User:Tkadm30/Notebook/Endocannabinoids

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.
• Note the effects of Cannabis derived endogenous ligands on excitatory synapses and in particular astrocytes.

Neuroprotective properties of endogenous cannabinoids/DHEA ligands

Reversible (competitive) acetylcholinesterase inhibition mecanism of THC

• 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:
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891218/
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366364/
• Unlike THC, caffeine is a noncompetitive reversible inhibitor of AChE

2-arachidonoylglycerol (2-AG)

• 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DAGL) and phospholipase C (PLC).
• Neuroprotective (anti-inflammatory)
• retrograde 2-AG signaling
  • modulate glutamatergic LTP/DSE
  • http://www.ncbi.nlm.nih.gov/pubmed/23307660
• Anxiolytic
• ionotropic (permeable to calcium) P2X7 receptor control 2-AG production
  • http://www.ncbi.nlm.nih.gov/pubmed/14976257
• monoacylglycerol lipase (MAGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685
• calcium dependent biosynthesis

anandamide (N-arachidonoylethanolamine)

• biosynthesis of endogenous phosphoanandamide/PLC ligands: http://www.ncbi.nlm.nih.gov/pubmed/16938887
• cannabinoid receptor type 1 (CB1) full agonist
  • http://www.ncbi.nlm.nih.gov/pubmed/21719698
  • CB1 receptor affinity=78nM: http://en.wikipedia.org/wiki/Cannabinoid_receptor
• See also http://en.wikipedia.org/wiki/Anandamide

Δ9-THC

• 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?
• Hippocampal neurogenesis is enhanced. http://www.ncbi.nlm.nih.gov/pubmed/16224541/
  • Synaptogenic effect of Δ9-THC/DHEA ligands promote hippocampal development.
  • Δ9-THC/DHEA ligands (synaptamide) affect neural stem/progenitor cells (NS/PC) proliferation in the hippocampus.

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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |

See also

• Astrocytes Notebook
• Cannabidiol Notebook
• Cannabidivarin Notebook
• Docosanoids Notebook