Amphotericin B, identified from a natural product screen, antagonizes CNS inhibitors to promote axon growth via activation of an Akt pathway in neurons

TY - JOUR

T1 - Amphotericin B, identified from a natural product screen, antagonizes CNS inhibitors to promote axon growth via activation of an Akt pathway in neurons

AU - Gao, Ying

AU - Deng, Kangwen

AU - Cao, Zixuan

AU - Graziani, Edmund I.

AU - Gilbert, Adam M.

AU - Koehn, Frank E.

AU - Wood, Andrew

AU - Doherty, Patrick

AU - Walsh, Frank S.

PY - 2010/6

Y1 - 2010/6

N2 - P>One of the major barriers to successful axon regeneration in the adult CNS is the presence of inhibitory molecules that originate from the myelin sheath and glial scar. So far, only a small number of pharmacological compounds have exhibited functional activity against CNS inhibitors in promoting axon regeneration after injury. To search for novel compounds that enhance neurite outgrowth in vitro, we initiated a screen of a collection of natural products. We identified four compounds with the potential to promote growth over a myelin substrate. Of these, Amphotericin B (AmB) was shown to enhance neurite outgrowth and antagonize activities of major myelin associated inhibitors and glial-scar-derived chondroitin sulfate proteoglycans. AmB was found to activate Akt and thereby suppress the activity of glycogen synthase kinase 3 beta. Also, a cell permeable peptide that inhibits Akt activity was shown to block the effect of AmB in promoting axonal growth, while another peptide that increases Akt activity stimulated axonal growth in the presence of the myelin associated inhibitors. Our results suggest that AmB can promote neurite outgrowth over a wide range of inhibitory substrates via a mechanism that involves activation of Akt.

AB - P>One of the major barriers to successful axon regeneration in the adult CNS is the presence of inhibitory molecules that originate from the myelin sheath and glial scar. So far, only a small number of pharmacological compounds have exhibited functional activity against CNS inhibitors in promoting axon regeneration after injury. To search for novel compounds that enhance neurite outgrowth in vitro, we initiated a screen of a collection of natural products. We identified four compounds with the potential to promote growth over a myelin substrate. Of these, Amphotericin B (AmB) was shown to enhance neurite outgrowth and antagonize activities of major myelin associated inhibitors and glial-scar-derived chondroitin sulfate proteoglycans. AmB was found to activate Akt and thereby suppress the activity of glycogen synthase kinase 3 beta. Also, a cell permeable peptide that inhibits Akt activity was shown to block the effect of AmB in promoting axonal growth, while another peptide that increases Akt activity stimulated axonal growth in the presence of the myelin associated inhibitors. Our results suggest that AmB can promote neurite outgrowth over a wide range of inhibitory substrates via a mechanism that involves activation of Akt.

U2 - 10.1111/j.1471-4159.2010.06704.x

DO - 10.1111/j.1471-4159.2010.06704.x

M3 - Article

VL - 113

SP - 1331

EP - 1342

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

IS - 5

ER -