User:Tkadm30/Notebook/Endocannabinoids: Difference between revisions
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Notes: | Notes: | ||
Novel | Novel synaptogenic endocannabinoids as selective PPAR-RXR agonist: | ||
* Role of GPCR heteromerization in synaptic plasticity? | * Role of GPCR heteromerization in synaptic plasticity? | ||
* Arachidonic acid metabolites are PPAR ligands and selectively activate FABPs. (Reference needed) | * Arachidonic acid metabolites are PPAR ligands and selectively activate FABPs. (Reference needed) | ||
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** DHA may reduce microglial activation and neuroinflammation of the hippocampus. | ** DHA may reduce microglial activation and neuroinflammation of the hippocampus. | ||
** Tonic endocannabinoid signaling? | ** Tonic endocannabinoid signaling? | ||
** Dopamine/melatonin interactions | |||
=== Retinoids as regulators of neural differentiation === | === Retinoids as regulators of neural differentiation === | ||
Revision as of 02:19, 23 June 2017
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 glutaminergic neurons using retrograde anandamide trafficking in order to protect microglial cells from drug-induced damage.
Neuroendopsychology 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 PPAR-gamma transcription factors and modulation of retrograde anandamide trafficking.
In particular, the allosteric modulation of GPR40-GPR55 heteromeric receptor may cooperatively regulate neuronal communication via GPCR receptor heteromerization.
Development of endocannabinoid-dependent neuroprotective heteromers:
Objective: Enhance/fine-tune neuronal phase coherence via retrograde anandamide trafficking and PPAR activation.
Hypothesis
Anandamide-mediated endogenous stimulation of GPR40 and GPR55 may exert neuroprotective effects on the microglia through selective binding of PPARs receptors:
- FABPs allosteric communication with PPARs modulate synaptic plasticity and BDNF-mediated synaptogenesis.
- Synaptamide receptor heteromerization enhance homeostatic endocannabinoid transport and mobilization of anandamide to glutaminergic neurons.
- Retrograde endocannabinoid trafficking fine-tune neuronal phase coherence through intracellular CB1 activation and PPARs cross-talk.
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 synthesis and trafficking via THC-mediated pharmacological activation of glutamatergic CB1 receptors
- On-demand hippocampal neuroprotection?
- Astrocytes-mediated dopaminergic neuroprotection?
- 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:
- Anandamide
- Melatonin
- Oxytocin
- Synaptamide (DHA)
- Vitamin D
Intrinsic roles of microglial PPAR transport in anandamide trafficking:
- Enhanced microglial homeostasis and neuroprotection
- Inhibition of nitric oxide?
- On-demand microglial neuroprotection
Allosteric modulation of GPR40-GPR55 receptor heteromer by anandamide may promote fatty acid homeostasis through PPAR-gamma activation:
- FABP5 and FABP7 expressions may selectively enhance PPAR-gamma regulation of transcription. [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.
Homeostatic regulation of hippocampal metaplasticity by dual PPAR-γ agonists
- Anandamide trafficking enhance Notch-1 signaling over APP. [2]
- Review: Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission.
CB1 receptor expression prevent drug-induced excitotoxicity and neuroinflammation
- Anti-inflammatory effect of anandamide signaling on prefrontal cortex neurons. [3]
- Anandamide/CB1 signaling may increase monoaminergic activity in the prefrontal cortex. [3]
Discussion
Endocannabinoid transport of proneurogenic compounds
Recent evidences suggest FABP5 activity decrease anandamide levels and improve cognitive functions. [4]
Endocannabinoid stimulation of FABPs synthesis: intracellular delivery of DHA to neurons may enhance neurogenesis and maintain brain homeostasis. [5]
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. [6][7]
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. [8]
Intracellular anandamide trafficking by GPR40 and GPR55 enhance BDNF/AKT1 expression and promote synaptic plasticity through endocannabinoid-mediated mobilization. [9]
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. [10]
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. [11][12]
- Estrogen signaling induces a rapid decrease of glutamatergic transmission at POMC synapses. [13]
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. [14][15][16]
Notes:
- Extracellular ATP and heteromeric adenosine-CB1 interactions:
- Inhibition of purinergic P2X7 receptor is neuroprotective in ALS model. [17]
- 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)
- Presynaptic action potential waveform is evidence of synaptic latency at cortical synapses. [18]
- Synaptic latency is determined by neural phase coherence at presynaptic CB1 receptors. (Reference needed)
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 microglial neuroprotection through FABPs synthesis and PPAR-gamma activation:
- PPAR-gamma activation may increase retrograde signaling through allosteric modulation of GPR40 and GPR55.
- Cross-talk of GPR40-GPR55 heteromer may potentiate intracellular CB1 receptor affinity?
Notes:
Novel synaptogenic endocannabinoids as selective PPAR-RXR agonist:
- Role of GPCR heteromerization in synaptic plasticity?
- Arachidonic acid metabolites are PPAR ligands and selectively activate FABPs. (Reference needed)
Identification of GPR40-GPR55 receptor heteromer:
- Anandamide as promoter of BDNF-mediated neurogenesis?
- Receptor heteromerization of GPR40-GPR55 by anandamide selectively enhance neurotrophic BDNF, CREB, and dopamine expression.
Effects of presynaptic GPR40-GPR55 receptor heteromerization on fatty acid homeostasis and synaptic plasticity:
- Intracellular FABPs signaling through PPAR transactivation may enhance corticostriatal synaptic plasticity. (Reference needed)
- DHA promotes membrane homeostasis and regulates LTP via PPAR-gamma activation.
- DHA may reduce microglial activation and neuroinflammation of the hippocampus.
- Tonic endocannabinoid signaling?
- Dopamine/melatonin interactions
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.[19]
Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [20]
Retinoic acid receptor (RAR) activation induces transcriptional regulation of CB1 receptor expression by endocannabinoids. [21]
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. [22] [23]
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:
- Wnt signaling?
Conclusion
- Synaptamide regulates neural differentiation and proliferation in the hippocampus through endocannabinoid-mediated retrograde signaling.
- Functional neurogenesis and synaptogenesis can be facilitated by intracellular delivery of DHA/DHEA to glutamatergic neurons.
- Synaptogenic endocannabinoids are a emerging class of functionalized fatty acids for programming of neural stem/progenitor cells (NSPCs) in the hippocampus and CNS.
- The neuroprotective properties of endocannabinoids protects neurons against drug-induced neuronal damage (excitotoxicity) and dopaminergic hypersensitivity.
- Transactivation of PPAR-RXR heterodimer by anandamide trafficking may enhance adult hippocampal neurogenesis and regulate positive CNS remyelination.
- Allosteric modulation of GPR40 and GPR55 by retrograde endocannabinoid signaling 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). [27]
- Glutamatergic CB1-induced corticostriatal activity may fine-tune aripiprazole selective binding to dopamine D2 receptors.
- 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
References
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Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.
-
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.
-
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.
-
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.
-
Presynaptic action potential waveform determines cortical synaptic latency.
-
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.
-
Adenosine–cannabinoid receptor interactions. Implications for striatal function.
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Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.
-
A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.
-
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.
-
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.
-
Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.
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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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∆FosB: a transcriptional regulator of stress and antidepressant responses.
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Bdnf gene is a downstream target of Nurr1 transcription factor in rat midbrain neurons in vitro.
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Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors.
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The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.
See also
Cannabinoids:
Docosanoids:
Endocannabinoids:
