User:Etienne Robillard/Notebook/Endocannabinoids

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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 dopaminergic neurons using retrograde endocannabinoid-like mobilization of fatty acid-binding proteins (FABPs) transport.

Neuroendopsychology of novel endocannabinoids:

Endocannabinoid-dependent receptor heteromerization may be a promising pharmacological objective with neuroprotective properties in the treatment of drug-induced neuronal damage through activation of PPARs and modulation of endocannabinoid (anandamide) transport. In particular, allosteric modulation of GPR40 and GPR55 (anandamide signaling?) may cooperatively regulate neuronal differentiation and proliferation via receptor heteromerization of synaptamide and glycinergic FABPs transport.

Development of endocannabinoid-dependent neuroprotective heteromers:

The suppression of microglial activation by retrograde endocannabinoid-like (N-acylethanolamides) molecules may increase synaptic plasticity and promote mature BDNF (mBDNF) expression. Thus the objective of the GPR40-GPR55 heteromer is to enhance brain metaplasticity and dopamine D2 receptors connectivity via retrograde anandamide trafficking.


FABPs endogenous stimulation of GPR40 and GPR55 may exert neuroprotective effects on the hippocampus through selective binding of PPARs receptors:

  1. FABP5/7 allosteric communication with PPARs receptors modulate synaptic homeostasis and synaptogenesis.
  2. Synaptamide receptor heteromerization enhance homeostatic endocannabinoid transport and mobilization of anandamide to dopaminergic neurons.
  3. 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.


Neuroprotection of the microglia via endogenous retrograde signaling

  • Arachidonic acid (AA) may selectively enhance CB1 receptor availability in the microglia.
    • Glycinergic-induced neuroprotection?
  • Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas.
  • Identification of synaptamide as a neuroprotective endocannabinoid for treatment of drug-induced neuronal damage and dopamine hypersensitivity:
  • Intrinsic role of PPAR-FABPs transport in anandamide trafficking ?
  • Does PPARs expression induce long-term potentiation (LTP) in the hippocampus ?

Allosteric modulation of GPR40-GPR55 receptor heteromer by synaptamide may promotes fatty acid homeostasis through PPAR-gamma activation:

Phosphorylation of BDNF/CREB by intracellular DHA delivery promote adult hippocampal neurogenesis via PPAR-gamma 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 (NSCs):

  • BDNF/CREB-dependent neuroprotection (see Nurr1) [2][3]
  • Neuron-astrocyte cell migration and differentiation
    • Proliferation of NSCs in the hippocampus.
  • DHA transactivation of PPARs reduce amyloid-beta (Abeta) generation in astrocytes. (Alzheimer)[4]
  • Neuroimmune modulation (ie: endogenous remyelination) [5]
  • BDNF-induced synaptogenesis
  • Endocannabinoids upregulate activity-dependent hippocampal neurogenesis and neural progenitor (NP) cell proliferation through CB1 and CB2 activation. [6]

Homeostatic regulation of hippocampal metaplasticity by dual PPAR-γ agonists

  • Anandamide trafficking enhance Notch-1 signaling over APP. [7]

CB1 receptor expression prevent drug-induced excitotoxicity and neuroinflammation

  • Anti-inflammatory effect of anandamide signaling on prefrontal cortex neurons. [8]
  • Anandamide/CB1 signaling may increase monoaminergic activity in the prefrontal cortex. [8]


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. [9] [10]

Endocannabinoid stimulation of FABPs synthesis: intracellular delivery of DHA to neurons may enhance neurogenesis and maintain brain homeostasis. [11]

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/progenitor cells and mature neurons. [12][13]

Is synaptogenesis an evidence of homeostatic endocannabinoid transport ?

