Breaking the cycle of excitotoxicity: blood glutamate scavenging provides robust neuroprotection in spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) triggers a rapid and sustained cascade of secondary damage, with glutamate (Glu) excitotoxicity recognized as a central mechanism driving neuronal death and functional decline. Despite extensive research, no effective therapy targeting excitotoxicity, and no neuroprotective treatment in general, is currently available. This highlights the urgent need for novel and effective therapeutic strategies for managing SCI. METHODS: We developed a combined blood-glutamate scavenging (cBGS) therapeutic platform comprising two recombinant enzymes (rGOT1 and rGPT1), their respective co-substrates (oxaloacetate and pyruvate), and the cofactor pyridoxal phosphate (PLP). The efficacy of cBGS was evaluated in mouse and rat models of moderate-to-severe spinal cord compression and contusion injury. Glutamate concentrations were quantified in blood and cerebrospinal fluid (CSF), while histological and functional outcomes were assessed from 1 day to 7 weeks post-injury to determine neuroprotective efficacy. RESULTS: Systemic cBGS administration significantly reduced Glu concentrations in both blood and CSF, leading to a marked reduction in apoptosis, neuroinflammation, demyelination, and glial scarring, while promoting neuronal and axonal survival. Treated animals demonstrated substantial locomotor recovery, up to 80% improvement in performance. Notably, cBGS remained effective when administered up to eight hours post-injury, indicating a clinically relevant therapeutic window and excellent safety profile. Core findings were independently validated in a rat severe compression model performed by an external Contract Research Organization (CRO). CONCLUSIONS: The cBGS platform represents a first-in-class systemic neuroprotective therapy that effectively mitigates glutamate excitotoxicity and secondary injury following SCI. Its robust efficacy, wide therapeutic window, and favorable safety profile support its strong potential for clinical translation in acute SCI and other excitotoxicity-driven neurotrauma conditions, where no effective treatments currently exist.