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 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.

Hypothesis

CB1 receptor: On-demand protection agaisnt excitatory neuronal activity.

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769341/
2. http://www.ncbi.nlm.nih.gov/pubmed/14526074/
3. DHEA bind and activate the CB1 receptor
4. neuroprotection
5. promotes hippocampal development: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215906/
6. synaptogenesis (synapse formation)
7. neurite growth and neurons survival
8. glutamatergic synaptic activity
9. Fatty acid amide hydrolase (FAAH) hydrolysis of synaptamide?
10. DHEA hydrolysis stimulate N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382453/
11. endocannabinoids degradation (THC, DHEA)
12. 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

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

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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 |
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See also

• Cannabidiol Notebook
• EGFR Notebook
• GABA Notebook