AD/PD 2021 – Neuroprotection

SCO-SPONDIN DERIVED PEPTIDE PROTECTS RAT AND HUMAN NEURONS AGAINST GLUTAMATE-INDUCED EXCITOTOXICITY

Sighild Lemarchant¹, Nathalie Delétage¹, Juliette Le Douce¹, Yann Godfrin^1,2

Introduction

The subcommissural organ (SCO)-spondin is a brain-specific glycoprotein that strongly contributes to neuronal survival during development. The SCO becomes atrophic in adults, thereby losing protective functions of damaged nervous cells. Using rat and human neuronal cultures, we have evaluated the neuroprotective effect of NX peptide, derived from the SCO-spondin, against glutamate toxicity.

Methods

Primary neurons were exposed to glutamate (glu) and treated with NX peptide (100, 250, 500 µg/mL). Neuronal survival and neurite network were assessed using immunohistochemistry or biochemistry. The mechanism of action was investigated by exposing neurons to inhibitors targeting receptors and intracellular mediators that trigger apoptosis, neuronal survival, or neurite growth.

Results

NX promoted neuronal survival and prevented neurite network retraction on rat cortical and hippocampal neurons. NX triggered neuroprotection via β₁-integrin and Notch receptors, activation of the PI3K/mTOR pathway and modulation of the apoptotic cascade.

NX neuroprotective effect was confirmed in human cortical neurons: reduction of lactate dehydrogenase release (-52% in NX/glu-treated neurons compared to glu-treated neurons) and recovery of normal basal level of apoptotic cells (14, 28 and 13% for vehicle-, glu- and NX/glu-treated neurons, respectively).

Conclusion/Perspectives

Collectively, these results show that NX peptide represents a promising translational drug-candidate to reduce glutamate-induced neuronal death. Proof of concepts in CNS animal models are under investigation to evaluate NX neuroprotective action. A phase 1 clinical trial in healthy volunteers is ongoing to evaluate the tolerability of NX peptide.