Interactive effects of C3, cyclic AMP and ciliary neurotrophic factor on adult retinal ganglion cell survival and axonal regeneration.
We tested whether combined therapy involving Rho inactivation, elevation of cAMP and supply of ciliary neurotrophic factor (CNTF) (i) increased axotomized adult retinal ganglion cell (RGC) survival and (ii) promoted axonal regeneration into peripheral nerve (PN) autografted onto the cut optic nerve. PN-grafted eyes were injected with combinations of a Rho-inactivating enzyme C3 transferase (C3-11), CNTF and a cell-permeant analogue of cAMP (CPT-cAMP). Four weeks after PN transplantation, RGC survival was quantified using beta-III tubulin immunohistochemistry. Regeneration was assessed using retrograde fluorogold tracing and pan-neurofilament immunostaining of grafts. Treatment with C3-11 increased RGC survival but co-injection with CPT-cAMP, CNTF or combined CNTF/CPT-cAMP did not further enhance RGC viability. There were greater numbers of regenerating RGCs after multiple C3-11 injections and regeneration was further and significantly increased after intravitreal injections of all three factors. In the combined C3-11/CNTF/CPT-cAMP treatment group about 15% of RGCs remained viable of which more than half regenerated an axon. These data emphasize the power of combinatorial pharmacotherapeutic and transplant strategies in the treatment of neurotrauma.
Hu
Ying
Y
School of Anatomy and Human Biology M309, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA 6009, Australia.
Cui
Qi
Q
Harvey
Alan R
AR
D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000367:Age Factors; D000818:Animals; D019771:Axotomy; D001905:Botulinum Toxins / Q000494:pharmacology*; D002452:Cell Count; 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; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
C488718:2'-O-methyl-8-(4-chlorophenylthio)cAMP; D020934:Ciliary Neurotrophic Factor; D013873:Thionucleotides; D014404:Tubulin; D000242:Cyclic AMP; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins