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The neuroprotective effects of the cannabis sativa plant are still poorly understood. The aim of this notebook is to design a method for intracellular delivery of N-docosahexaenoylethanolamide (DHEA) to (dopaminergic?) neurons using retrograde anandamide trafficking in order to protect microglial cells from drug-induced damage.

Neuropharmacology of synaptogenic endocannabinoids:

GPCR-dependent receptor heteromerization is a potential synaptogenic pathway with neuroprotective properties in the management of drug-induced neuronal damage through activation of dopamine transcription factors (Nurr1) and modulation of retrograde anandamide trafficking. (Reference needed)


Anandamide trafficking may exert neuroprotective effects on the microglia through selective binding of transcriptional dopamine receptors:

  1. FABP-PPAR allosteric communication with CB1 receptors enhance long-range synchronicity in the gamma range of dopamine neurotransmission.
  2. Synaptamide receptor heteromerization enhance biphasic endocannabinoid transport.
  3. Retrograde endocannabinoid signaling fine-tune neuronal phase coherence through intracellular CB1 activation.


On-demand neuroprotection of the microglia via endogenous retrograde signaling

Pharmacological activation of the endocannabinoid transport system

Identification of neuroprotective endocannabinoid transporters for management of drug-induced neuronal damage and dopamine hypersensitivity in the microglia:

  • Arachidonic acid (ARA)
  • Arachidonyl-2-chloroethylamide (ACEA)
  • Melatonin
  • Oxytocin
  • Synaptamide (DHA, DHEA)
  • Vitamin D

Intrinsic roles of microglial dopamine/anandamide cross-talk:

  • Enhanced microglial homeostasis and neuroprotection
  • Inhibition of drug-induced nitric oxide/glutamate production?
  • On-demand microglial neuroprotection through Nurr1 and Notch1 transcriptional regulation of dopamine synthesis?
    • Activation of CB1 receptor by anandamide may promote fatty acid homeostasis through PPAR-gamma and (Nurr1?) signaling. (Reference needed)
    • FABP5 and FABP7 expressions may selectively enhance PPAR-gamma regulation of (dopamine?) transcription factors (Notch1, Nurr1). [1]

Phosphorylation-induced activation of phospholipase C promote adult hippocampal neurogenesis

CB1-mediated receptor heteromerization may modulates hippocampal neurogenesis through phosphorylation of PLC and activation of Wnt. (Reference needed)

CB1 receptor expression prevent drug-induced corticostriatal excitotoxicity and microglial activation

Reference needed


Endocannabinoid transport of eicosanoids

Intracellular delivery of DHA to dopaminergic neurons may enhance eicosanoids synthesis. [2]

Endocannabinoid-mediated regulation of homeostatic synaptic plasticity

Anandamide and DHA may exert a synergistic effect on lipid homeostasis, glutamatergic and monoaminergic transports, and synaptic plasticity through retrograde signaling. Thus the mobilization of N-acylethanolamines via FABPs transport may provide a persistent supply of arachidonic acid to neuronal stem cells and mature neurons. [3][4]

Is synaptogenesis evidence of homeostatic endocannabinoid transport?

Intracellular anandamide trafficking may enhance BDNF/AKT1/CB1 expression. [5]

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 retrograde signaling. (Reference needed)

In specific, mitochondrial neuroprotection is enhanced via ACEA-induced intracellular CB1 receptor activation. [6]

Role of estrogenic attenuation of CB1 mediated energy homeostasis

  • Females may have reduced endocannabinoid levels. (Reference needed)
  • Females may express higher sensitivity to THC? (Reference needed)
  • The estrogen receptor (ER) activation modulates cannabinoid-induced energy homeostasis. [7][8]
  • Estrogen signaling induces a rapid decrease of glutamatergic transmission at POMC synapses. [9]

Neuroprotective effects of endocannabinoids are mediated by presynaptic CB1 receptor activation and calcium channel inhibition

Retrograde endocannabinoid signaling may protect on-demand hippocampal neurons from neuroinflammation upon exposure to NMDA-induced excitotoxicity. (Reference needed)

Presynaptic CB1 receptor activation may yield activity-dependent neuroprotection against excitotoxic glutamate releases in the hippocampus. [10][11][12]


  • Extracellular ATP and heteromeric adenosine-CB1 interactions:
    • Inhibition of purinergic P2X7 receptor expression (by adenosine?) is neuroprotective in ALS model. [13]
    • Heteromeric adenosine-CB1 receptor activation inhibit on-demand extracellular ATP/glutamate releases. (Reference needed)
      • Transactivation of adenosine (A1) receptor is protecting neurons from NMDA-induced excitotoxicity. (Reference needed)
      • Adenosine-CB1 allosteric modulation may facilitate pharmacological inhibition of P2X7/ATP receptor. (Reference needed)

Retrograde signaling drives adult hippocampal neurogenesis

Synaptogenic endocannabinoids constitute a family of intercellular lipids with anti-inflammatory, anti-oxidative and neuroprotective bioactivity to inhibit microglial activation during stress-induced neuroinflammation of the hippocampus. (Reference needed)

Retinoids as regulators of neural differentiation

  • Directed differentiation of neural progenitor cells by retinoic acid (RA) is induced by PPARs transactivation. (Reference needed)
  • RA may enhance neuron-astrocyte signaling through activation of retinoid X receptor (RXR/PPAR) heterodimer.[14]
  • RA may promote endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [15]
  • Retinoic acid receptor (RAR) activation may induce transcriptional regulation of CB1 receptor expression by endocannabinoids. [16]
  • See also: Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells.

Peripheral 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. [17] [18]

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:
    • BDNF/TrkB signaling is dependent on adenosine kinase (ADK)phosphorylation. [19] [20]
    • The adenosine A2A receptor transactivation of BDNF/TrkB receptors may enhance ADK-mediated neuroprotection and cardioprotection. [21]
  • Wnt signaling?


  • Functional neurogenesis and synaptogenesis is facilitated by intracellular delivery of DHEA to dopaminergic neurons.
    • Synaptogenic endocannabinoids are a emerging class of DHA conjugates for synthesis and maintenance of neural stem cells (NSCs) in the hippocampus, striatum, and microglia.
    • The neuroprotective properties of synaptogenic endocannabinoids protect microglial neurons against drug-induced neuronal damage (excitotoxicity) and dopaminergic hypersensitivity.
  • Transactivation of PPAR-RXR heterodimer by DHEA enhance microglial neuroprotection.
    • Allosteric modulation of CB1 expression by synaptamide facilitate intracellular FABP-PPAR signaling and fatty acid homeostasis.


  • Cannabinoids (THC) transactivation of CB1 receptors may fine-tune(?) purinergic P2X7 neurotransmission. (Reference needed)
  • Adenosine antagonism (caffeine) may autoregulate dopamine-CB1 receptors affinity and density. (cross-talk)? [22]
  • Endocannabinoid signaling may autoregulate dopamine/melatonin synthesis in vivo.
  • Chronic THC exposure may downregulate endocannabinoid signaling. (Reference needed)


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, ethanolamide, FABP7, PPAR, GPCR, receptor heteromerization, CREB, GPR40, GPR55, arachidonic acid, neural stem/progenitor cells, retinoids, thrombin, excitotoxicity, glutamate, neuroprotection, neurotoxicant, TrkB, remyelination, tryptophan, microtubules, striatum, retrograde signaling, homeostasis, dopamine, glycine, cAMP, calmodulin, receptor trafficking, tubulin, PLC, Wnt, oxytocin, melatonin, eicosanoids


