User:Tkadm30/Notebook/Endocannabinoids
Introduction
The neurocognitive effects of the marijuana plant are still subject of provocative debates. Hence, the delivery of cannabinoids drug (THC, CBD) to the brain and central nervous system (CNS) remains poorly understood. Moreover, the role of endogenous cannabinoids may be a beneficial asset in the treatment of neurological disorders including epilepsy, Alzheimer, and depression.
Synopsis
- Stimulation of endocannabinoid transport with polyunsaturated (22:6n-3) fatty acids (DHA, DHEA, EPA) to target major depressive disorders (MDD) , epilepsy and Alzheimer disease (AD).
- Distribution of endocannabinoid-dependent activity (LTP, LTD, 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
- Novel GPR55-DHA heteromer (N-acyl amine) with potent anti-inflammatory, antiglutamatergic and neuroprotective properties.
- Antioxidant (cytoprotective) properties of GPR55-DHA heteromer.
- Effects of the endothelial CB2 receptor persistent activation on monocyte subpopulations/microglia migration. PMID
Endogenous cannabinoids as a therapeutic platform
2-arachidonoylglycerol (2-AG), a novel gliotransmitter controlled by the P2X7 receptor, exert neuroprotective effects on excitotoxic brain injury.
- 2-AG is an endogenous cannabinoid ligand synthesized by diacylglycerol lipase (DGL-α) and phospholipase C (PLC).
- Neuroprotective (anti-inflammatory) and a potent cytoprotective agent (antioxidant)
- retrograde 2-AG signaling
- modulate glutamatergic LTP/DSE PMID
- Anxiolytic
- ionotropic (permeable to calcium) P2X7 receptor control 2-AG production PMID
- monoacylglycerol lipase (MGL), a selective 2-AG hydrolase: http://www.uniprot.org/uniprot/Q99685
- calcium dependent biosynthesis
- ATP-induced 2-AG production from astrocytes PMID PMID
- 2-AG activate endogenous phospholipase C-dependent TRPV1 channel in the brain.
- doi:10.1038/srep04329
Anandamide (N-arachidonoyl-ethanolamine)
- Biosynthesis of endogenous phosphoanandamide/PLC ligands: PMID
- Cannabinoid receptor type 1 (CB1) full agonist PMID
- Anandamide signaling is metabotropic (CB1) and limit TRPV1-mediated Ca2+ influx. PMID
- Anandamide appears a good target to activate TRPV1 receptor and trigger antiepileptogenesis.
- Anandamide provides on demand neuroprotection agaisnt in vivo excitotoxicity PMID
NADA (N-arachidonoyl-dopamine)
- A putative endocannabinoid with potential atheroprotective properties.PMID PMID
- NADA modulate anti-inflammatory activation of the endothelium. PMID
- Full agonist at the CB1/CB2 receptors and TRPV1 ion channel.
- Pleiotropic role of the CB2 receptor: Immunomodulation of the endothelium. PMID PMID
- Structural analog of the dopamine conjugate of DHA.
Endocannabinoid transport
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.
First, THC 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.
In addition, endocannabinoids may protect neurons from excitoxicity and neuroinflammation upon exposure to stress. Hence, endocannabinoids constitute a family of intracellular lipid signaling molecules with potent anti-inflammatory, anti-oxidative and anti-excitotoxic bioactivity to treat major neurological and neurodegenerative disorders (Depression, Alzheimer's disease) efficiently.
Keywords
endocannabinoids, hippocampus, anandamide, 2-AG, 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, microglia, mitochondria
References
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