Photosensitization in Porphyrias and Photodynamic Therapy Involves TRPA1 and TRPV1.

Abstract

UNLABELLED:

Photosensitization, an exaggerated sensitivity to harmless light, occurs genetically in rare diseases, such as porphyrias, and in photodynamic therapy where short-term toxicity is intended. A common feature is the experience of pain from bright light. In human subjects, skin exposure to 405 nm light induced moderate pain, which was intensified by pretreatment with aminolevulinic acid. In heterologous expression systems and cultured sensory neurons, exposure to blue light activated TRPA1 and, to a lesser extent, TRPV1 channels in the absence of additional photosensitization. Pretreatment with aminolevulinic acid or with protoporphyrin IX dramatically increased the light sensitivity of both TRPA1 and TRPV1 via generation of reactive oxygen species. Artificial lipid bilayers equipped with purified human TRPA1 showed substantial single-channel activity only in the presence of protoporphyrin IX and blue light. Photosensitivity and photosensitization could be demonstrated in freshly isolated mouse tissues and led to TRP channel-dependent release of proinflammatory neuropeptides upon illumination. With antagonists in clinical development, these findings may help to alleviate pain during photodynamic therapy and also allow for disease modification in porphyria patients.

SIGNIFICANCE STATEMENT:

Cutaneous porphyria patients suffer from burning pain upon exposure to sunlight and other patients undergoing photodynamic therapy experience similar pain, which can limit the therapeutic efforts. This study elucidates the underlying molecular transduction mechanism and identifies potential targets of therapy. Ultraviolet and blue light generates singlet oxygen, which oxidizes and activates the ion channels TRPA1 and TRPV1. The disease and the therapeutic options could be reproduced in models ranging from isolated ion channels to human subjects, applying protoporphyrin IX or its precursor aminolevulinic acid. There is an unmet medical need, and our results suggest a therapeutic use of the pertinent antagonists in clinical development.

• Authors: Alexandru Babes, Susanne K Sauer, Lavanya Moparthi, Tatjana I Kichko, Cristian Neacsu, Barbara Namer, Milos Filipovic, Peter M Zygmunt, Peter W Reeh, Michael J M Fischer
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 36 Issue 19 Pg. 5264-78 (05 11 2016) ISSN: 1529-2401 [Electronic] United States
• PMID: 27170124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the authors 0270-6474/16/365264-15$15.00/0.

Chemical References

• Neuropeptides
• Photosensitizing Agents
• Protoporphyrins
• Reactive Oxygen Species
• TRPA1 Cation Channel
• TRPV Cation Channels
• TRPV1 protein, mouse
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• Aminolevulinic Acid
• protoporphyrin IX

Topics

• Aminolevulinic Acid (pharmacology)
• Animals
• Cells, Cultured
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred C57BL
• Neuropeptides (metabolism)
• Photochemotherapy
• Photosensitizing Agents (pharmacology)
• Porphyrias (metabolism, therapy)
• Protoporphyrins (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sensory Receptor Cells (metabolism)
• Skin (drug effects, radiation effects)
• TRPA1 Cation Channel
• TRPV Cation Channels (metabolism)
• Transient Receptor Potential Channels (metabolism)