Targeting LRP1 in a rodent cervical injury model to promote functional recovery

Impairments following spinal cord injuries (SCI) are due to the primary trauma and secondary complications. Secondary complications include 1) degeneration of white matter tracts and 2) persistent neuroinflammation. Here we test a novel compound, NOVO-118 that is designed to mitigate these secondary complications in a rodent model of SCI. NOVO-118 is an antagonist of the low-density lipoprotein receptor regulated protein 1 (LRP1) which is expressed in all cell types in the central nervous system. Antagonism of LRP1 in neurons is implicated in promoting axon regeneration by reducing RhoA activation. Further, antagonism of LRP1 within microglia may reduce myelin uptake and mitigate the transition to their pro-inflammatory state. We hypothesize that LRP1, we can promote regeneration and mitigate neuroinflammation leading to functional recovery following cervical contusion SCI. As LRP1 is broadly expressed throughout many organ systems, we delivered NOVO-118 (or vehicle) to the intrathecal space above the lesion over a 30-day period after injury to mitigate off target effects. We measured the effect of NOVO-118 on ventilation and locomotor function using whole body plethysmography and open-field activity chambers. Behavioral assessments were performed pre-injury, 3, 7-, 14-, 21-, and 28-days post injury. Minute ventilation under normoxia was reduced in both groups at days 3 and 7 post injury which recovered towards pre-injury levels by day 14. The vehicle treated animals also had reduced minute ventilation during hypoxic challenge at days 3 and 14 post injury. However, the NOVO-118 treated rats were able to maintain pre-injury minute ventilation under hypoxic challenge at all time points. This suggests LRP1 as a new therapeutic target to promote recovery after SCI. Ongoing work is investigating the possible mechanisms through which NOVO-118 led to these functional improvements. Novoron Bioscience (WJA, MDS), NIH NINDS R01NS101105 (WJA) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.