User:Tkadm30/Notebook/Endocannabinoids

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:

Endocannabinoids 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, GPR40 and GPR55 may cooperatively regulate neuronal differentiation and proliferation via receptor heteromerization of synaptamide and astrocytes-expressed fatty acid-binding proteins (FABPs).

Development of endocannabinoid mobilized proneurogenic compounds:

In addition, the suppression of microglial activation by endocannabinoids may increase adult hippocampal neurogenesis and promote mBDNF expression. Thus the objective of the GPR40-GPR55 heteromer is to enhance hippocampal plasticity and neuroprotection via atypical endocannabinoid stimulation of endogenous BDNF in the hippocampus using DHA as the proneurogenic promoter to increase BDNF expression and inhibit microglial activation.

Synopsis

• Stimulation of endocannabinoid transport with polyunsaturated (22:6n-3) fatty acids (DHA, EPA) to target major depressive disorders (MDD) , epilepsy, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), posttraumatic stress disorder (PTSD), and Alzheimer's disease (AD).
• Distribution of endocannabinoid-dependent activity (LTP, synaptogenesis) in the hippocampus promoting brain-derived neurotrophic factor (BDNF) expression, a biological marker for learning-dependent synapse formation. PMID PMID
• Neuroprotective effects of the mitochondrial CB1 receptor on excitatory (glutamatergic) synapses and in particular astrocytes. PMID PMID
• Identification of a functional GPR40-GPR55 heteromer with potent anti-inflammatory, antiglutamatergic and neuroprotective properties.
  • Anti-proliferative effects of DHEA on prostate cancer cell lines. PMC
  • A synaptogenic endocannabinoid which promotes synaptogenesis. [1]
  • Antioxidant (cytoprotective) properties of GPR40-GPR55 heteromer.
• Effects of the endothelial CB2 receptor persistent activation on monocyte subpopulations/microglial activation PMID
  • Anti-inflammatory role of anandamide and 2-AG signaling in LPS-stimulated microglial activation of endogenous CB2 receptor. Link
  • Neuroprotection by inhibition of microglial activation. PMID PMID
  • CB2 stimulation is proneurogenic on adult hippocampal neurogenesis PMC

Results

DHA stimulation of PPARs decreases brain anandamide levels and improves synaptic function through FABP5 expression

• http://www.sciencedaily.com/releases/2014/05/140502132458.htm
• Identification of DHA as a proneurogenic PPAR agonist for treatment of neurological disorders.
• Intrinsic role of BDNF expression in (retrograde) anandamide signaling: PPARs expression induce long-term potentiation (LTP) in the hippocampus. PMID
• Evidences that DHEA is a synaptogenic endocannabinoid and potent activator of hippocampal LTP.
  • Stimulation of GPR40-GPR55 receptor heteromer by DHA promotes heterosynaptic LTP through peroxisome proliferator-activated receptors (PPARs) activation. Link doi:10.1186/1471-2202-13-109
  • FABP7 is a CB1/CB2 independent ligand for GPR55-mediated hippocampal plasticity.

Role of GPR40-GPR55 expression in neurodegenerative diseases: BDNF modulation of Wnt by anandamide promote neuronal differentiation and proliferation of neural progenitor cells

• Receptor heteromerization of GPR40-GPR55 modulates hippocampal neurogenesis through Wnt activation.
  • Effects of PPARs agonists on BDNF expression:
    • Neuroprotection?
    • Neuron-astrocyte cell migration and differentiation PMID
    • Proliferation of neural stem/progenitor cells (NSPCs)
    • DHA activation of PPARs inhibit amyloid-beta (Abeta) generation in astrocytes. (Alzheimer) PMID PMID
    • Neuroimmune modulation (ie: endogenous remyelination) PMID PMC PMC
    • BDNF-induced synaptogenesis
• Endocannabinoid mobilized LTP upregulate activity-dependent hippocampal neurogenesis and neural progenitor (NP) cell proliferation. (doi: 10.1074/jbc.M111.291294) PMID

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. (N-acyl ethanolamide)

Endocannabinoids and 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 neurons.

Is hippocampal plasticity an evidence of proneurogenic endocannabinoid transport ?

"Metaplasticity" is perhaps a biological activity relevant to hippocampal plasticity and may facilitate heterosynaptic LTP through retrograde endocannabinoid signaling and diffusion in the hippocampus. PMID

The evidences of GPR55 expression in the hippocampus therefore indicate a promising proneurogenic promoter to mediate hippocampal plasticity in neurodegenerative diseases. Hence, intracellular anandamide trafficking by GPR55 may enhance BDNF expression and promote synaptic function.

Mitochondrial function

DHA supplementation may increase mitochondrial function and enhance CB1/CB2 dependent neuroprotection through endocannabinoids mobilization.

Neuroprotective effects of endocannabinoids

Endocannabinoids may protect on-demand neurons from excitotoxicity and neuroinflammation upon exposure to stress-induced excitotoxic insults. PMID PMID

Intracellular anandamide/GPR55 signaling

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 CNS.

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

References

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   A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.

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   Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.

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

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

13. Yu S, Levi L, Casadesus G, Kunos G, and Noy N. 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. J Biol Chem. 2014 May 2;289(18):12748-58. DOI:10.1074/jbc.M114.559062 |

    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

See also

• Anandamide Notebook
• Astrocytes Notebook
• Cannabidiol Notebook
• Cannabidivarin Notebook
• DHA Notebook
• Docosanoids Notebook
• THC Notebook