  1. https://www.ncbi.nlm.nih.gov/pubmed/12077340 [Tan-2002]
    Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.
  2. https://www.ncbi.nlm.nih.gov/pubmed/26109933 [Chen-2015]
    Homeostatic regulation of brain functions by endocannabinoid signaling.
  3. https://www.ncbi.nlm.nih.gov/pubmed/23570577 [Rashid-2013]
    N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation.
  4. https://www.ncbi.nlm.nih.gov/pubmed/9231736 [Hansen-1997]
    Characterization of glutamate-induced formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons.
  5. https://www.ncbi.nlm.nih.gov/pubmed/18620024 [Wu-2008]
    Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition.
  6. https://www.ncbi.nlm.nih.gov/pubmed/26215450 [Ma-2015]
    Mitochondrial CB1 receptor is involved in ACEA-induced protective effects on neurons and mitochondrial functions.
  7. https://www.ncbi.nlm.nih.gov/pubmed/19758570 [Kellert-2009]
    Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis.
  8. https://www.ncbi.nlm.nih.gov/pubmed/19427130 [Farhang-2009]
    Sex differences in the cannabinoid regulation of energy homeostasis.
  9. https://www.ncbi.nlm.nih.gov/pubmed/22538462 [Washburn-2013]
    Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.
  10. https://www.ncbi.nlm.nih.gov/pubmed/21150911 [Zoppi-2011]
    Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation.
  11. https://www.ncbi.nlm.nih.gov/pubmed/23296873 [Zogopoulos-2013]
    The neuroprotective role of endocannabinoids against chemical-induced injury and other adverse effects.
  12. https://www.ncbi.nlm.nih.gov/pubmed/14526074 [Marsicano-2003]
    CB1 cannabinoid receptors and on-demand defense against excitotoxicity.
  13. https://www.ncbi.nlm.nih.gov/pubmed/20534165 [Gandelman-2010]
    Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis.
  14. https://www.ncbi.nlm.nih.gov/pubmed/23105114 [Yu-2012]
    Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ).
  15. https://www.ncbi.nlm.nih.gov/pubmed/21131950 [Huang-2011]
    Retinoid X receptor gamma signaling accelerates CNS remyelination.
  16. https://www.ncbi.nlm.nih.gov/pubmed/20410309 [Mukhopadhyay-2010]
    Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma.
  17. https://www.ncbi.nlm.nih.gov/pubmed/21414931 [Hashimotodani-2011]
    Neuronal protease-activated receptor 1 drives synaptic retrograde signaling mediated by the endocannabinoid 2-arachidonoylglycerol.
  18. https://www.ncbi.nlm.nih.gov/pubmed/16343349 [Ehrhart-2005]
    Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation.
  19. https://www.ncbi.nlm.nih.gov/pubmed/24271058 [Assaife-2014]
    Regulation of TrkB receptor translocation to lipid rafts by adenosine A(2A) receptors and its functional implications for BDNF-induced regulation of synaptic plasticity.
  20. https://www.ncbi.nlm.nih.gov/pubmed/20573894 [Assaife-2010]
    Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: implications for neuromodulation.
  21. https://www.ncbi.nlm.nih.gov/pubmed/19508402 [Sebastiao-2009]
    Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection.
  22. http://onlinelibrary.wiley.com/doi/10.1111/joim.12737/abstract [Cornelis-2018]
    Metabolomic response to coffee consumption: application to a three-stage clinical trial.
  23. https://www.ncbi.nlm.nih.gov/pubmed/19682204 [ref1]
    Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.
  24. https://www.ncbi.nlm.nih.gov/pubmed/15363397 [Chevaleyre-2004]
    Endocannabinoid-mediated metaplasticity in the hippocampus.
  25. https://www.ncbi.nlm.nih.gov/pubmed/21810478 [Kim-2011]
    A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.
  26. https://www.ncbi.nlm.nih.gov/pubmed/24533014 [Duster-2014]
    Purinergic signaling and hippocampal long-term potentiation.
  27. https://www.ncbi.nlm.nih.gov/pubmed/22959887 [Kim-2013]
    Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function.
  28. https://www.ncbi.nlm.nih.gov/pubmed/16908411 [Monory-2006]
    The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus.
  29. https://www.ncbi.nlm.nih.gov/pubmed/21079038 [Pertwee-2010]
    International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2.
  30. https://www.ncbi.nlm.nih.gov/pubmed/23088259 [Meijerink-2013]
    N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads.
  31. https://www.ncbi.nlm.nih.gov/pubmed/24644281 [Yu-2014]
    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.
  32. https://www.ncbi.nlm.nih.gov/pubmed/20413894 [Wang-2010]
    PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.
  33. https://www.ncbi.nlm.nih.gov/pubmed/17891163 [Arevalo-Martin-2008]
    CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies.
  34. https://www.ncbi.nlm.nih.gov/pubmed/23372698 [Compagnucci-2013]
    Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells.
  35. https://www.ncbi.nlm.nih.gov/pubmed/22891244 [Tanveer-2012]
    The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats.
  36. https://www.ncbi.nlm.nih.gov/pubmed/25093286 [Lazenka-2014]
    Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.
  37. https://www.ncbi.nlm.nih.gov/pubmed/20813842 [Gavala-2010]
    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.
  38. https://www.ncbi.nlm.nih.gov/pubmed/22325231 [McLaughlin-2012]
    Prefrontal cortical anandamide signaling coordinates coping responses to stress through a serotonergic pathway.
  39. https://www.ncbi.nlm.nih.gov/pubmed/25446562 [Nestler-2015]
    ∆FosB: a transcriptional regulator of stress and antidepressant responses.
  40. https://www.ncbi.nlm.nih.gov/pubmed/17506860 [Volpicelli-2007]
    Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.
  41. https://www.ncbi.nlm.nih.gov/pubmed/17704824 [Sullivan-2007]
    Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors.
  42. https://www.ncbi.nlm.nih.gov/pubmed/25698444 [Blazquez-2015]
    The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.
  43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060591/ [Debanne-2011]
    Presynaptic action potential waveform determines cortical synaptic latency.
  44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776936/ [Akirav-2013]
    Targeting the endocannabinoid system to treat haunting traumatic memories
  45. https://www.ncbi.nlm.nih.gov/pubmed/22532560 [Moreno-2012]
    Cannabinoid receptors CB1 and CB2 form functional heteromers in brain.
  46. https://www.ncbi.nlm.nih.gov/pubmed/16033894 [Bodor-2005]
    Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types.
  47. https://www.ncbi.nlm.nih.gov/pubmed/24899717 [Hajos-2014]
    Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release.
  48. https://www.ncbi.nlm.nih.gov/pubmed/28446875 [Ratano-2017]
    Cannabinoid Modulation of Memory Consolidation in Rats: Beyond the Role of Cannabinoid Receptor Subtype 1.
  49. https://www.ncbi.nlm.nih.gov/pubmed/28355238 [Page-2017]
    Terpene synthases from Cannabis sativa
  50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839320/ [Conde-2017]
    Testosterone Rapidly Augments Retrograde Endocannabinoid Signaling in Proopiomelanocortin Neurons to Suppress Glutamatergic Input from Steroidogenic Factor 1 Neurons via Upregulation of Diacylglycerol Lipase-α

See also