Stimulation of axon regeneration in the mature optic nerve by intravitreal application of the toll-like receptor 2 agonist Pam3Cys.
OBJECTIVE
After injury of the optic nerve, mature retinal ganglion cells (RGCs) are normally unable to regenerate axons and undergo apoptosis. However, inflammatory stimulation in the eye induced by the release of beta/gamma-crystallins from the injured lens or intravitreal zymosan injection transforms RGCs into an active regenerative state, protecting these neurons from cell death and allowing them to regenerate axons back into the optic nerve.


METHODS
The authors tested whether intravitreal application of the selective, water-soluble, toll-like receptor 2 agonist Pam(3)Cys can delay axotomized RGC cell death and stimulate the regeneration of axons using an in vitro and in vivo paradigm.


RESULTS
Intravitreal injection of Pam(3)Cys, as lens injury (LI), induced the upregulation of ciliary neurotrophic factor and glial fibrillary acidic protein expression in retinal glia accompanied by the activation of the JAK/STAT3 pathway in RGCs. As a consequence, RGCs switched to a regenerative state, indicated by a significant upregulation of GAP43 expression and increased neurite outgrowth of RGCs in culture. Repeated intravitreal Pam(3)Cys application in vivo induced neuroprotective effects and caused stronger axon regeneration in the injured optic nerve than observed after LI.


CONCLUSIONS
Pam(3)Cys may be a suitable agent for stimulating CNS regeneration.
Hauk
Thomas G
TG
Department of Experimental Neurology, University of Ulm, Ulm, Germany.
Leibinger
Marco
M
Müller
Adrienne
A
Andreadaki
Anastasia
A
Knippschild
Uwe
U
Fischer
Dietmar
D
D000818:Animals; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007267:Injections; D053612:Janus Kinases / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D015854:Up-Regulation; D014822:Vitreous Body
D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D008074:Lipoproteins; D018696:Neuroprotective Agents; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D053612:Janus Kinases; D003545:Cysteine