rstb.2011.0357 | PubMed ID:22826346 | HubMed [Duman-2012]
  10. Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, and Lutz B. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron. 2006 Aug 17;51(4):455-66. DOI:10.1016/j.neuron.2006.07.006 | PubMed ID:16908411 | HubMed [Monory-2006]
  11. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, and Ross RA. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂. Pharmacol Rev. 2010 Dec;62(4):588-631. DOI:10.1124/pr.110.003004 | PubMed ID:21079038 | HubMed [Pertwee-2010]

All Medline abstracts: PubMed | HubMed

See also

Retrieved from "https://openwetware.org/mediawiki/index.php?title=User:Tkadm30/Notebook/Endocannabinoids&oldid=885133"