Therapeutic benefit of targeting neuroinflammation in spinal cord injury with a novel small molecule inhibitor of the RNA regulator HuR

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Spinal cord injury (SCI) is devastating and most often affects younger Veterans. There is significant long-term morbidity, a shortened life span, and a high financial burden. Because of the poor regenerative capacity of the spinal cord, development of early interventions that minimize secondary tissue injury is a priority. A major contribution to secondary tissue damage and the initiation of neuropathic pain is the inflammatory cascade triggered by activated glial cells (microglia and astroglia). This cascade begins immediately after SCI with glial release of cytokines, reactive species, and vasoactive substances. This secretome produces damage to neurons, oligodendrocytes and other cells at and beyond the level of injury through direct cytotoxic mechanisms or indirectly through the promotion of cytotoxic and vasogenic edema, vascular compromise, and tissue ischemia. These inflammatory mediators also trigger pathways that lead to chronic pain. The inflammatory cascade is further accelerated by glial production of chemokines which recruit peripheral immune cells, including neutrophils and monocytes, within the acute phase of injury. A major driver of the initial glial response is HuR, an RNA regulator that promotes expression of key inflammatory mediators through posttranscriptional mechanisms. Inflammatory mediators such as IL-1β, IL-6, TNF-α and iNOS contain adenine- and uridine-rich elements in the 3’ untranslated region (ARE) to which HuR binds and positively regulates their expression. Our prior work in SCI shows that HuR is activated in the acute phase of SCI and exacerbates injury when overexpressed in glia. Our team has developed a novel class of small molecule HuR inhibitors that blocks induction of inflammatory mediators in glial cells. In a pilot study of SCI using a mid- thoracic contusion model, we observed attenuation of clinical deficits and neuronal loss with the prototype HuR inhibitor, SRI-42127. We also found that SRI-42127 reduced allodynic pain in a peripheral nerve injury model. In this proposal we hypothesize that HuR drives expression of a pro-inflammatory and toxic secretome by resident glia that is triggered in the early stages of SCI, and that inhibiting HuR will reduce secondary tissue injury, improve motor outcome and reduce neuropathic pain. We propose 3 specific aims: (1) Further characterize the beneficial effect of HuR inhibition by SRI-42127on SCI recovery, (2) Assess mechanisms by which HuR inhibition improves recovery after SCI, and (3) Assess the contribution of glial HuR to inflammatory responses and tissue injury in SCI. The long term objectives of this proposal are to advance our small molecule HuR inhibitors as a therapy in acute SCI and to gain a mechanistic understanding of how ARE-mediated post-transcriptional regulation impacts SCI (secondary tissue injury, motor recovery and neuropathic pain). The innovation of this proposal is the investigation of a novel class of HuR inhibitors for therapeutically targeting the acute inflammatory response in SCI and the mechanistic investigation of post- transcriptional pathways (to date essentially unexplored) in SCI. The significance of this application is its focus on a treatment approach that might eventually be used in the battlefield at the time of acute injury as our preclinical studies indicate excellent and fast penetration of SRI-42127 into the central nervous system with peripheral administration, and a mitigating effect on neuronal loss and neuropathic pain. The signfiicance extends beyond SCI as the same HuR-regulated pathways drive neuroinflammation in other acute CNS injuries (e.g. traumatic brain injury or stroke) and chronic neurological diseases (e.g. ALS and Alzheimers).