Utilisateur:JackBortone/2018/Notebook/Endocannabinoids

Introduction

The aim of this notebook was to design a experimental method to protect brain cells from aripiprazole-induced neuronal damage via dietary supplementation of synaptogenic endocannabinoids.

Hypothesis

Anandamide trafficking may exert neuroprotective effects on the microglia through selective binding of transcriptional dopamine receptors:

1. FABP-PPAR allosteric communication with CB1 receptors enhance long-range synchronicity in the gamma range of dopamine neurotransmission.
2. Synaptamide receptor heteromerization enhance biphasic endocannabinoid transport.
3. Retrograde endocannabinoid signaling fine-tune neuronal phase coherence through intracellular CB1 activation.

Results

On-demand neuroprotection of the microglia via endogenous retrograde signaling

• Arachidonic acid (ARA) may selectively enhance presynaptic CB1 receptor availability in the microglia? (Reference needed)
• Anandamide trafficking via THC-mediated activation of glutamatergic CB1 receptors may enhance NMDA neuroprotection: (Reference needed)
  • On-demand hippocampal/NMDA neuroprotection?
  • Astrocytes-mediated dopaminergic neuroprotection?
    • Review: Endocannabinoids Mediate Neuron-Astrocyte Communication
    • Review: Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas.
• See also: https://www.ncbi.nlm.nih.gov/pubmed/23531681

Pharmacological activation of the endocannabinoid transport system

Identification of neuroprotective endocannabinoid transporters for management of drug-induced neuronal damage and dopamine hypersensitivity in the microglia:

• Arachidonic acid (ARA)
• Arachidonyl-2-chloroethylamide (ACEA)
• Melatonin
• Oxytocin
• Synaptamide (DHA, DHEA)
• Vitamin D

Intrinsic roles of microglial dopamine/anandamide cross-talk:

• Enhanced microglial homeostasis and neuroprotection
• Inhibition of drug-induced nitric oxide/glutamate production?
• On-demand microglial neuroprotection through Nurr1 and Notch1 transcriptional regulation of dopamine synthesis?
  • Activation of CB1 receptor by anandamide may promote fatty acid homeostasis through PPAR-gamma and (Nurr1?) signaling. (Reference needed)
  • FABP5 and FABP7 expressions may selectively enhance PPAR-gamma regulation of (dopamine?) transcription factors (Notch1, Nurr1). [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. (Reference needed)

• Review: Wnts in adult brain: from synaptic plasticity to cognitive deficiencies

CB1 receptor expression prevent drug-induced corticostriatal excitotoxicity and microglial activation

Reference needed

Conclusion

• Functional neurogenesis and synaptogenesis is facilitated by intracellular delivery of DHEA to dopaminergic neurons.
  • Synaptogenic endocannabinoids are a emerging class of DHA conjugates for synthesis and maintenance of neural stem cells (NSCs) in the hippocampus, striatum, and microglia.
  • The neuroprotective properties of synaptogenic endocannabinoids protect microglial neurons against drug-induced neuronal damage (excitotoxicity) and dopaminergic hypersensitivity.
• Transactivation of PPAR-RXR heterodimer by DHEA enhance microglial neuroprotection.
  • Allosteric modulation of CB1 expression by synaptamide facilitate intracellular FABP-PPAR signaling and fatty acid homeostasis.

Notes

• Cannabinoids (THC) transactivation of CB1 receptors may fine-tune(?) purinergic P2X7 neurotransmission. (Reference needed)
• Adenosine antagonism (caffeine) may autoregulate dopamine-CB1 receptors affinity and density. (cross-talk)? [2]
• Endocannabinoid signaling may autoregulate dopamine/melatonin synthesis in vivo.
• Chronic THC exposure may downregulate endocannabinoid signaling. (Reference needed)

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, melatonin, eicosanoids

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See also

• Synopsis
• FAAH Notebook
• THC Notebook