Arginase I and Polyamines Act Downstream from Cyclic AMP in Overcoming Inhibition of Axonal Growth MAG and Myelin In Vitro

Elevation of cAMP can overcome myelin inhibitors to encourage regeneration of the CNS. We show that a consequence of elevated cAMP is the synthesis of polyamines, resulting from an up-regulation of Arginase I, a key enzyme in their synthesis. Inhibiting polyamine synthesis blocks the cAMP effect on...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2002-08, Vol.35 (4), p.711-719
Main Authors: Cai, Dongming, Deng, Kangwen, Mellado, Wilfredo, Lee, Junghee, Ratan, Rajiv R, Filbin, Marie T
Format: Article
Language:English
Subjects:
Animals
Arginase - biosynthesis
Arginase - genetics
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - pharmacology
Bucladesine - pharmacology
Central Nervous System - cytology
Central Nervous System - growth & development
Central Nervous System - metabolism
CHO Cells
Cricetinae
Cyclic AMP - metabolism
DNA, Complementary - genetics
Down-Regulation - drug effects
Down-Regulation - genetics
Enzyme Inhibitors - pharmacology
Ganglia, Spinal - drug effects
Ganglia, Spinal - growth & development
Ganglia, Spinal - metabolism
Gene expression
Growth Cones - drug effects
Growth Cones - metabolism
Growth Cones - ultrastructure
Kinases
Molecular Sequence Data
Myelin Sheath - metabolism
Myelin-Associated Glycoprotein - biosynthesis
Nerve Growth Factors - pharmacology
Nerve Regeneration - physiology
Neurons
Polyamines
Polyamines - antagonists & inhibitors
Polyamines - metabolism
Putrescine - pharmacology
Rats
Transcription, Genetic - drug effects
Transcription, Genetic - physiology
Transfection
Up-Regulation - drug effects
Up-Regulation - physiology
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Summary:Elevation of cAMP can overcome myelin inhibitors to encourage regeneration of the CNS. We show that a consequence of elevated cAMP is the synthesis of polyamines, resulting from an up-regulation of Arginase I, a key enzyme in their synthesis. Inhibiting polyamine synthesis blocks the cAMP effect on regeneration. Either over-expression of Arginase I or exogenous polyamines can overcome inhibition by MAG and by myelin in general. While MAG/myelin support the growth of young DRG neurons, they become inhibitory as DRGs mature. Endogenous Arginase I levels are high in young DRGs but drop spontaneously at an age that coincides with the switch from promotion to inhibition by MAG/myelin. Over-expressing Arginase I in maturing DRGs blocks that switch. Arginase I and polyamines are more specific targets than cAMP for intervention to encourage regeneration after CNS injury.
ISSN:0896-6273
1097-4199
DOI:10.1016/S0896-6273(02)00826-7