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 progenitor cells using endocannabinoid-like mobilization of docosahexaenoic acid (DHA).

Neuroendopsychology of atypical endocannabinoids:

Endocannabinoid-dependent receptor heteromerization may be a promising pharmacological target with neuroprotective properties in the treatment of neurological disorders through activation of PPARs and modulation of endocannabinoid transport. In particular, GPR40 and GPR55 may cooperatively regulate neuronal differentiation and proliferation via receptor heteromerization of synaptamide and astrocytes-expressed fatty acid-binding proteins (FABPs).

Development of endocannabinoid-mobilized proneurogenic heteromers:

The suppression of microglial activation by endocannabinoid-like (N-acyl) ethanolamides may increase adult hippocampal neurogenesis and promote mBDNF expression. Thus the objective of the GPR40-GPR55 heteromer is to enhance hippocampal plasticity and brain neuroprotection via endocannabinoid stimulation of endogenous BDNF in the hippocampus using synaptamide as the proneurogenic promoter of synaptic function.

Hypothesis

FABPs stimulation of GPR40 and GPR55 may exert neuroprotective effects on the hippocampus through selective binding of PPARs agonist. Moreover, synaptamide stimulation of FABPs enhance endocannabinoid transport and may regulate neuronal differentiation and proliferation through neuron-astrocytes signaling.

Method

• Using Google search and PubMed, identify keywords and extract informations for data-mining analysis.
• Identify the concepts and references for the experiment.
• Categorize the informations processed.
• Identify the hypothesis and analyze results.
• Compare results found with published publications and review hypothesis if needed.

Results

DHA stimulation of PPARs decreases brain anandamide levels and improves synaptic function through FABP5 expression

• http://www.sciencedaily.com/releases/2014/05/140502132458.htm
• Identification of DHA as a proneurogenic PPARγ agonist for treatment of neurological disorders.
• Intrinsic role of FABPs expression in (retrograde) anandamide signaling: PPARs expression induce long-term potentiation (LTP) in the hippocampus. PMID
• Evidences that DHEA is a synaptogenic endocannabinoid and potent activator of FABPs.
  • Stimulation of GPR40-GPR55 receptor heteromer by DHA promotes heterosynaptic LTP through peroxisome proliferator-activated receptors (PPARs) activation. Link doi:10.1186/1471-2202-13-109
  • FABP7 is a CB1/CB2 independent ligand for GPR55-mediated hippocampal metaplasticity.
  • FABP5 expression occurs in the lungs and the brain.
    • FABP5 deficiency increase sensitivity to H1N1 infection. Link
  • FABPs expression selectively enhance PPARs regulation of transcription. PMID

Role of GPR40-GPR55 expression in neurodegenerative diseases: PPARγ modulation of BDNF/CREB by synaptamide promote neural differentiation and proliferation of progenitor cells

• Receptor heteromerization of GPR40-GPR55 modulates hippocampal neurogenesis through cAMP/PKA/CREB signaling.
  • Effects of PPARs agonists on BDNF expression:
    • Neuroprotection?
    • Neuron-astrocyte cell migration and differentiation PMID
    • Proliferation of neural stem/progenitor cells (NSPCs)
    • DHA activation of PPARs reduce amyloid-beta (Abeta) generation in astrocytes. (Alzheimer) PMID PMID PMID
    • Neuroimmune modulation (ie: endogenous remyelination) PMID PMC PMC
    • BDNF-induced synaptogenesis
• Endocannabinoid mobilized synaptamide upregulate activity-dependent hippocampal neurogenesis and neural progenitor (NP) cell proliferation. doi: 10.1074/jbc.M111.291294 PMID

Discussion

Endocannabinoid transport of proneurogenic compounds

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)

Endocannabinoids and synaptic plasticity

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.

Is hippocampal plasticity an evidence of proneurogenic endocannabinoid transport ?

"Metaplasticity" is perhaps a biological activity relevant to hippocampal plasticity and may facilitate heterosynaptic LTP through retrograde endocannabinoid signaling and diffusion in the hippocampus. PMID

The evidences of GPR55 expression in the hippocampus therefore indicate a promising proneurogenic promoter to mediate hippocampal metaplasticity in neurodegenerative diseases. Hence, intracellular anandamide trafficking by GPR40 and GPR55 may enhance BDNF expression and promote synaptic function.

Mitochondrial function

DHA supplementation may increase mitochondrial function and enhance CB1/CB2 dependent neuroprotection through endocannabinoids mobilization. Thus, mitochondrial respiration is increased by DHA.

Neuroprotective effects of endocannabinoids

Endocannabinoids may protect on-demand neurons from excitotoxicity and neuroinflammation upon exposure to stress-induced excitotoxic insults. PMID PMID

Intracellular anandamide/GPR55 signaling

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 hippocampus.

Endocannabinoid-dependent GPR40-GPR55 heteromers

Design of a novel pharmacological target targeting neuroinflammation through endocannabinoid-mediated FABPs signaling: PPAR-gamma increase endocannabinoid-dependent synaptic function via retrograde signaling and FABPs.

Notes:

Novel endocannabinoids (synaptamide) compounds as selective PPARs agonist: Role of GPCR heteromization in synaptic plasticity?

Identification of GPR40-GPR55 receptor heteromer: Is synaptamide a proneurogenic pharmacological target?

Receptor heteromization of GPR40 and GPR55 selectively enhance BDNF/CREB expression.

DHA (synaptamide) promotes synaptic function and LTP via hippocampal metaplasticity.

DHA reduce microglial activation and neuroinflammation of the hippocampus.

Retinoids as regulators of neural differentiation

Astrocytes in regenerative medicine: directed differentiation of neural progenitor cells by retinoic acid (vitamin A) is enhanced by DHA supplementation. Thus, retinoic acid may enhance neuron-astrocyte signaling through distribution of retinoid X receptor (RXR) activity. PMID

Retinoic acid promotes endogenous CNS remyelination. PMID

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, FABP7, PPAR, GPCR, receptor heteromerization, CREB, GPR40, GPR55, arachidonic acid, neural stem/progenitor cells, retinoids

References

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   Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.

2. 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.

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 |

   Emerging neurotrophic role of GABAB receptors in neuronal circuit development.

4. 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.

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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. Yu S, Levi L, Siegel R, and Noy N. Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ). J Biol Chem. 2012 Dec 7;287(50):42195-205. DOI:10.1074/jbc.M112.410381 |

    Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ).

11. 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.

12. 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.

13. Rashid MA, Katakura M, Kharebava G, Kevala K, and Kim HY. N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J Neurochem. 2013 Jun;125(6):869-84. DOI:10.1111/jnc.12255 |

    N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.

14. Yu S, Levi L, Casadesus G, Kunos G, and Noy N. Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by decreasing anandamide levels and by activating the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in the brain. J Biol Chem. 2014 May 2;289(18):12748-58. DOI:10.1074/jbc.M114.559062 |

    Fatty Acid-binding Protein 5 (FABP5) Regulates Cognitive Function Both by Decreasing Anandamide Levels and by Activating the Nuclear Receptor Peroxisome Proliferator-activated Receptor β/δ (PPARβ/δ) in the Brain

See also

Cannabinoids:

• Cannabidiol Notebook
• Cannabidivarin Notebook
• THC Notebook

Docosanoids:

• Docosanoids Notebook

Endocannabinoids:

• Anandamide Notebook
• 2-AG Notebook
• DHA Notebook
• Synopsis