2. Academic Validation
  3. Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain

  • Sci Adv. 2022 Aug 5;8(31):eabo5633. doi: 10.1126/sciadv.abo5633.
Chirag Vasavda 1,  Risheng Xu 2,  Jason Liew 1,  Ruchita Kothari 1,  Ryan S Dhindsa 3 4,  Evan R Semenza 1,  Bindu D Paul 1 5 6,  Dustin P Green 7,  Mark F Sabbagh 8,  Joseph Y Shin 9,  Wuyang Yang 2,  Adele M Snowman 1,  Lauren K Albacarys 1,  Abhay Moghekar 10,  Carlos A Pardo-Villamizar 10,  Mark Luciano 2,  Judy Huang 2,  Chetan Bettegowda 2,  Shawn G Kwatra 11 12,  Xinzhong Dong 1 2 11 13,  Michael Lim 2 14,  Solomon H Snyder 1 5 6
Affiliations

Affiliations

  • 1 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 4 Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
  • 5 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 7 Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX, USA.
  • 8 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • 9 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 10 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 11 Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 12 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 13 Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 14 Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA.
PMID: 35921423 DOI: 10.1126/sciadv.abo5633
Abstract

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates Reactive Oxygen Species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

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