title: Antioxidant activity of sestrin 2 controls neuropathic pain after peripheral nerve injury.
abstract: OBJECTIVE
  Neuropathic pain is a chronic debilitating disease that is often unresponsive to currently available treatments. Emerging lines of evidence indicate that reactive oxygen species (ROS) are required for the development and maintenance of neuropathic pain. However, little is known about endogenous mechanisms that neutralize the pain-relevant effects of ROS. In the present study, we tested whether the stress-responsive antioxidant protein Sestrin 2 (Sesn2) blocks the ROS-induced neuropathic pain processing in vivo.
  
  
  RESULTS
  We observed that Sesn2 mRNA and protein expression was up-regulated in peripheral nerves after spared nerve injury, a well-characterized model of neuropathic pain. Sesn2 knockout (Sesn2(-/-)) mice exhibited considerably increased late-phase neuropathic pain behavior, while their behavior in acute nociceptive and in inflammatory pain models remained unaffected. The exacerbated neuropathic pain behavior of Sesn2(-/-) mice was associated with elevated ROS levels and an enhanced activating transcription factor 3 up-regulation in sensory neurons, and it was reversed by the ROS scavenger N-tert-Butyl-α-phenylnitrone. In contrast, administration of the ROS donor tert-butyl hydroperoxide induced a prolonged pain behavior in naive Sesn2(-/-) mice.
  
  
  METHODS
  We show that the antioxidant function of Sesn2 limits neuropathic pain processing in vivo.
  
  
  CONCLUSIONS
  Sesn2 controls ROS-dependent neuropathic pain signaling after peripheral nerve injury and may, thus, provide a potential new target for the clinical management of chronic neuropathic pain conditions.
authors.affiliation: 1 Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University Medical School , Frankfurt am Main, Germany .
authors.forename: Wiebke
authors.initials: W
authors.lastname: Kallenborn-Gerhardt
authors.forename: Ruirui
authors.initials: R
authors.lastname: Lu
authors.forename: Katharina M J
authors.initials: KM
authors.lastname: Syhr
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Thorsten
authors.initials: T
authors.lastname: Bangsow
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism*; D059225:Nociception; D009687:Nuclear Proteins / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D010544:Peroxidases; D017382:Reactive Oxygen Species / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D015854:Up-Regulation; D015054:Zymosan; D000084622:Sestrins
chemical_list: D051700:Activating Transcription Factor 3; D000975:Antioxidants; D009687:Nuclear Proteins; D010544:Peroxidases; D017382:Reactive Oxygen Species; D015054:Zymosan; C103002:Atf3 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins