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=== Retinoids as regulators of neural differentiation === | === 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. | 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.<cite>Yu-2012</cite> | ||
Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [https://www.ncbi.nlm.nih.gov/pubmed/21131950 PMID] | Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. [https://www.ncbi.nlm.nih.gov/pubmed/21131950 PMID] | ||
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#Gandelman-2010 pmid=20534165 | #Gandelman-2010 pmid=20534165 | ||
//Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis. | //Extracellular ATP and the P2X7 receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis. | ||
#Huang-2011 pmid=21131950 | |||
//Retinoid X receptor gamma signaling accelerates CNS remyelination. | |||
#Website1 http://www.sciencedaily.com/releases/2014/05/140502132458.htm | #Website1 http://www.sciencedaily.com/releases/2014/05/140502132458.htm | ||
#Website2 http://jur.byu.edu/?p=18609 | #Website2 http://jur.byu.edu/?p=18609 | ||
Revision as of 08:23, 15 November 2015
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 atypical 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-mobilized proneurogenic 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 and brain neuroprotection via endocannabinoid stimulation of endogenous BDNF in the hippocampus using synaptamide as the proneurogenic promoter of synaptic function.
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 (DHEA) receptor heteromerization enhance endocannabinoid transport, degradation of anandamide to arachidonic acid, and may regulate neuronal differentiation and proliferation of neural stem cells through neuron-astrocytes and 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.
Results
DHA stimulation of PPAR-RXR heterodimer decreases brain arachidonic acid levels and improves neural differentiation through FABP5 expression
- Identification of DHA as a proneurogenic 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]
- 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]
- FABP5 deficiency increase sensitivity to H1N1 infection.
Modulation of BDNF/CREB by DHA promote neural proliferation of hippocampal progenitor cells via PPARγ 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
- Effects of PPAR-RXR transactivation on maintenance of neural stem/progenitor cells (NSPCs):
- 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 synaptogenesis promoter that mediate synaptic retrograde signaling in the hippocampus.
- Anandamide enhance Notch-1 signaling over APP. [10]
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. [11] [12]
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. [13]
Is neurogenesis an evidence of homeostatic endocannabinoid transport ?
Homeostatic metaplasticity is perhaps a biological activity relevant to hippocampal plasticity and may facilitate heterosynaptic LTP and neurogenesis through retrograde endocannabinoid signaling and diffusion in the hippocampus. [3]
The evidences of GPR40-GPR55 expression in the hippocampus 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.
Mitochondrial function
DHA supplementation may increase mitochondrial function and enhance CB1/CB2 dependent neuroprotection through endocannabinoids mobilization. Thus, mitochondrial respiration is increased by DHA.
Neuroprotective effects of endocannabinoids are mediated by CB1 receptor activation
Endocannabinoids may protect on-demand neurons from excitotoxicity and neuroinflammation upon exposure to NMDA-induced excitotoxicity. Hence, CB1 receptor activation yields activity-dependent neuroprotection against excitotoxic glutamate releases in the hippocampus. [14][15]
Notes:
- Extracellular ATP and CB1 interactions: inhibition of P2X7 receptor is neuroprotective in ALS model. [16]
- Hypothesis: mitochondrial CB1 receptor expression inhibit on-demand extracellular ATP releases by activation of adenosine (A1) receptor, thus protecting neurons from NMDA-induced excitotoxicity.
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 neuroinflammation of the hippocampus.
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 heteromization in synaptic plasticity?
Identification of GPR40-GPR55 receptor heteromer:
- Is retinoic acid (RA)-induced synaptamide a proneurogenic promoter of synaptic function?
- Receptor heteromization 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.
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.[17]
Retinoic acid promotes endogenous CNS remyelination, axonal regeneration, and neuritogenesis. PMID
Retinoic acid receptor (RAR) activation induces transcriptional regulation of CB1 receptor expression by endocannabinoids. PMID
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 microglial activation by 2-AG contributes to thrombin/PAR1 inhibition.
PAR1 inhibitors are a novel therapeutic/antiplatelet platform which inhibits thrombin induced dysfunctions. CB2 receptor inactivation of thrombin/PAR1 induce homeostatic plasticity in the hippocampus via retrograde signaling.
Conclusion
Synaptamide regulates neural differentiation and proliferation in the hippocampus through endocannabinoid-mediated retrograde signaling. 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 excitotoxicity and lipid peroxidation.
Activation of PPAR-RXR heterodimer by synaptamide and retinoic acid enhance adult hippocampal neurogenesis. Allosteric modulation of GPR40 and GPR55 facilitate intracellular FABPs signaling.
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, adenosine, acetylcholine, synaptic plasticity, heterosynaptic metaplasticity, astrocytes, cytokines, neuroinflammation, Alzheimer, 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
References
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See also
Cannabinoids:
Docosanoids:
Endocannabinoids:
