Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve.
The optic nerve is a CNS pathway containing molecules capable of inhibiting axon elongation. The growth program in embryonic retinal ganglion cell (RGC) neurons enables axons to regenerate in the optic nerve through at least two mechanisms. Namely, high cyclic AMP (cAMP) levels abrogate the ability of CNS molecules to inhibit elongation, and the pattern of gene expression enables axons to undergo rapid, sustained, and lengthy elongation. In adult mammals, recovery of visual function after optic nerve injury is limited by both the death of most RGC neurons and the inability of surviving axons to regenerate. We now report that a single intraocular injection of the membrane-permeable cAMP analogue dibutyryl cAMP (db cAMP) promotes the regeneration of RGC axons in the optic nerves of adult rats, but does not prevent the death of RGC neurons. This regeneration in optic nerves crushed within the orbit (2 mm from the eye) was equally effective either 1 day before or 1 day after db cAMP injection. The number of regenerating axons, which was maximal 14 days after crush, declined with increasing time after injury (i.e., 28, 56, and 112 days) and distance beyond the crush site (i.e., 0.25, 0.5, and 1.0 mm). Thus, db cAMP promotes optic nerve regeneration without increasing the survival of axotomized RGC neurons. Furthermore, since db cAMP does not enable axons to undergo rapid, sustained, and lengthy elongation, strategies that increase survival and promote these changes in elongation may critically complement the ability of db cAMP to promote regeneration.
Monsul
Nicholas T
NT
Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD 21287-6953, USA.
Geisendorfer
Abram R
AR
Han
Paul J
PJ
Banik
Rudrani
R
Pease
Mary Ellen
ME
Skolasky
Richard L
RL
Hoffman
Paul N
PN
D000818:Animals; D001369:Axons / Q000187:drug effects*; D003994:Bucladesine / Q000494:pharmacology*; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002772:Cholera Toxin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000378:metabolism; D009409:Nerve Crush / Q000379:methods; D009416:Nerve Regeneration / Q000187:drug effects*; D009900:Optic Nerve / Q000166:cytology / Q000187:drug effects*; D009915:Orbit / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000378:metabolism; D013266:Stilbamidines / Q000378:metabolism; D013997:Time Factors
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D005456:Fluorescent Dyes; D013266:Stilbamidines; C052635:cholera toxin, B subunit-horseradish peroxidase; D003994:Bucladesine; D002772:Cholera Toxin; D006735:Horseradish Peroxidase