Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain

Nisha K. Singh, Srinivasa R. Gandu, Lun Li, Li Ni, Cigdem Acioglu, Ersilia Mirabelli, Liam L. Hiester, Stella Elkabes, Bonnie L. Firestein

Research output: Contribution to journalArticlepeer-review

Abstract

Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain. Since neuropathic pain is a comorbidity associated with spinal cord injury (SCI), we pos-tulated that small molecule cypin inhibitor B9 treatment could attenuate SCI-induced neuropathic pain, potentially by interfering with UA production. However, we also considered that this treatment could hinder the neuroprotective effects of UA and, in doing so, exacerbate SCI outcomes. To address our hypothesis, we induced a moderate midthoracic contusion SCI in female mice and assessed whether transient intra-thecal administration of B9, starting at 1 d postinjury (dpi) until 7 dpi, attenuates mechanical pain in hin-dlimbs at 3 weeks pi. We also evaluated the effects of B9 on the spontaneous recovery of locomotor function. We found that B9 alleviates mechanical pain but does not affect locomotor function. Importantly, B9 does not exacerbate lesion volume at the epicenter. In accordance with these findings, B9 does not aggravate glutamate-induced excitotoxic death of SC neurons in vitro. Moreover, SCI-induced increased astrocyte reactivity at the glial scar is not altered by B9 treatment. Our data suggest that B9 treatment reduces mechanical pain without exerting major detrimental effects following SCI.

Original languageAmerican English
JournaleNeuro
Volume11
Issue number2
DOIs
StatePublished - Feb 2024

ASJC Scopus subject areas

  • General Neuroscience

Keywords

  • cypin
  • guanine deaminase
  • neuropathic pain
  • pharmacological inhibition
  • spinal cord injury
  • von Frey test

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