Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration

Abstract

Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.

Keywords: PI3K/AKT; axonal regeneration; motoneuron; motor function recovery; muscle atrophy; neurodegeneration; neuroheal; sirtuin 1; systems biology.

Figure 1

Neuroheal exerts neuroprotective and regenerative effects after peripheral nerve injury. Left, String protein network representation of minimal mechanism of action of NeuroHeal. In red are highlighted key nodes experimentally proven to be modulated by neuroheal: an increased activity of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) and serine/threonine-protein kinase protein kinase B (AKT), and an augmented presence of integrin subunit integrin beta-1 (ITGB1), kinesin-related protein KIF5 and dynactin subunit 1 (DCNT1). Right, pleiotropic effects promoted by neuroheal at different levels: the spinal cord motoneuronal soma (MNs) (blue), astrocytes (yellow), and microglia (green), the motor nerve at the peripheral nerve system (blue line), and the muscle (orange). NMJ: Neuromuscular junctions.