Brain & Brain Pet 2022

Glasgow, Scotland

A subcommissural organ-spondin-derived peptide (NX210C) improves recovery of synaptic transmission after ischemia in vitro

Mélissa Sourioux¹, Sighild Lemarchant¹, Juliette Le Douce¹, Sandrine Hugues², Mélissa Farinelli² & Yann Godfrin^1,3

¹Axoltis Pharma, Lyon, France ²E-Phy-Science, Biot, France ³Godfrin Life-Sciences, Caluire-et-Cuire, France

Cerebral ischemia is characterized by a transient deprivation of oxygen and nutrients to the brain leading to neuronal dysfunction, cell death, and subsequent motor and cognitive impairments. Hence, there is a substantial need for solutions to prevent this condition or treat its consequences. The aim of this study was thus to evaluate the efficacy of a subcommissural organ-spondin-derived peptide (NX210c) to restore synaptic transmission in an in vitro model of cerebral ischemia.

Method:

Mouse hippocampal brain slices were submitted to oxygen-glucose deprivation (OGD) to mimic ischemia in vitro. NX210c (250 μg/mL) or vehicle was bath- applied either from the beginning or the end of OGD exposure. Functional recovery was assessed by recording field excitatory postsynaptic potentials (fEPSPs) evoked at Schaffer collateral-CA1 synapses.

Results/Conclusions:

While OGD causes synaptic depression, concurrent administration of NX210c improves recovery. Indeed, fEPSP slopes were significantly higher in NX210c-treated than in vehicle-treated slices within 30-60 minutes from OGD induction (fEPSP slope expressed as a % of baseline: 47.2±4.5 and 61.7±5.0 for vehicle and NX210c respectively, p<0.05) and this beneficial effect persisted for 80-90 minutes post-OGD (72.4±2.9 and 92.6±2.4 for vehicle and NX210c respectively, p<0.001). Staggeringly, NX210c was efficient even if added after OGD exposure (77.1±2.7 and 88.0±1.9 for vehicle and NX210c respectively, 90-120 minutes post-OGD, p<0.01). According to complementary studies, this beneficial effect of NX210c on the restoration of synaptic transmission could be explained by its preferential action on GluN2A-containing NMDA receptors. Finally, NX210c is a promising drug-candidate to improve neurological outcomes after ischemic insult.