Increased synthesis of spermidine as a result of upregulation of arginase I promotes axonal regeneration in culture and in vivo.
Adult spinal axons do not spontaneously regenerate after injury. However, if the peripheral branch of dorsal root ganglion neurons is lesioned before lesioning the central branch of the same neurons in the dorsal column, these central axons will regenerate and, if cultured, are not inhibited from extending neurites by myelin-associated inhibitors of regeneration such as myelin-associated glycoprotein (MAG). This effect can be mimicked by elevating cAMP and is transcription dependent. The ability of cAMP to overcome inhibition by MAG in culture involves the upregulation of the enzyme arginase I (Arg I) and subsequent increase in synthesis of polyamines such as putrescine. Now we show that a peripheral lesion also induces an increase in Arg I expression and synthesis of polyamines. We also show that the conditioning lesion effect in overcoming inhibition by MAG is initially dependent on ongoing polyamine synthesis but, with time after lesion, becomes independent of ongoing synthesis. However, if synthesis of polyamines is blocked in vivo the early phase of good growth after a conditioning lesion is completely blocked and the later phase of growth, when ongoing polyamine synthesis is not required during culture, is attenuated. We also show that putrescine must be converted to spermidine both in culture and in vivo to overcome inhibition by MAG and that spermidine can promote optic nerve regeneration in vivo. These results suggest that spermidine could be a useful tool in promoting CNS axon regeneration after injury.
Deng
Kangwen
K
Biology Department, Hunter College, New York, New York 10065, USA.
He
Huifang
H
Qiu
Jin
J
Lorber
Barbara
B
Bryson
J Barney
JB
Filbin
Marie T
MT
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000201:enzymology / Q000502:physiology; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D009900:Optic Nerve / Q000201:enzymology / Q000502:physiology; D020221:Optic Nerve Injuries / Q000201:enzymology / Q000503:physiopathology; D011073:Polyamines / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012584:Sciatic Nerve / Q000201:enzymology / Q000293:injuries / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013095:Spermidine / Q000378:metabolism*; D015854:Up-Regulation
D018992:Myelin-Associated Glycoprotein; D011073:Polyamines; D001119:Arginase; C542908:arginase I, rat; D013095:Spermidine; D011700:Putrescine