Homeostatic endocannabinoid transport is likely relevant to synaptogenesis and enhance heterosynaptic LTP and synaptic homeostasis through retrograde signaling in the hippocampus. [14]

Intracellular anandamide trafficking by GPR40 and GPR55 enhance BDNF expression and promote synaptic plasticity through endocannabinoid-mediated mobilization. [15]

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. Thus, mitochondrial respiration may increase by intracellular CB1 receptor activation. [16]

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. [17][18]
  • Estrogen signaling induces a rapid decrease of glutamatergic transmission at POMC synapses. [19]

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. [20][21][22]


  • Extracellular ATP and adenosine-CB1 interactions:
    • Inhibition of purinergic P2X7 receptor is neuroprotective in ALS model. [23]
    • Heteromeric adenosine-CB1 receptor activation inhibit on-demand extracellular ATP releases.
    • Transactivation of adenosine (A1) receptor is protecting neurons from NMDA-induced excitotoxicity.
    • May adenosine-CB1 allosteric modulation facilitate pharmacological transactivation of P2X7/ATP receptor ?

Retrograde GPR40-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 GPR40-GPR55 heteromers

Design of a novel pharmacological heteromer to induce on-demand neuroprotection through FABPs synthesis:

  • PPAR-gamma activation increase retrograde signaling through allosteric modulation of GPR40 and GPR55.
  • Synaptic activation of GPR40-GPR55 heteromer potentiate intracellular CB1 affinity?


Novel endocannabinoids (synaptamide) compounds as selective PPARs agonist:

  • Role of GPCR heteromerization in synaptic plasticity?
  • Arachidonic acid metabolites are PPAR ligands and selectively activate FABPs.

Identification of GPR40-GPR55 receptor heteromer:

  • Is retinoic acid (RA)-induced synaptamide a proneurogenic promoter of BDNF-mediated synaptic function?
  • Receptor heteromerization of GPR40-GPR55 selectively enhance neurotrophic 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 signaling.

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 activation of retinoid X receptor (RXR/PPAR) heterodimer.[24]

Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [25]

Retinoic acid receptor (RAR) activation induces transcriptional regulation of CB1 receptor expression by endocannabinoids. [26]

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. [27] [28]

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. [29] [30]
    • Adenosine A(2A) receptor transactivation of BDNF/TrkB receptors: Implications for neuroprotection by ADK. [31]


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 neurons against NMDA-induced excitotoxicity and dopamine hypersensitivity.

Activation of PPAR-RXR heterodimer by synaptamide, THC, and retinoic acid enhance adult hippocampal neurogenesis and regulate positive CNS remyelination. Allosteric modulation of GPR40 and GPR55 by endocannabinoids facilitate intracellular FABPs signaling and fatty acid homeostasis.

Synaptic endocannabinoids are intracellular N-acylethanolamines for treatment of:

  • Brain hyperexcitability
  • Neuronal injury
  • Post-traumatic stress disorder (PTSD)
  • Depression
  • Metabolic disorders (Diabetes)
  • Epilepsy
  • Alzheimer's disease (AD)
  • Multiple sclerosis (MS)
  • Neuroinflammation
  • Autism
  • Parkinson disease (PD)
  • Migraines
  • Glaucoma
  • Traumatic brain injury (TBI)
  • Crohn's disease
  • Amyotrophic lateral sclerosis (ALS)
  • Huntington's disease (HD)
  • Dopamine hypersensitivity
  • Hypertension


  • Cannabinoids (THC) transactivation of CB1 receptors may fine-tune P2X7 neurotransmission.
  • Adenosine-cannabinoid heteromers potentiate CB1 receptor affinity. [32]
  • CB1-induced corticostriatal activity fine-tune aripiprazole selective binding.


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, thrombin, excitotoxicity, glutamate, neuroprotection, neurotoxicant, TrkB, remyelination, tryptophan, microtubules, striatum, retrograde signaling, homeostasis, dopamine, glycine


  1. [Tan-2002]
    Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.





    Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.



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



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



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



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



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



    Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.



    A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.



    Homeostatic regulation of brain functions by endocannabinoid signaling.



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



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



    Endocannabinoid-mediated metaplasticity in the hippocampus.



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



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



    Estrogen rapidly attenuates cannabinoid-induced changes in energy homeostasis.



    Sex differences in the cannabinoid regulation of energy homeostasis.



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



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



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



    CB1 cannabinoid receptors and on-demand defense against excitotoxicity.



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



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



    Retinoid X receptor gamma signaling accelerates CNS remyelination.



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



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



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



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



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



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





    Purinergic signaling and hippocampal long-term potentiation.



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



    The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus.



    International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2.



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



    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.



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



    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.



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



    Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors.









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