POLYARGININE PEPTIDE R18D IMPROVES ACUTE MOTOR AND WHITE-MATTER OUTCOMES FOLLOWING MILD TRAUMATIC BRAIN INJURY IN FERRETS

Mild traumatic brain injury (mTBI) commonly induces diffuse white-matter injury accompanied by early motor and cognitive dysfunction. R18D is a cationic poly-arginine peptide with multimodal neuroprotective properties. This study aimed to determine whether R18D improves acute behavioural and neuropathological outcomes following mTBI in a gyrencephalic ferret model that more closely replicates human brain biomechanics. Adult male ferrets (7-8 months) were randomised to sham, vehicle, or R18D treatment (100 or 300 nmol/kg). Diffuse mTBI was induced using the CHIMERA model, with intravenous R18D or saline administered 30 min post-injury. Behavioural outcomes were assessed up to 72 h post-injury using tests of motor coordination, executive function, and spatial learning. At 72 h, brains were analysed for axonal injury markers (amyloid precursor protein and RMO-14) and glial responses (IBA-1 and GFAP) across major white-matter tracts. Vehicle-treated mTBI animals exhibited impaired motor coordination, with increased ladder-walk foot faults compared with sham. R18D at 100 nmol/kg prevented this deficit, while 300 nmol/kg showed a partial effect. Histologically, R18D reduced amyloid precursor protein accumulation and attenuated microglial activation within the corpus callosum and fornix, with more consistent effects observed at the lower dose. Astrocytic reactivity showed partial normalisation following R18D treatment. These findings demonstrate that R18D improves acute motor recovery and mitigates white-matter pathology following mTBI in a gyrencephalic model, supporting dose selection and justifying larger, longer-term studies. This research was funded by Argenica Therapeutics and approved by SAHMRI.