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# Dual ligands design
# Dual ligands design
## CB1 and PPAR-gamma targeting: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056814/
## CB1 and PPAR-gamma targeting: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056814/
# folic acid (Vitamin B9) enhance cannabimimetic activity and DHA plasma concentration


=== Documentation ===
=== Documentation ===

Revision as of 11:09, 23 November 2014

Introduction

Medicinal marijuana has been for centuries a medicinal herb to cure many diseases naturally, and its effects are still subject of intense controversial debates. In this study is presented a method to induce cognitive enhancements through the combination of medicinal marijuana with fatty acids supplements (omega 3), and to stimulate neuronal activity and shape brain connectivity with natural products. Furthermore the functions of metabolic endocannabinoids ligands are investigated to identify key evidences of endocannabinoid-dependent LTP and synaptic plasticity in the hippocampus.

Endocannabinoid-dependent activity promote persistent synaptic plasticity in the hippocampus.

Hypothesis

  1. DHA may potentiate synaptic plasticity (and cognition) via retrograde CB1 signaling.
    1. DHA activate the (presynaptic?) NMDA receptor and upregulate the release of glutamate. [1]
      1. DHA-induced synapses (CA3) enhance synaptic plasticity, thus learning is enhanced. [2]
      2. Induction of Long-Term Potentiation/Persistent synaptic plasticity (LTP). (Pathway)
    2. Activation of inhibitory GABAergic synapse (GABA(B) receptor ?) by endocannabinoids (DHA) may promote synaptic function and learning. [3]
      1. TrkB receptor regulate activity-dependent synaptogenesis and BDNF expression [4]

Model

  1. The Promoters:
    1. DHA (docosahexaenoic acid) conjugate in the hippocampus is N-docosahexaenoyl ethanolamine (DHEA).
      1. DHEA subclass is N-acyl ethanolamines (NAE)
    2. THC (delta-9-tetrahydrocannabinol)
  1. The Wet Blanket: (CB1 receptor)
    1. Role: Protect the hippocampus and neurons from glutamate excitoxicity.
    2. DHEA bind and activate the CB1 receptor
      1. neuroprotection
      2. promotes hippocampal development: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215906/
        1. synaptogenesis (synapse formation)
        2. neurite growth and neurons survival
        3. glutamatergic synaptic activity
    3. FAAH hydrolysis of DHEA (a endocannabinoid like molecule/N-acyl ethanolamine or anandamide)
      1. http://www.ncbi.nlm.nih.gov/pubmed/20601112
      2. http://www.ncbi.nlm.nih.gov/pubmed/21294934
      3. DHEA biosynthesis stimulate N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity
        1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382453/
      4. endocannabinoids degradation
        1. cannabidiol (CBD) and anandamide signaling
  2. The Suppression of Inhibition:
    1. TrkB (2.7.10.1) potentiate GABAergic synaptic activation:
      1. BDNF expression is Ca2+ and CREB dependent
    2. DSI (CB1-mediated inhibition of GABAergic transmission/Depolarization-induced Suppression of Inhibition) -> EPSC (excitatory post-synaptic currents) -> NMDA-dependent(?) LTP at excitatory, and glutamatergic synapses
      1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574086
      2. http://www.ncbi.nlm.nih.gov/pubmed/12080342
      3. http://www.ncbi.nlm.nih.gov/pubmed/17392410
      4. http://www.sciencedirect.com/science/article/pii/S0896627304005732
      5. endocannabinoids-mediated metaplasticity : http://www.ncbi.nlm.nih.gov/pubmed/15363397 http://www.ncbi.nlm.nih.gov/pubmed/18523004
        1. metaplastic control of synaptic transmission
        2. mGluR activation
        3. synaptic inhibition
        4. DSI/glutamate hypothesis:
          1. http://www.ncbi.nlm.nih.gov/pubmed/10561426
          2. http://www.ncbi.nlm.nih.gov/pubmed/23527052
  3. PPAR signaling: http://www.ncbi.nlm.nih.gov/pubmed/17704824
    1. endocannabinoid dependent activation of PPAR-alpha
    2. neurogenesis?
    3. THC/DHEA activate PPAR-gamma
  4. Dual ligands design
    1. CB1 and PPAR-gamma targeting: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056814/
  5. folic acid (Vitamin B9) enhance cannabimimetic activity and DHA plasma concentration

Documentation

Protocol:

Cannabinoids and hippocampal neurogenesis:

DHA:

Anandamide signaling:

FAAH (fatty acid amide hydrolase):

Introduction to fatty amides:

Synaptic Plasticity:

Keywords

hippocampus, anandamide, FAAH, DHA, THC, neurogenesis, synaptogenesis, GABA, synaptamide, BDNF, LTP

References

  1. Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, and Kim HY. Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem. 2009 Oct;111(2):510-21. DOI:10.1111/j.1471-4159.2009.06335.x | PubMed ID:19682204 | HubMed [ref1]
  2. Hagena H and Manahan-Vaughan D. Learning-facilitated synaptic plasticity at CA3 mossy fiber and commissural-associational synapses reveals different roles in information processing. Cereb Cortex. 2011 Nov;21(11):2442-9. DOI:10.1093/cercor/bhq271 | PubMed ID:21493717 | HubMed [ref2]
  3. Gaiarsa JL and Porcher C. Emerging neurotrophic role of GABAB receptors in neuronal circuit development. Front Cell Neurosci. 2013;7:206. DOI:10.3389/fncel.2013.00206 | PubMed ID:24282395 | HubMed [GABA-2013]
  4. Huang ZJ. Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond. J Physiol. 2009 May 1;587(Pt 9):1881-8. DOI:10.1113/jphysiol.2008.168211 | PubMed ID:19188247 | HubMed [TrkB-2009]
  5. Kim HY, Spector AA, and Xiong ZM. A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Other Lipid Mediat. 2011 Nov;96(1-4):114-20. DOI:10.1016/j.prostaglandins.2011.07.002 | PubMed ID:21810478 | HubMed [ref4]
  6. Chen AI, Nguyen CN, Copenhagen DR, Badurek S, Minichiello L, Ranscht B, and Reichardt LF. TrkB (tropomyosin-related kinase B) controls the assembly and maintenance of GABAergic synapses in the cerebellar cortex. J Neurosci. 2011 Feb 23;31(8):2769-80. DOI:10.1523/JNEUROSCI.4991-10.2011 | PubMed ID:21414899 | HubMed [ref5]

All Medline abstracts: PubMed | HubMed

See also

EGFR Notebook

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