User:Tkadm30/Notebook/Endocannabinoids

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Introduction

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 and modulation of retrograde anandamide trafficking. (Reference needed)

Hypothesis

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

1. FABPs allosteric communication with dopamine neurotransmitters modulate synaptic plasticity and BDNF-mediated synaptogenesis.
2. Synaptamide receptor heteromerization enhance homeostatic endocannabinoid transport.
3. Retrograde endocannabinoid signaling fine-tune neuronal phase coherence through intracellular CB1 activation.

Experimental Method

• Data mining of open access papers.

Results

Neuroprotection of the microglia via endogenous retrograde signaling

• Arachidonic acid (ARA) may selectively enhance presynaptic CB1 receptor availability in the microglia? (Reference needed)
• Anandamide trafficking via THC-mediated activation of glutamatergic CB1 receptors may enhance NMDA neuroprotection: (Reference needed)
  • On-demand hippocampal/NMDA neuroprotection?
  • Astrocytes-mediated dopaminergic neuroprotection?
    • Review: Endocannabinoids Mediate Neuron-Astrocyte Communication
    • Review: Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas.
• See also: https://www.ncbi.nlm.nih.gov/pubmed/23531681

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 (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
• 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.

• Review: Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

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

• Anti-inflammatory effect of anandamide signaling on prefrontal cortex neurons. [2]
• Anandamide/CB1 signaling may increase monoaminergic activity in the prefrontal cortex. [2]

Discussion

Endocannabinoid transport of eicosanoids

Intracellular delivery of DHA to dopaminergic neurons may enhance eicosanoids synthesis. [3]

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. [4][5]

Is synaptogenesis evidence of homeostatic endocannabinoid transport?

Intracellular anandamide trafficking may enhance BDNF/AKT1/CB1 expression. [6]

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. [7]

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. [8][9]
• Estrogen signaling induces a rapid decrease of glutamatergic transmission at POMC synapses. [10]

Neuroprotective effects of endocannabinoids are mediated by presynaptic CB1 receptor activation

Endocannabinoid signaling may protect on-demand hippocampal neurons from neuroinflammation upon exposure to NMDA-induced excitotoxicity and neuronal damage. Hence, presynaptic CB1 receptor activation may yields activity-dependent neuroprotection against excitotoxic glutamate releases in the hippocampus. [11][12][13]

Notes:

• Extracellular ATP and heteromeric adenosine-CB1 interactions:
  • Inhibition of purinergic P2X7 receptor is neuroprotective in ALS model. [14]
  • 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.[15]
• RA may promote endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [16]
• Retinoic acid receptor (RAR) activation may induce transcriptional regulation of CB1 receptor expression by endocannabinoids. [17]
• 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. [18] [19]

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. [20] [21]
  • The adenosine A2A receptor transactivation of BDNF/TrkB receptors may enhance ADK-mediated neuroprotection and cardioprotection. [22]
• Wnt signaling?

Conclusion

• Functional neurogenesis and synaptogenesis is facilitated by intracellular delivery of DHEA to dopaminergic neurons.
  • Synaptogenic endocannabinoids are a emerging class of functionalized neurotransmitters for synthesis 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 adult hippocampal neurogenesis.
  • Allosteric modulation of CB1 expression by synaptamide facilitate intracellular FABPs signaling and fatty acid homeostasis.

Notes

• Cannabinoids (THC) transactivation of CB1 receptors and PPARs may fine-tune purinergic P2X7 neurotransmission.
• Adenosine antagonism may potentiate dopamine-CB1 receptors affinity (cross-talk). [23]
• Endocannabinoid signaling may fine-tune (enhance) dopamine/melatonin synthesis in vivo.

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, 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

References

1. https://www.ncbi.nlm.nih.gov/pubmed/12077340

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

2. https://www.ncbi.nlm.nih.gov/pubmed/22325231

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

3. https://www.ncbi.nlm.nih.gov/pubmed/26109933

   Homeostatic regulation of brain functions by endocannabinoid signaling.

4. https://www.ncbi.nlm.nih.gov/pubmed/23570577

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

5. https://www.ncbi.nlm.nih.gov/pubmed/9231736

   Characterization of glutamate-induced formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons.

6. https://www.ncbi.nlm.nih.gov/pubmed/18620024

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

7. https://www.ncbi.nlm.nih.gov/pubmed/26215450

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

8. https://www.ncbi.nlm.nih.gov/pubmed/19758570

   Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis.

9. https://www.ncbi.nlm.nih.gov/pubmed/19427130

   Sex differences in the cannabinoid regulation of energy homeostasis.

10. https://www.ncbi.nlm.nih.gov/pubmed/22538462

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

11. https://www.ncbi.nlm.nih.gov/pubmed/21150911

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

12. https://www.ncbi.nlm.nih.gov/pubmed/23296873

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

13. https://www.ncbi.nlm.nih.gov/pubmed/14526074

    CB1 cannabinoid receptors and on-demand defense against excitotoxicity.

14. https://www.ncbi.nlm.nih.gov/pubmed/20534165

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

15. https://www.ncbi.nlm.nih.gov/pubmed/23105114

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

16. https://www.ncbi.nlm.nih.gov/pubmed/21131950

    Retinoid X receptor gamma signaling accelerates CNS remyelination.

17. https://www.ncbi.nlm.nih.gov/pubmed/20410309

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

18. https://www.ncbi.nlm.nih.gov/pubmed/21414931

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

19. https://www.ncbi.nlm.nih.gov/pubmed/16343349

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

20. https://www.ncbi.nlm.nih.gov/pubmed/24271058

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

21. https://www.ncbi.nlm.nih.gov/pubmed/20573894

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

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

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    Adenosine–cannabinoid receptor interactions. Implications for striatal function.

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    A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.

27. https://www.ncbi.nlm.nih.gov/pubmed/24533014

    Purinergic signaling and hippocampal long-term potentiation.

28. https://www.ncbi.nlm.nih.gov/pubmed/22959887

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

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    The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus.

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

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    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.

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

36. https://www.ncbi.nlm.nih.gov/pubmed/22891244

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

37. https://www.ncbi.nlm.nih.gov/pubmed/25093286

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

38. https://www.ncbi.nlm.nih.gov/pubmed/20813842

    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.

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See also

Cannabinoids:

• Cannabidiol Notebook
• Cannabidivarin Notebook
• THC Notebook
• THCV Notebook

Docosanoids:

• Docosanoids Notebook

Endocannabinoids:

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