Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence

David Romeo-Guitart,Caty Casas,Elena Galea,Tatiana Leiva-Rodríguez,Xavier Navarro,Mireia Herrando-Grabulosa,Mireia Coma,Francisco González-Pérez,José Manuel Mas,Valerie Petegnief,Raquel Valls,Assumpció Bosch,Joaquim Forés

doi:10.1038/s41598-018-19767-3

Abstract

Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma.

Highlights

We report the discovery of a neuroprotective and pro-regenerative drug combination with the therapeutic performance mapping system (TPMS), a platform for drug discovery based on systems biology and artificial intelligence
That there should be a shift in the paradigm of drug discovery from a focus on single targets to the systems has been argued[47], in neuropathology[48]
We reasoned that proteomic profiles from suitable preclinical models of MN neurodegeneration would provide unbiased data for use as input to machine learning and mathematical modeling to search for novel drug combinations

Summary

Introduction

We report the discovery of a neuroprotective and pro-regenerative drug combination with the therapeutic performance mapping system (TPMS), a platform for drug discovery based on systems biology and artificial intelligence (www.Anaxomics.com). In order to discover such a multifunctional therapy, we built molecular maps using TPMS and quantitative and unbiased proteomic data obtained from a pre-clinical rat model of RA that leads to retrograde degeneration of MNs and from a rat model of distal axotomy (DA) and suture that leads to MN survival and nerve regeneration[6]. We screened these maps for neuroprotective combinations of FDA-approved drugs, and we validated the selected combinations in the RA model. NeuroHeal warrants further evaluation for early treatment after peripheral nerve and RA injuries

Methods

Results

Conclusion