User:Tkadm30/Notebook/Endocannabinoids

Introduction

The neurocognitive 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 endogenous cannabinoids may be a beneficial asset in the treatment of neurological disorders including epilepsy, Alzheimer, and depression.

Synopsis

• Stimulation of endocannabinoid transport with polyunsaturated (n-3) fatty acids (DHA, EPA) to target major depressive disorders (MDD) and Alzheimer disease (AD).
• Distribution of endocannabinoid-dependent activity (LTP, LTD, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression. PMID
• Neuroprotective effects of the CB1 receptor on excitatory (glutamatergic) synapses and in particular astrocytes. PMID PMID
• Novel GPR55-DHA heteromer with potent anti-inflammatory, antiglutamatergic and neuroprotective properties.
• Antioxidant (cytoprotective) properties of GPR55-DHA heteromer.
• Effects of the endothelial CB2 receptor persistent activation on monocyte subpopulations/microglia migration. PMID

Endogenous cannabinoids as a therapeutic platform

2-arachidonoylglycerol (2-AG)

• 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DGL-α) and phospholipase C (PLC).
• Neuroprotective (anti-inflammatory) and a potent cytoprotective agent (antioxidant)
• 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 PMID
• monoacylglycerol lipase (MGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685
• calcium dependent biosynthesis
• ATP-induced 2-AG production, a novel gliotransmitter controlled by the P2X7 receptor PMID PMID
  • 2-AG activate endogenous phospholipase C-dependent TRPV1 channel in the brain.
  • doi:10.1038/srep04329

Anandamide (N-arachidonoyl-ethanolamine)

• Biosynthesis of endogenous phosphoanandamide/PLC ligands: PMID
• Cannabinoid receptor type 1 (CB1) full agonist PMID
• Anandamide signaling is metabotropic (CB1) and limit TRPV1-mediated Ca2+ influx. PMID
• Anandamide appears a good target to activate TRPV1 receptor and trigger antiepileptogenesis.
• Anandamide provides on demand neuroprotection agaisnt in vivo excitotoxicity PMID

NADA (N-arachidonoyl-dopamine)

• A putative endocannabinoid with potential atheroprotective properties.PMID PMID
• NADA modulate anti-inflammatory activation of the endothelium. PMID
• Full agonist at the CB1/CB2 receptors and TRPV1 ion channel.
• Pleiotropic role of the CB2 receptor: Immunomodulation of the endothelium. PMID PMID
• Structural analog of the dopamine conjugate of DHA.

Endocannabinoid transport

DHA is an effective promoter of long-term potentiation (LTP) and new evidences suggest its effects on synaptic plasticity as a potent endocannabinoid-like transporter.

First, THC may exert a synergistic effect on DHA regulation, glutamatergic transport, and synaptic plasticity through retrograde signaling. Thus the modulation of DHA with endogenous cannabinoids may provide a persistent supply of endocannabinoids to neurons.

In addition, endocannabinoids may protect neurons from excitoxicity and neuroinflammation upon exposure to stress. Hence, endocannabinoids constitute a family of intracellular lipid signaling molecules with potent anti-inflammatory, anti-oxidative and anti-excitotoxic bioactivity to treat major neurological and neurodegenerative disorders (Depression, Alzheimer's disease) efficiently.

Keywords

endocannabinoids, hippocampus, anandamide, 2-AG, CBD, FAAH, DHA, DHEA, THC, TRPV1, neurogenesis, synaptogenesis, GABA, synaptamide, BDNF, LTP, ATP, P2X7, NADA, purinergic signaling, adenosine, acetylcholine, synaptic plasticity, heterosynaptic metaplasticity, astrocytes, cytokines, neuroinflammation, Alzheimer, endothelium

References

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   Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.

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   Endocannabinoid-mediated metaplasticity in the hippocampus.

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   Emerging neurotrophic role of GABAB receptors in neuronal circuit development.

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   A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.

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   Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition.

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   Purinergic signaling and hippocampal long-term potentiation.

7. 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 |

   Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function.

8. 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 |

   The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus.

9. 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 |

   International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2.

10. Zogopoulos P, Vasileiou I, Patsouris E, and Theocharis S. The neuroprotective role of endocannabinoids against chemical-induced injury and other adverse effects. J Appl Toxicol. 2013 Apr;33(4):246-64. DOI:10.1002/jat.2828 |

    The neuroprotective role of endocannabinoids against chemical-induced injury and other adverse effects.

11. Meijerink J, Balvers M, and Witkamp R. N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads. Br J Pharmacol. 2013 Jun;169(4):772-83. DOI:10.1111/bph.12030 |

    N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads.

See also

• Astrocytes Notebook
• Cannabidiol Notebook
• Cannabidivarin Notebook
• DHA Notebook
• Docosanoids Notebook
• THC Notebook