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Activation of the PD-1 pathway for Pain therapy: Sildenafil [Phosphodiesterase-5 inhibitor], a drug used in the treatment of erectile dysfunction and pulmonary arterial hypertension,  increases the expression of PD-L1, attenuates acutes and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability via up-regulation of its target gene, 17/January/2017, 1.29 pm

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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: Activation of the PD-1 pathway for Pain therapy: Sildenafil [Phosphodiesterase-5 inhibitor], a drug used in the treatment of erectile dysfunction and pulmonary arterial hypertension increases the expression of PD-L1, attenuates acutes 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:

The study presented here suggests, for the first time, that Sildenafil, 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 PD-1 receptor; (c) phosphorylate SHP-1; (d) inhibit sodium channels and nociceptive neuron excitability.

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

Figure 2. The chemical structure of Sildenafil  and the source from which it is dervided is indicated above.. Diclofenac attenuates pain through induction of PDL1.

Thus, pharmacological formulations encompassing Sildenafil or its analogues, either alone in combination with other drugs,” may be used to attenuate short-term and long-term pain.


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  Sildenafil increases the expression of PD-L1

# Research cooperation


References:

Citation: Boominathan, L., Activation of the PD-1 pathway for Pain therapy: Sildenafil [Phosphodiesterase-5 inhibitor], a drug used in the treatment of erectile dysfunction and pulmonary arterial hypertension increases the expression of PD-L1, attenuates acutes and chronic pain, and suppresses mechanical and thermal hypersensitivity and inhibits nociceptive neuron excitability via up-regulation of its target gene, 17/January/2017, 1.29 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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

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