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 novel 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, allosteric modulation of GPR40 and GPR55 may cooperatively regulate neuronal differentiation and proliferation via receptor heteromerization of synaptamide and astrocytes-expressed fatty acid-binding proteins (FABPs) synthesis.

Development of endocannabinoid-dependent neuroprotective heteromers:

The suppression of microglial activation by endocannabinoid-like (N-acylethanolamides) phospholipids may increase adult hippocampal neurogenesis and promote mature BDNF (mBDNF) expression. Thus the objective of the GPR40-GPR55 heteromer is to enhance hippocampal metaplasticity (cAMP/BDNF) and brain neuroprotection via anandamide trafficking.

Hypothesis

FABPs endogenous stimulation of GPR40 and GPR55 may exert neuroprotective effects on the hippocampus through selective binding of PPARs receptors. In particular, FABP5 allosteric communication with PPARs receptors may modulate lipid and glucose homeostasis. Moreover, synaptamide receptor heteromerization may enhance homeostatic endocannabinoid transport and degradation of anandamide to arachidonic acid. Furthermore, DHA delivery to hippocampal progenitor cells may facilitate neuronal differentiation and proliferation through intracellular CB1 signaling.

Experimental Method

• Using Google search and PubMed, extract informations from web pages for data-mining analysis.
• Identify the concepts and references for the study.
• Categorize the informations processed.
• Identify the hypothesis and analyze results.
• Compare results found with published publications and review hypothesis if needed.
• Reject non open access publications.

Results

DHA activation of PPAR-RXR heterodimer increase tonic endocannabinoid synthesis

• Identification of DHA as a neuroprotective PPARγ agonist for treatment of neurodegenerative disorders.
• Intrinsic role of FABPs expression in (retrograde) anandamide signaling: PPARs expression induce long-term potentiation (LTP) in the hippocampus.
• Evidences that DHEA is a synaptogenic endocannabinoid and potent intracellular transporter of FABPs. [1]
  • Allosteric modulation of GPR40-GPR55 receptor heteromer by DHA promotes heterosynaptic LTP through peroxisome proliferator-activated receptors (PPARs) activation. [2]
  • FABP7 is a CB1/TRPV1-independent protein for endocannabinoid-mediated hippocampal metaplasticity. [3]
• FABP5 expression occurs in the lungs and the brain.
  • FABP5 deficiency increase sensitivity to H1N1 infection.
    • PPAR-gamma/FABP5 signaling downregulate the expression of proinflammatory cytokines and promote the differentiation of immune cells towards anti-inflammatory (M2) phenotypes.
  • FABPs expression selectively enhance PPARs regulation of transcription. [4]

Phosphorylation of BDNF/CREB by intracellular DHA delivery promote neurogenesis of hippocampal progenitor cells via PPARγ and RXR transactivation

• Receptor heteromerization of GPR40-GPR55 modulates hippocampal neurogenesis through cAMP/PKA/CREB signaling.
  • Effects of PPAR-RXR transactivation on maintenance of neural stem/progenitor cells (NSPCs):
    • CREB-dependent neuroprotection (Nurr1) [5]
    • Neuron-astrocyte cell migration and differentiation
    • Proliferation of NSPCs in the hippocampus.
    • DHA activation of PPARs reduce amyloid-beta (Abeta) generation in astrocytes. (Alzheimer)[6]
    • Neuroimmune modulation (ie: endogenous remyelination) [7]
    • BDNF-induced synaptogenesis
• Endocannabinoids upregulate activity-dependent hippocampal neurogenesis and neural progenitor (NP) cell proliferation through CB1 and CB2 activation. [8]
• Homeostatic regulation of hippocampal metaplasticity by endocannabinoids: [9]
  • 2-AG is a proteolytic PAR1-induced promoter that mediate synaptic retrograde signaling in the hippocampus.
  • Anandamide enhance Notch-1 signaling over APP. [10]

