User:Tkadm30/Notebook/Endocannabinoids: Difference between revisions
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* 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. | * 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 | * 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DAGL). | ||
* Neuroprotective (anti-inflammatory) | * Neuroprotective (anti-inflammatory) | ||
* retrograde 2-AG signaling = modulate LTP/DSE | * retrograde 2-AG signaling = modulate LTP/DSE | ||
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** http://www.ncbi.nlm.nih.gov/pubmed/14976257 | ** http://www.ncbi.nlm.nih.gov/pubmed/14976257 | ||
* monoacylglycerol lipase (MAGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685 | * monoacylglycerol lipase (MAGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685 | ||
=== Δ9-THC === | === 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/ |
Revision as of 12:26, 11 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 and depression.
Synopsis
- Define a neurological 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.
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. [1] [2]
Furthermore, BDNF expression may requires Adenosine receptors (A2a) activation to induce long-term potentiation (LTP). [3]
Thus, BDNF-induced synaptogenesis is enhanced by DHA supplementation to neurons, while endogenous cannabinoids may protect neurons from glutamate excitoxicity and inflammation. [4] [5]
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/
- 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:
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 P2X7 receptors:
- Astrocytes mediated synaptic plasticity :
- Exocytosis of ATP
- Downregulation of glutamatergic synaptic transmission
- P2X7 receptor activation induce exocytosis of ATP [6]
- non-exocytotic glutamate release
- http://www.ncbi.nlm.nih.gov/pubmed/15371507
Neuroprotective properties of endogenous CB1/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:
- 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-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DAGL).
- Neuroprotective (anti-inflammatory)
- retrograde 2-AG signaling = modulate LTP/DSE
- Anxiolytic
- ionotropic (permeable to calcium) P2X7 receptor control 2-AG production
- monoacylglycerol lipase (MAGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685
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
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |