Fig. 1

Proposed targets for neuroprotective therapies. The pathways involved in neuroprotection include 1) Active axonal degeneration pathway activation (mediated by depletion of NAD levels by NMNAT2, PHR1 and Sarm1 activation); 2) trophic factor signaling (PI3K, MAPKK, NFkB); 3) oxidative stress (induced by inflammatory cells and mitochondria dysfunction); 4) energy depletion (due to mitochondria impairment and increased demand from Ca channels); 5) axonal transport blockade (failing to deliver mitochondria, signaling and molecular complexes to soma, nodes of Ranvier or synpasis); 6) ionic imbalance (due to ion channel redistribution and changes in activity, leading to increase of intracellular calcium); 7) Excitotoxicity (mediated by excess of glutamate signaling through the NMDA receptors); 8) remyelination (from OPC repopulation of demyelinated areas to myelination of denuded axons by mature oligodendrocytes (OG), which provide metabolic support to the axon (NAA or PC); 9) protective effects of astrocytes (providing trophic factors such as IGF-1 or BDNF, metabolic substrates such as lactate, or pro-survival signals such as CD200-CD200L) and M2 microglia (with scavenger and tissue healing activity)