User:Tkadm30/Notebook/Endocannabinoids

Introduction

Medicinal marijuana has been for centuries a medicinal herb to cure many diseases naturally, and its effects are still subject of intense controversial debates. In this study is presented a method to induce cognitive enhancements through the combination of medicinal marijuana with fatty acids supplements (omega 3).

Furthermore the functions of metabolic endocannabinoids ligands are investigated to identify key evidences of endocannabinoid-dependent activity (LTP, synaptogenesis) in the hippocampus.

Hypothesis

Astrocytic activity promote persistent synaptic plasticity in the hippocampus.

1. DHA may potentiate synaptic plasticity (and cognition) via retrograde CB1 signaling.
2. DHA activate the (presynaptic?) NMDA receptor and upregulate the release of glutamate. [1]
3. Activation of inhibitory GABAergic synapse (GABA(B) receptor) by endocannabinoids (DHA, THC) may promote synaptic plasticity (LTP). [2]
   1. TrkB receptor regulate activity-dependent synaptogenesis and BDNF expression. [3]
   2. GABA(B) is a metabotropic receptor modulating synaptogenesis. [2]
4. The Promoters:
   1. DHA (docosahexaenoic acid) conjugate in the hippocampus is N-docosahexaenoyl ethanolamine (DHEA).
      1. DHA synthesis is produced by astrocytes from α-linolenic acid (ALA), a polyunsaturated (n-3) fatty acid precursor.
   2. DHEA subclass is N-acyl ethanolamines (NAE)
5. The Wet Blanket:
   1. CB1 and CB2 receptors
   2. Role: Protect the hippocampus and neurons from glutamate excitoxicity.
   3. DHEA bind and activate the CB1 receptor
      1. neuroprotection
      2. promotes hippocampal development: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215906/
         1. synaptogenesis (synapse formation)
         2. neurite growth and neurons survival
         3. glutamatergic synaptic activity
   4. FAAH hydrolysis of DHEA (a endocannabinoid like molecule/N-acyl ethanolamine or anandamide)
      1. http://www.ncbi.nlm.nih.gov/pubmed/20601112
      2. http://www.ncbi.nlm.nih.gov/pubmed/21294934
      3. DHEA biosynthesis stimulate N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity
         1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382453/
      4. endocannabinoids degradation (THC, DHEA)
         1. cannabidiol (CBD) and anandamide signaling

2-AG as a novel gliotransmitter modulate astrocytes-mediated metaplasticity

1. depolarization-induced suppression of inhibition (DSI):
   1. dont forget depolarization-induced suppression of excitation (DSE)
   2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574086
   3. http://www.ncbi.nlm.nih.gov/pubmed/12080342
   4. http://www.ncbi.nlm.nih.gov/pubmed/17392410
   5. http://www.sciencedirect.com/science/article/pii/S0896627304005732
2. endocannabinoids-mediated heterosynaptic metaplasticity:
   1. http://www.ncbi.nlm.nih.gov/pubmed/15363397
   2. http://www.ncbi.nlm.nih.gov/pubmed/18523004

Astrocytes mediate activity-dependent LTP via purinergic signaling receptors

1. Adenosine and cannabinoids connection
   1. BDNF requires Adenosine receptor (A2a) activation to induce LTP: http://www.ncbi.nlm.nih.gov/pubmed/24533014
   2. DHA modulation of ATP response is controlled via the (use-dependent) inhibition of ionotropic P2X7 receptors:
      1. http://www.ncbi.nlm.nih.gov/pubmed/17099292
      2. http://www.ncbi.nlm.nih.gov/pubmed/12351710
2. Astrocytes mediated synaptic plasticity :
   1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279365/
   2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915348/
   3. http://www.nature.com/tp/journal/v3/n1/full/tp2012136a.html
3. Exocytosis of ATP
   1. Downregulation of glutamatergic synaptic transmission
   2. P2X7 receptor activation induce exocytosis of ATP [4]
   3. non-exocytotic glutamate release
   4. http://www.ncbi.nlm.nih.gov/pubmed/15371507

Neuroprotective properties of THC/DHA

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

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 synthetized by the P2X7 receptor.
• Neuroprotective (anti-inflammatory)
• retrograde 2-AG signaling = modulate LTP/DSE
  • http://www.ncbi.nlm.nih.gov/pubmed/23307660
• Anxiolytic
• ionotropic 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

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

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. Huang ZJ. Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond. J Physiol. 2009 May 1;587(Pt 9):1881-8. DOI:10.1113/jphysiol.2008.168211 |
4. 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 |
5. Hagena H and Manahan-Vaughan D. Learning-facilitated synaptic plasticity at CA3 mossy fiber and commissural-associational synapses reveals different roles in information processing. Cereb Cortex. 2011 Nov;21(11):2442-9. DOI:10.1093/cercor/bhq271 |
6. 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 |
7. Chen AI, Nguyen CN, Copenhagen DR, Badurek S, Minichiello L, Ranscht B, and Reichardt LF. TrkB (tropomyosin-related kinase B) controls the assembly and maintenance of GABAergic synapses in the cerebellar cortex. J Neurosci. 2011 Feb 23;31(8):2769-80. DOI:10.1523/JNEUROSCI.4991-10.2011 |

8. http://www.jbc.org/content/286/13/11370

See also

• Cannabidiol Notebook
• EGFR Notebook
• GABA Notebook