Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Arginase / biosynthesis*
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Arginase / genetics
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Brain-Derived Neurotrophic Factor / pharmacology
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Bucladesine / pharmacology
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CHO Cells
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Central Nervous System / cytology
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Central Nervous System / growth & development*
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Central Nervous System / metabolism
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Cricetinae
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Cyclic AMP / metabolism*
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DNA, Complementary / genetics
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Enzyme Inhibitors / pharmacology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / growth & development
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Ganglia, Spinal / metabolism
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Growth Cones / drug effects
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Molecular Sequence Data
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Myelin Sheath / metabolism*
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Myelin-Associated Glycoprotein / biosynthesis*
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Nerve Growth Factors / pharmacology
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Nerve Regeneration / physiology
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Polyamines / antagonists & inhibitors
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Polyamines / metabolism*
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Putrescine / pharmacology
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Rats
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
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Transfection
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Brain-Derived Neurotrophic Factor
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DNA, Complementary
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Enzyme Inhibitors
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Myelin-Associated Glycoprotein
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Nerve Growth Factors
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Polyamines
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Bucladesine
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Cyclic AMP
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Arginase
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Putrescine