# Repurposing of Chemokine Antagonists for Combined Phase‐Resolved Spinal Cord Injury Treatment

## TL;DR

This paper explores how blocking specific chemokine receptors can help treat spinal cord injuries by reducing inflammation and improving recovery.

## Contribution

The study proposes a novel combined, time-resolved therapeutic approach using chemokine antagonists for spinal cord injury treatment.

## Key findings

- SCI in mammals causes a cytokine storm in cerebrospinal fluid, mainly driven by CXCL1, IL-6, and CCL2-5.
- Blocking CCR5 and CXCR1/2 receptors improves acute SCI recovery, while anti-CCR4 antibody mogamulizumab reduces secondary inflammation.
- A combined time-related therapy using chemokine antagonists may help during acute, sub-acute, and chronic phases of SCI.

## Abstract

Spinal cord injury (SCI) is a medical challenge that results in the formation of a glial scar preventing recovery of axonal conductivity. Cytokines and chemokines significantly affect the pathogenesis of SCI and represent important targets for therapeutic intervention. Here, dozens of cytokines and chemokines are dynamically monitored in plasma, cerebrospinal fluid, and injury site released in response to experimental SCI conducted in two rodent strains and patients undergoing surgical removal of intramedullary tumors. Dataset comprising 6,172 cytokine/chemokine values across 8 time points suggests that SCI in mammals is accompanied by a massive cytokine storm in cerebrospinal fluid, mainly driven by CXCL1, IL‐6, and CCL2‐5. Sub‐acute phase is mostly associated with IL‐2, IL‐7, CCL22 and CX3CL1, whereas TNFα and IL17α permanently persists in CNS for even weeks following SCI. The effects of mogamulizumab and chemical antagonists of C‐C/C‐X‐C chemokine receptors TAK‐799, SB225002, and MK‐7123 on SCI recovery in rodents are further estimated. Here blockade of CCR5 and CXCR1/2 chemokine receptors is shown beneficial for amelioration of acute SCI, whereas anti‐CCR4 antibody mogamulizumab readily prevents secondary inflammation in the injured area. Summarizing, the current report claims for a novel combined time‐resolved therapeutic modality in SCI treatment, which supports feasibility and motivates off‐label clinical evaluation in appropriate cohorts.

Spinal cord injury (SCI) in mammals is accompanied by a massive cytokine storm in cerebrospinal fluid, mainly driven by CXCL1, IL‐6, and CCL2‐5. Sub‐acute phase is mostly associated with IL‐2, IL‐7, CCL22, and CX3CL1, whereas TNFα and IL17α permanently persists in CNS even weeks following SCI. Time‐related combined therapy by CXCR1/2 or ‐CCR5 chemical antagonists, mogamulizumab and infliximab, might ameliorate the evolution of SCI sequelae during the acute, sub‐acute, and chronic phases, respectively.