ΔFosB downregulation of CB1 receptor modulate stress and antidepressant responses

• Chronic THC administration produces CB1 desensitization and downregulation via ΔFosB activation in vivo. [11]
  • AP-1 mediated transcription factor activation induce P2X7 expression. [12]

Antipsychotic effect of endocannabinoids on prefrontal cortex neurons

• Anandamide signaling may increase monoaminergic activity in the prefrontal cortex. [13]

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. [14] [15]

Endocannabinoid stimulation of FABPs synthesis: intracellular delivery of DHA to neurons may enhance neurogenesis and maintain brain homeostasis. [9]

Endocannabinoid signaling and homeostatic 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 neuronal stem/progenitor cells. [16]

Is hippocampal neurogenesis an evidence of homeostatic endocannabinoid transport ?

Homeostatic metaplasticity is perhaps a brain activity relevant to hippocampal plasticity and may facilitate heterosynaptic LTP and neurogenesis through retrograde endocannabinoid signaling and mobilization in the hippocampus. [3]

The evidences of GPR40-GPR55 expression in the hippocampus and striatum therefore identify DHA (synaptamide) as a proneurogenic fatty acid to mediate neuroprotection in neurodegenerative diseases. Hence, intracellular anandamide trafficking by GPR40 and GPR55 may enhance BDNF expression and promote synaptic plasticity through endocannabinoid-mediated mobilization. [17]

Mitochondrial function is mediated by CB1 receptor activation and regulate neuronal energy metabolism

DHA supplementation may increase mitochondrial function and enhance CB1/CB2 dependent neuroprotection through endocannabinoids mobilization. Thus, mitochondrial respiration is increased by intracellular DHA delivery. [18]

Role of estrogenic attenuation of CB1 mediated energy homeostasis

• Females don't react to cannabis like males as they express higher sensitivity to THC.
• The estrogen receptor (ER) activation modulates cannabinoid-induced energy homeostasis. [19][20]
• Estrogen signaling induces a rapid decrease of glutamatergic transmission at POMC synapses. [21]

Neuroprotective effects of endocannabinoids are mediated by presynaptic CB1 receptor activation

Endocannabinoids may protect on-demand neurons from neuroinflammation upon exposure to NMDA-induced excitotoxicity. Hence, presynaptic CB1 receptor activation yields activity-dependent neuroprotection against excitotoxic glutamate releases in the hippocampus. [22][23][24]

Notes:

• Extracellular ATP and CB1 interactions: inhibition of P2X7 receptor is neuroprotective in ALS model. [25]
  • Hypothesis: mitochondrial CB1 receptor expression inhibit on-demand extracellular ATP releases by activation of adenosine (A1) receptor, thus protecting neurons from NMDA-induced excitotoxicity.
• Is adenosine (A2A) receptor antagonist (caffeine) facilitate pharmacological inhibition of P2X7 receptor ?

Intracellular anandamide/GPR55 signaling drives adult hippocampal neurogenesis

Endocannabinoids constitute a family of intracellular lipid signaling molecules with potent anti-inflammatory, anti-oxidative and anti-excitotoxic bioactivity to reduce microglial activation during stress-induced neuroinflammation of the hippocampus.

Receptor heteromerization of endocannabinoid-dependent GPR40-GPR55 heteromers

Design of a novel pharmacological target to induce adult hippocampal neurogenesis through endocannabinoid-mediated FABPs signaling: PPAR-gamma activation increase endocannabinoid-dependent synaptic function through allosteric modulation of GPR40 and GPR55.

Notes:

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

Identification of GPR40-GPR55 receptor heteromer:

• Is retinoic acid (RA)-induced synaptamide a proneurogenic promoter of synaptic function?
• Receptor heteromerization of GPR40 and GPR55 selectively enhance BDNF/CREB expression.

