Vitamin-E based therapy for pain management: Mechanistic insights into how VitmainE isoform γ-tocotrienol (γT3) functions as an analgesic agent: γ-tocotrienol (γT3) increases the expression of PD-L1, decreases the expression of Cox-2, TRPV1, and CGPR, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 3/November/2019, 9.29 am

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Introduction: What they say:

A recent study from Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China; and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, US shows that “PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1.” This study was published, in the 22 May 2017 issue of Nature Neuroscience (one of the best journals in Neurobiology with an impact factor of 16.724+), by Prof Ru-Rong Ji, Chen G, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, the Director-cum-chief Scientist of GBMD, reports that:  Vitamin-E based therapy for pain management: Mechanistic insights into how VitmainE isoform γ-tocotrienol (γT3) functions as an analgesic agent: γ-tocotrienol (γT3) increases the expression of PD-L1, decreases the expression of Cox-2, TRPV1, and CGPR, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene


What is known?

It has recently been shown that blocking PD-1 with antibodies one could make tumors shrink. This work, relating to Cancer immunotherapy, has been chosen as Science’s breakthrough of the year. However, the work published recently, which is described below, may highlight the caveat in such an approach, as blocking PD-L1 may promote spontaneous pain and allodynia in cancer-bearing mice.

Prof. Ji has shown recently that: (1) Programmed cell death ligand-1 (PD-L1), produced by melanoma and normal neural tissues, inhibits acute and chronic pain; (2) injection of PD-L1 alleviates pain, and thereby functions as an analgesic agent; (3) Neutralization of PD-L1 or Block of PD1 promotes mechanical allodynia (hypersensitivity to pain); (4) PD1 null mice suffer from thermal and mechanical hypersensitivity; (5) PD-L1 promotes phosphorylation of SHP-1 and inhibits Sodium channels via PD-1 activation; and (6) PD-L1 inhibits nociceptive neuron excitability in dorsal root ganglion and thereby functions as a neuromodulator, suggesting that increasing the expression or the level of PD-L1/PD1 may alleviate pain and thermal and mechanical hypersensitivity.


From research findings to therapeutic opportunity:

γ-tocotrienol (γT3), an isoform of Vitamin-E, is used in the treatment of a number of disease conditions, including arthritis, and others.  Although γ-tocotrienol (γT3)  is in use for decades, the mechanistic basis of its therapeutic effect, especially in attenuating arthritis, remains largely unknown up until now. This study provides, for the first time, mechanistic insights into how γ-tocotrienol (γT3)  may attenuate pain, lower back pain, headache, migraine, trauma, and others.

γ-tocotrienol (γT3), by decreasing the expression of its target gene, it increases PD-L1 and mGLUR2 (Metabotropic glutamate receptor 2) ; and decreases Cox-2 (Cyclooxygenase-2), Prostaglandin E2 (PGE2), TRPV1 (transient receptor potential vanilloid 1) and CGPR (Calcitonin gene-related peptide)  levels (fig. 1). Thereby, it: (a) inhibits acute and chronic pain and trauma; (b) alleviates thermal and mechanical hypersensitivity; (c) activates signal transduction cascade downstream of PD-1 receptor; (c) phosphorylates SHP-1; (d) inhibits sodium channels and nociceptive neuron excitability (Fig 2-4).

Figure 1.Mechanistic insights into how γ-tocotrienol (γT3) inhibits acute and chronic pain.   γT3 enhances PD-L1 and mGLUR2, while decreasing Cox-2 & TRPV1 levels. Thereby, it suppresses thermal and mechanical hypersensitivity, phosphorylates SHP-1, inhibits activation of sodium channels, alleviates nociceptive neuron excitability, attenuates acute and chronic pain, low back pain, headaches, and migraine.

Figure 2.  γ-tocotrienol (γT3)  functions as an analgesic medication through induction of PD-L1 and mGLUR2, and downregulation of Cox-2, TRPV1, and CGPR.

Figure 3. γ-tocotrienol (γT3), derived from palm fruit, barley, annatto, and others, attenuates rheumatoid arthritis through the downregulation of Cox-2, PGE2, TRPV1, CGPR and others, and the up-regulation of PD-L1 and mGLUR2.

Figure 4. γ-tocotrienol (γT3), one of the main constituent of commonly consumed palm oil, attenuates acute and chronic pain and trauma through the downregulation of Cox-2, PGE2, TRPV1, CGPR, and others, and the up-regulation of PD-L1 and mGLUR2.

Figure 5. While pharmacological activation of PD-L1 has been shown to attenuate acute and chronic pain, this study suggests that Vitamin-E isoform γ-tocotrienol (γT3) attenuates acute and chronic pain and chronic lower back pain, through up-regulation of PD-L1, mGLUR2, and others.

Thus, γ-tocotrienol (γT3), either alone or in conjunction with other pain medications, can be used to treat acute and chronic pain, lower back pain, migraine, and trauma.

Given the evidence-based mechanistic reasoning as to how γ-tocotrienol (γT3) (fig.1) may aid in alleviating short- and long-term pain, lower back pain,  migraine, and trauma, Physicians/Orthopedicians/Pain therapists/Anesthesiologists/Primary Care and Interventional Pain Physicians/researchers may consider taking up this interesting observation for further experimental study.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by:  Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Amount: $1, 500#

Undisclosed mechanistic information: How does γ-tocotrienol (γT3) increase the expression of PD-L1 and mGLUR2 and attenuate the expression of  Cox-2, PGE2, TRPV1, and CGPR?

# Research cooperation


References:

Citation: Boominathan, L., Vitamin-E based therapy for pain management: Mechanistic insights into how VitmainE isoform γ-tocotrienol (γT3) functions as an analgesic agent: γ-tocotrienol (γT3) increases the expression of PD-L1, decreases the expression of Cox-2, TRPV1, and CGPR, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 3/November/2019, 9.28 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

Web: http://genomediscovery.org or http://newbioideas.com

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