User:Tkadm30/Notebook/Endocannabinoids

Introduction

The neuroprotective effects of the marijuana plant are still poorly understood. The aim of this study is to present a method for delivery of N-docosahexaenoyl ethanolamide (DHEA) to hippocampal neurons using endocannabinoid-like mobilization of docosahexaenoic acid (DHA).

Neuroendopsychology of endocannabinoids:

Endocannabinoids may be a promising therapeutic platform with neuroprotective properties in the treatment of neurological disorders including epilepsy, Alzheimer, and depression by inhibiting microglial activation and stress-induced neuroinflammation of the CNS.

Synopsis

• Stimulation of endocannabinoid transport with polyunsaturated (22:6n-3) fatty acids (DHA, EPA) to target major depressive disorders (MDD) , epilepsy and Alzheimer disease (AD).
• Distribution of endocannabinoid-dependent activity (LTP, LTD, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression, a biological marker for learning-dependent synapse formation. PMID PMID
• Neuroprotective effects of the mitochondrial CB1 receptor on excitatory (glutamatergic) synapses and in particular astrocytes. PMID PMID
• Putative GPR55-DHA heteromer (N-docosahexaenoyl ethanolamide) with potent anti-inflammatory, antiglutamatergic and neuroprotective properties
  • Anti-proliferative effects of DHEA on prostate cancer cell lines. PMC
  • A synaptogenic endocannabinoid which promotes synaptogenesis. [1]
  • Antioxidant (cytoprotective) properties of GPR55-DHA heteromer.
• Effects of the endothelial CB2 receptor persistent activation on monocyte subpopulations/microglial activation PMID
  • Anti-inflammatory role of anandamide and 2-AG signaling in LPS-stimulated microglial activation of endogenous CB2 receptor. Link
  • Neuroprotection by preventing microglial activation. PMID PMID
  • CB2 stimulation is proneurogenic on adult hippocampal neurogenesis PMC

Endogenous cannabinoids as a therapeutic platform

2-arachidonoylglycerol (2-AG), a novel gliotransmitter controlled by the P2X7 receptor, exert neuroprotective effects on excitotoxic brain injury.

• 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 PMID
• 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 from astrocytes 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) partial 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 and neuroinflammation. 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 of synaptogenic amides. (N-acyl ethanolamide)

First, anandamide and 2-AG 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.

Also, DHA supplementation may increase mitochondrial function and enhance CB1/CB2 dependent neuroprotection through endocannabinoids mobilization.

In addition, endocannabinoids may protect neurons from excitotoxicity and neuroinflammation upon exposure to stress-induced excitotoxic insults. PMID PMID

Hence, endocannabinoids constitute a family of intracellular lipid signaling molecules with potent anti-inflammatory, anti-oxidative and anti-excitotoxic bioactivity to reduce microglial activation during neuroinflammation of the CNS.

Keywords

endocannabinoids, hippocampus, anandamide, 2-AG, CB1, CB2, 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, microglial activation, mitochondrial phospholipids, cardioprotection, synaptamide, ethanolamide

References

1. 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 |

   A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.

2. 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 |

   Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.

3. Chevaleyre V and Castillo PE. Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron. 2004 Sep 16;43(6):871-81. DOI:10.1016/j.neuron.2004.08.036 |

   Endocannabinoid-mediated metaplasticity in the hippocampus.

4. 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 |

   Emerging neurotrophic role of GABAB receptors in neuronal circuit development.

5. 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 |

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

6. 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 |

   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