TY - JOUR
T1 - Cypin Inhibition as a Therapeutic Approach to Treat Spinal Cord Injury–Induced Mechanical Pain
AU - Singh, Nisha K.
AU - Gandu, Srinivasa R.
AU - Li, Lun
AU - Ni, Li
AU - Acioglu, Cigdem
AU - Mirabelli, Ersilia
AU - Hiester, Liam L.
AU - Elkabes, Stella
AU - Firestein, Bonnie L.
N1 - Publisher Copyright: © 2024 Singh et al.
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
KW - cypin
KW - guanine deaminase
KW - neuropathic pain
KW - pharmacological inhibition
KW - spinal cord injury
KW - von Frey test
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U2 - 10.1523/ENEURO.0451-23.2024
DO - 10.1523/ENEURO.0451-23.2024
M3 - Article
C2 - 38302457
SN - 2373-2822
VL - 11
JO - eNeuro
JF - eNeuro
IS - 2
ER -