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 LTP in the hippocampus.

Endocannabinoid-dependent activity promote persistent synaptic plasticity in the hippocampus.

Hypothesis

1. DHA may potentiate synaptic plasticity (and cognition) via retrograde CB1 signaling.
   1. DHA activate the (presynaptic?) NMDA receptor and upregulate the release of glutamate. [1]
      1. DHA-induced synapses (CA3) enhance synaptic plasticity, thus learning is enhanced. [2]
      2. Induction of Long-Term Potentiation/Persistent synaptic plasticity (LTP). (Pathway)
   2. Activation of inhibitory GABAergic synapse (GABA(B) receptor ?) by endocannabinoids (DHA) may promote synaptic function and learning. [3]
      1. TrkB receptor regulate activity-dependent synaptogenesis and BDNF expression [4]

Model

1. The Promoters:
   1. DHA (docosahexaenoic acid) conjugate in the hippocampus is N-docosahexaenoyl ethanolamine (DHEA).
      1. DHEA subclass is N-acyl ethanolamines (NAE)
   2. THC (delta-9-tetrahydrocannabinol)

1. The Wet Blanket: (CB1 receptor)
   1. Role: Protect the hippocampus and neurons from glutamate excitoxicity.
   2. 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
   3. 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. The Suppression of Inhibition:
   1. TrkB (2.7.10.1) potentiate GABAergic synaptic activation:
      1. BDNF expression is Ca2+ and CREB dependent
   2. DSI (CB1-mediated inhibition of GABAergic transmission/Depolarization-induced Suppression of Inhibition) -> EPSC (excitatory post-synaptic currents) -> NMDA-dependent(?) LTP at excitatory, and glutamatergic synapses
      1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574086
      2. http://www.ncbi.nlm.nih.gov/pubmed/12080342
      3. http://www.ncbi.nlm.nih.gov/pubmed/17392410
      4. http://www.sciencedirect.com/science/article/pii/S0896627304005732
      5. endocannabinoids-mediated metaplasticity : http://www.ncbi.nlm.nih.gov/pubmed/15363397 http://www.ncbi.nlm.nih.gov/pubmed/18523004
         1. metaplastic control of synaptic transmission
         2. mGluR activation
         3. synaptic inhibition
         4. DSI/glutamate hypothesis:
            1. http://www.ncbi.nlm.nih.gov/pubmed/10561426
            2. http://www.ncbi.nlm.nih.gov/pubmed/23527052
3. PPAR signaling: http://www.ncbi.nlm.nih.gov/pubmed/17704824
   1. endocannabinoid dependent activation of PPAR-alpha
   2. neurogenesis?
   3. THC/DHEA activate PPAR-gamma
4. Dual ligands design
   1. CB1 and PPAR-gamma targeting: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056814/
5. Folic acid (Vitamin B9) amplify cannabimimetic activity and DHA plasma concentration: http://www.scq.ubc.ca/fakepaper1.pdf
6. Adenosine and cannabinoids connection
   1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931547/
   2. TrkB, lipid rafts: http://www.ncbi.nlm.nih.gov/pubmed/20573894
   3. BDNF requires Adenosine receptor (A2a) activation to induce LTP: http://www.ncbi.nlm.nih.gov/pubmed/24533014
   4. DHA modulation of ATP response is controlled via the (use-dependent) inhibition of ionotropic P2X receptors:
      1. http://www.ncbi.nlm.nih.gov/pubmed/17099292
      2. http://www.ncbi.nlm.nih.gov/pubmed/12351710

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

Keywords

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

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. 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 |
3. 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 |
4. 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 |
5. 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 |
6. 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 |

See also

• EGFR Notebook
• Cannabidiol Notebook