Effects of DHA on brain homeostasis and synaptic plasticity:

• Evidences that intracellular FABPs signaling through endocannabinoid-mediated PPAR activation enhance proneurogenic functions of DHA.
• DHA promotes membrane homeostasis and regulates LTP via PPAR-gamma activation.
• DHA reduce microglial activation and neuroinflammation of the hippocampus.
• Tonic endocannabinoid synthesis.

Retinoids as regulators of neural differentiation

Astrocytes in regenerative medicine: directed differentiation of neural progenitor cells by retinoic acid (vitamin A) is induced by PPARs transactivation. Thus, retinoic acid and DHA may enhance neuron-astrocyte signaling through distribution of retinoid X receptor (RXR/PPAR) heterodimer.[26]

Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [27]

Retinoic acid receptor (RAR) activation induces transcriptional regulation of CB1 receptor expression by endocannabinoids. [28]

CB2 receptors stimulation inhibit thrombin-induced neurovascular injury through suppression of microglial activation

Induction of CB2 receptor expression by 2-AG may mediate neuroprotection agaisnt neurovascular unit dysfunctions, including multiple sclerosis and amyotrophic lateral sclerosis. Hence, the suppression of thrombin-induced microglial activation by CB2 receptor expression may promote PAR1 inhibition in the microglia. [29] [30]

PAR1 inhibitors are a novel therapeutic/antiplatelet platform which inhibits thrombin induced dysfunctions.

BDNF/TrkB signaling prevent glutamate-induced excitoxicity in the hippocampus

• Regulation of BDNF/TrkB signaling is mediated by adenosine activation: TrkB phosphorylation is dependent on ADK. [31] [32]
  • Adenosine A(2A) receptor transactivation of BDNF/TrkB receptors: Implications for neuroprotection by ADK. [33]

Endocannabinoid-mediated hypercomputation of conscious states

• Endocannabinoid signaling may induce synaptic exocytosis through coherent quantum vibrations in microtubules. [34]

Conclusion

Synaptamide regulates neural differentiation and proliferation in the hippocampus through endocannabinoid-mediated retrograde signaling. Functional neurogenesis can be facilitated by intracellular delivery of DHA to neurons. Endocannabinoids are a emerging platform for programming of neural stem/progenitor cells in the hippocampus. The neuroprotective effects of endocannabinoids protects against glutamate-induced excitotoxicity and lipid peroxidation.

Activation of PPAR-RXR heterodimer by synaptamide and retinoic acid enhance adult hippocampal neurogenesis and regulate positive CNS remyelination. Allosteric modulation of GPR40 and GPR55 by endocannabinoids facilitate intracellular FABPs signaling. Endocannabinoids are intracellular N-acylethanolamines for treatment of brain hyperexcitability, PTSD, depression, metabolic disorders, epileptic seizures, Alzheimer disease (AD), Multiple sclerosis (MS), neuroinflammation, autism, Parkinson disease (PD), and migraines.

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, ADK, adenosine kinase, acetylcholine, synaptic plasticity, heterosynaptic metaplasticity, astrocytes, cytokines, neuroinflammation, Alzheimer, epilepsy, endothelium, microglial activation, mitochondrial phospholipids, cardioprotection, synaptamide, ethanolamide, FABP7, PPAR, GPCR, receptor heteromerization, CREB, GPR40, GPR55, arachidonic acid, neural stem/progenitor cells, retinoids, protease, thrombin, excitotoxicity, glutamate, neuroprotection, neurotoxicant, TrkB, remyelination, tryptophan

References

1. 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

2. http://jur.byu.edu/?p=18609

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. Tan NS, Shaw NS, Vinckenbosch N, Liu P, Yasmin R, Desvergne B, Wahli W, and Noy N. Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription. Mol Cell Biol. 2002 Jul;22(14):5114-27. DOI:10.1128/MCB.22.14.5114-5127.2002 |

   Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.

