Abstract
Semaphorin3A is considered a classical repellent molecule for developing neurons and a potent inhibitor of regeneration after nervous system trauma. Vinaxanthone and other Sema3A inhibitors are currently being tested as possible therapeutics to promote nervous system regeneration from injury. Our previous study on Sema3A demonstrated a switch in Sema3A’s function toward induction of nerve regeneration in adult murine corneas and in culture of adult peripheral neurons. The aim of the current study is to determine the direct effects of Vinaxanthone on the Sema3A induced adult neuronal growth. We first demonstrate that Vinaxanthone maintains its anti-Sema3A activity in embryonic dorsal root ganglia neurons by inhibiting Sema3A-induced growth cone collapse. However, at concentrations approximating its IC50 Vinaxanthone treatment does not significantly inhibit neurite formation of adult peripheral neurons induced by Sema3A treatment. Furthermore, Vinaxanthone has off target effects when used at concentrations above its IC50, and inhibits neurite growth of adult neurons treated with either Sema3A or NGF. Our results suggest that Vinaxanthone’s pro-regenerative effects seen in multiple in vivo models of neuronal injury in adult animals need further investigation due to the pleiotropic effect of Sema3A on various non-neuronal cell types and the possible effect of Vinaxanthone on other neuroregenerative signals.
Highlights
Semaphorins are a glycoprotein family of which five classes appear in vertebrates and most commonly bind plexin and neuropilin receptors
Because Semaphorin proteins play a role in inflammation, angiogenesis, and remyelination of neurons[18,24], we undertook our current study to test the effects of Vinaxanthone, a described specific inhibitor of Sema3A, on isolated neurons, separating the effects of other cell types involved in neuronal growth
We tested if Vinaxanthone (Vx) could block both the axonal growth cone collapse induced by Sema3A in embryonic neurons and the growth promoting effects induced by Sema3A in adult neurons
Summary
Semaphorins are a glycoprotein family of which five classes appear in vertebrates and most commonly bind plexin and neuropilin receptors. Because Semaphorin proteins play a role in inflammation, angiogenesis, and remyelination of neurons[18,24], we undertook our current study to test the effects of Vinaxanthone, a described specific inhibitor of Sema3A, on isolated neurons, separating the effects of other cell types involved in neuronal growth. We tested if Vinaxanthone (Vx) could block both the axonal growth cone collapse induced by Sema3A in embryonic neurons and the growth promoting effects induced by Sema3A in adult neurons. This approach allowed us to examine if this inhibitor acts directly on Sema3A activity in neurons or if its pro-regenerative effect seen in vivo may be related to additional targets involved in nerve regeneration
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