The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3',5'-monophosphate (Epac) for central nervous system trauma.

Millions of people worldwide are affected by traumatic spinal cord injury, which usually results in permanent sensorimotor disability. Damage to the spinal cord leads to a series of detrimental events including ischaemia, haemorrhage and neuroinflammation, which over time result in further neural tissue loss. Eventually, at chronic stages of traumatic spinal cord injury, the formation of a glial scar, cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.

Epac2 Elevation Reverses Inhibition by Chondroitin Sulfate Proteoglycans and Transforms Postlesion Inhibitory Environment to Promote Axonal Outgrowth in an Model of Spinal Cord Injury.

Millions of patients suffer from debilitating spinal cord injury (SCI) without effective treatments. Elevating cAMP promotes CNS neuron growth in the presence of growth-inhibiting molecules. cAMP's effects on neuron growth are partly mediated by Epac, comprising Epac1 and Epac2; the latter predominantly expresses in postnatal neural tissue.

The cAMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by cAMP.

Aims: During restenosis, vascular smooth muscle cells (VSMCs) migrate from the vascular media to the developing neointima. Preventing VSMC migration is therefore a therapeutic target for restenosis. Drugs, such as prostacyclin analogues, that increase the intracellular concentration of cyclic adenosine monophosphate (cAMP) can inhibit VSMC migration, but the mechanisms via which this occurs are unknown.

Mammalian growth cone turning assays identify distinct cell signalling mechanisms that underlie axon growth, guidance and regeneration.

The cell signalling mechanisms underlying mammalian central nervous system axon growth and guidance change during development, such that axons that establish appropriate connectivity in the embryo fail to regenerate after injury to the adult nervous system. The growth cone turning assay has been used in Xenopus neurons to elucidate mechanisms of axon guidance during development. Here, we describe how we have adapted this assay for rat dorsal root ganglion neurons to study the influence of extracellular secreted factors causing growth cone attraction and repulsion.

VEGF signaling through neuropilin 1 guides commissural axon crossing at the optic chiasm.

During development, the axons of retinal ganglion cell (RGC) neurons must decide whether to cross or avoid the midline at the optic chiasm to project to targets on both sides of the brain. By combining genetic analyses with in vitro assays, we show that neuropilin 1 (NRP1) promotes contralateral RGC projection in mammals. Unexpectedly, the NRP1 ligand involved is not an axon guidance cue of the class 3 semaphorin family, but VEGF164, the neuropilin-binding isoform of the classical vascular growth factor VEGF-A.