5. http://www.pnas.org/content/107/27/12317.short

6. Wang HM, Zhao YX, Zhang S, Liu GD, Kang WY, Tang HD, Ding JQ, and Chen SD. PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes. J Alzheimers Dis. 2010;20(4):1189-99. DOI:10.3233/JAD-2010-091336 |

   PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

7. Arévalo-Martín A, García-Ovejero D, Gómez O, Rubio-Araiz A, Navarro-Galve B, Guaza C, Molina-Holgado E, and Molina-Holgado F. CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies. Br J Pharmacol. 2008 Jan;153(2):216-25. DOI:10.1038/sj.bjp.0707466 |

   CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies.

8. Compagnucci C, Di Siena S, Bustamante MB, Di Giacomo D, Di Tommaso M, Maccarrone M, Grimaldi P, and Sette C. Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One. 2013;8(1):e54271. DOI:10.1371/journal.pone.0054271 |

   Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells.

9. Chen C. Homeostatic regulation of brain functions by endocannabinoid signaling. Neural Regen Res. 2015 May;10(5):691-2. DOI:10.4103/1673-5374.156947 |

   Homeostatic regulation of brain functions by endocannabinoid signaling

10. Tanveer R, Gowran A, Noonan J, Keating SE, Bowie AG, and Campbell VA. The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats. J Biol Chem. 2012 Oct 5;287(41):34709-21. DOI:10.1074/jbc.M112.350678 |

    The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats.

11. Lazenka MF, David BG, Lichtman AH, Nestler EJ, Selley DE, and Sim-Selley LJ. Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions. Biochem Pharmacol. 2014 Oct 1;91(3):380-9. DOI:10.1016/j.bcp.2014.07.024 |

    Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.

12. Gavala ML, Hill LM, Lenertz LY, Karta MR, and Bertics PJ. Activation of the transcription factor FosB/activating protein-1 (AP-1) is a prominent downstream signal of the extracellular nucleotide receptor P2RX7 in monocytic and osteoblastic cells. J Biol Chem. 2010 Oct 29;285(44):34288-98. DOI:10.1074/jbc.M110.142091 |

    Activation of the transcription factor FosB/activating protein-1 (AP-1) is a prominent downstream signal of the extracellular nucleotide receptor P2RX7 in monocytic and osteoblastic cells.

13. McLaughlin RJ, Hill MN, Bambico FR, Stuhr KL, Gobbi G, Hillard CJ, and Gorzalka BB. Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway. Eur Neuropsychopharmacol. 2012 Sep;22(9):664-71. DOI:10.1016/j.euroneuro.2012.01.004 |

    Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway.

14. 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.

15. 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.

16. 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.

17. 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.

18. Ma L, Jia J, Niu W, Jiang T, Zhai Q, Yang L, Bai F, Wang Q, and Xiong L. Mitochondrial CB1 receptor is involved in ACEA-induced protective effects on neurons and mitochondrial functions. Sci Rep. 2015 Jul 28;5:12440. DOI:10.1038/srep12440 |

    Mitochondrial CB1 receptor is involved in ACEA-induced protective effects on neurons and mitochondrial functions.

19. Kellert BA, Nguyen MC, Nguyen C, Nguyen QH, and Wagner EJ. Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis. Eur J Pharmacol. 2009 Nov 10;622(1-3):15-24. DOI:10.1016/j.ejphar.2009.09.001 |

    Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis.

20. Farhang B, Diaz S, Tang SL, and Wagner EJ. Sex differences in the cannabinoid regulation of energy homeostasis. Psychoneuroendocrinology. 2009 Dec;34 Suppl 1(0 1):S237-46. DOI:10.1016/j.psyneuen.2009.04.007 |

    Sex differences in the cannabinoid regulation of energy homeostasis.

21. Washburn N, Borgquist A, Wang K, Jeffery GS, Kelly MJ, and Wagner EJ. Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. Neuroendocrinology. 2013;97(2):160-75. DOI:10.1159/000338669 |

    Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.

