Papers of the Week

Cypin (tosolic ostsynaptic density protein 95 teractor) is the primary guanine deaminase (GDA) 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 postulated 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 mid-thoracic contusion SCI in female mice and assessed whether transient intrathecal administration of B9, starting at 1 day post injury (pi) until 7 days pi, attenuates mechanical pain in hindlimbs 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 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. Neuropathic pain is a debilitating comorbidity associated with spinal cord injury (SCI). Available pharmacological therapies are ineffective or have adverse effects. Development of new and targeted drugs that can effectively alleviate neuropathic pain is urgently needed. Cypin is the primary guanine deaminase in the central nervous system and an essential enzyme in the purine salvage pathway. Activation of the purine salvage pathway leads to production of uric acid, which promotes pain, but also, neuroprotection. We found that inhibition of cypin post-SCI alleviates mechanical pain. The inhibitor does not prevent the spontaneous recovery of locomotor function or exacerbate lesion volume and astrogliosis at the injury epicenter. Thus, cypin inhibitors could be promising therapies for the treatment of neuropathic pain.