Network-based therapeutic approach for brain ischemia: A broad therapy for a specific patient

Despite years of efforts, translational stroke research has yield to no neuroprotective therapy. Moreover, only single-drug targets remain hitherto being pursued whilst we know that complex diseases are defined by multitarget modules which should be tackled simultaneously ( Fig. 1A). Therefore, we here propose a network-based approach for multi-target identification based on human disease genes linked to ischemic stroke, in combination with a network pharmacology, drug repurposing therapeutic approach. Indeed, network pharmacology exploits this concept by simultaneously targeting several components of an impaired signalling pathway, using mechanistically related and thus synergistic drugs with a maximal therapeutic effect. Upon stroke, the proposed in silico-based network pharmacology therapy significantly improved reduced infarct volume in line with improved neuro-motor functioning until 14 days after stroke induction ( Fig. 1B-C). RNA sequencing and subsequent gene set enrichment analysis revealed an upregulation of genes modulating synaptic plasticity, while neuroinflammatory and infiltration-related pathways were significantly downregulated ( Fig. 1D). In line with these findings, histological assessment confirmed a reduced neuronal cell death, astrogliosis, microglia activation in the penumbra. This blood-brain barrier stabilising effect was associated with a diminished abundance of infiltrated immune cells during the sub-acute phase after cerebral ischaemia and furthermore decreased concentration of pro-inflammatory cytokines such as TNF-α and GM-CSF in treated animals. However, it remains evident that not all stroke patients suffer from the same dysregulated mechanisms upon stroke. Then, we propose to combine a network pharmacology therapeutic approach with diagnostic endothenotyping of patients who could maximally benefit from our proposed therapy; thus ensuring a personalised, mechanism-based, synergistic therapy with a quick access to the pharmaceutic market.