22. Zoppi S, Pérez Nievas BG, Madrigal JL, Manzanares J, Leza JC, and García-Bueno B. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology. 2011 Mar;36(4):805-18. DOI:10.1038/npp.2010.214 |

    Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation.

23. 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.

24. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, and Lutz B. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003 Oct 3;302(5642):84-8. DOI:10.1126/science.1088208 |

    CB1 cannabinoid receptors and on-demand defense against excitotoxicity.

25. Gandelman M, Peluffo H, Beckman JS, Cassina P, and Barbeito L. Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis. J Neuroinflammation. 2010 Jun 9;7:33. DOI:10.1186/1742-2094-7-33 |

    Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis.

26. 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).

27. Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Baron-Van Evercooren A, Chambon P, Ffrench-Constant C, and Franklin RJM. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011 Jan;14(1):45-53. DOI:10.1038/nn.2702 |

    Retinoid X receptor gamma signaling accelerates CNS remyelination.

28. Mukhopadhyay B, Liu J, Osei-Hyiaman D, Godlewski G, Mukhopadhyay P, Wang L, Jeong WI, Gao B, Duester G, Mackie K, Kojima S, and Kunos G. Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma. J Biol Chem. 2010 Jun 18;285(25):19002-11. DOI:10.1074/jbc.M109.068460 |

    Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma.

29. Hashimotodani Y, Ohno-Shosaku T, Yamazaki M, Sakimura K, and Kano M. Neuronal protease-activated receptor 1 drives synaptic retrograde signaling mediated by the endocannabinoid 2-arachidonoylglycerol. J Neurosci. 2011 Feb 23;31(8):3104-9. DOI:10.1523/JNEUROSCI.6000-10.2011 |

    Neuronal protease-activated receptor 1 drives synaptic retrograde signaling mediated by the endocannabinoid 2-arachidonoylglycerol.

30. Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, and Shytle RD. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation. 2005 Dec 12;2:29. DOI:10.1186/1742-2094-2-29 |

    Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation.

31. Assaife-Lopes N, Sousa VC, Pereira DB, Ribeiro JA, and Sebastião AM. Regulation of TrkB receptor translocation to lipid rafts by adenosine A(2A) receptors and its functional implications for BDNF-induced regulation of synaptic plasticity. Purinergic Signal. 2014;10(2):251-67. DOI:10.1007/s11302-013-9383-2 |

    Regulation of TrkB receptor translocation to lipid rafts by adenosine A(2A) receptors and its functional implications for BDNF-induced regulation of synaptic plasticity.

32. Assaife-Lopes N, Sousa VC, Pereira DB, Ribeiro JA, Chao MV, and Sebastião AM. Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: implications for neuromodulation. J Neurosci. 2010 Jun 23;30(25):8468-80. DOI:10.1523/JNEUROSCI.5695-09.2010 |

    Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: implications for neuromodulation.

33. Sebastião AM and Ribeiro JA. Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection. Br J Pharmacol. 2009 Sep;158(1):15-22. DOI:10.1111/j.1476-5381.2009.00157.x |

    Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection.

34. http://www.thenakedscientists.com/forum/index.php?topic=66012.0

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. Nestler EJ. ∆FosB: a transcriptional regulator of stress and antidepressant responses. Eur J Pharmacol. 2015 Apr 15;753:66-72. DOI:10.1016/j.ejphar.2014.10.034 |

    ∆FosB: a transcriptional regulator of stress and antidepressant responses.

41. http://www.sciencedaily.com/releases/2014/05/140502132458.htm

42. http://ajplung.physiology.org/content/305/1/L64.short

See also

Cannabinoids:

• Cannabidiol Notebook
• Cannabidivarin Notebook
• THC Notebook

Docosanoids:

• Docosanoids Notebook

Endocannabinoids:

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