Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons.
In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to diffusible growth factors and myelin-associated inhibitory molecules. Here we used an established in vivo model of adult central nervous system injury to investigate the effects of elevated cAMP on neuronal survival and axonal regeneration. We studied the effects of intraocular injections of neurotrophic factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of cAMP alone did not significantly increase RGC survival or the number of regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal regrowth, the latter effect substantially enhanced by coapplication with CPT-cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons. Neurotrophin-4/5 injections also increased RGC viability, but there was reduced long-distance axonal regrowth into grafts, an effect partially ameliorated by cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic factors to promote axonal regeneration in the injured adult mammalian central nervous system.
Cui
Qi
Q
School of Anatomy and Human Biology, Western Australian Institute for Medical Research, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia. cuiqi@anhb.uwa.edu.au
Yip
Henry K
HK
Zhao
Robert C H
RC
So
Kwok-Fai
KF
Harvey
Alan R
AR
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D016380:Brain Tissue Transplantation; D002232:Carbocyanines; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000637:transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000254:growth & development* / Q000293:injuries; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013266:Stilbamidines; D013873:Thionucleotides / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C035005:3,3'-dihexadecylindocarbocyanine; D002232:Carbocyanines; D020934:Ciliary Neurotrophic Factor; D005456:Fluorescent Dyes; D009414:Nerve Growth Factors; D013266:Stilbamidines; D013873:Thionucleotides; D014404:Tubulin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D016650:Fluorescein-5-isothiocyanate; C073922:neurotrophin 4