Repurposing the anti-angina drug Ranolazine into an analgesic drug: Ranolazine-based activation of the PD-1 pathway for Pain therapy: Ranolazine  increases the expression of PD-L1, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 24/August/2018, 11.20 pm

The pregnancy hormone Relaxin relieves you of acute and chronic pain (No kidding): Relaxin-based activation of the PD-1 pathway for Pain therapy: Relaxin, a protein hormone that facilitates labor and relaxes the uterine musculature,  increases the expression of PD-L1, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 24/August/2018, 11.08 pm
August 24, 2018
Awakening the sleeping/cancer-protecting angels in mutant p53-expressing human tumors: PCGF2/Mel-18 increases the expression of tumor suppressors genes, such as  APAF1, FOXO1, p53, TAp63, TAp73, INK4a/ARF, and others, induces regression of p53-mutated human tumors, via down-regulation of its target gene, 24/August/2018, 11.34 pm
August 24, 2018
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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 Ji RR, Chen G, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Repurposing the anti-angina drug Ranolazine into an analgesic drug: Ranolazine-based activation of the PD-1 pathway for Pain therapy: Ranolazine  increases the expression of PD-L1, 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 suffers 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:

This study suggests, first the first time, a new function for the known anti-angina drug Ranolazine in attenuating acute and chronic pain.

Ranolazine, by increasing the expression of its target genes, it may increase PD-L1 levels (figs. 1-2). Thereby, it may: (a) inhibit acute and chronic pain; (b) alleviate thermal and mechanical hypersensitivity; (c) activate signal transduction cascade downstream of the PD-1 receptor; (c) phosphorylate SHP-1; (d) inhibit sodium channels and nociceptive neuron excitability. Thus, Ranolazine or its analogs, either alone or in combination with other drugs,” may be used to attenuate short-term and long-term pain.

Figure 1.Mechanistic insights into how Ranolazine inhibits acute and chronic pain. Ranolazine enhances PD-L1 levels, suppresses thermal and mechanical hypersensitivity, phosphorylates SHP-1, inhibits activation of sodium channels, and alleviates nociceptive neuron excitability

Figure 2.Repurposing the pregnancy hormone Ranolazine into an analgesic agent. Relaxin  attenuates pain through induction of PDL1.

 

 

 

 


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: $500#

Undisclosed mechanistic information: How does Ranolazine increase the expression of PD-L1?

# Research cooperation


References:

Citation: Boominathan, L., Repurposing the anti-angina drug Ranolazine into an analgesic drug: Ranolazine-based activation of the PD-1 pathway for Pain therapy: Ranolazine  increases the expression of PD-L1, attenuates acute and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability, via up-regulation of its target gene, 24/August/2018, 11.20 pm, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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

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