Investigative ophthalmology & visual science · 2009
Stimulation of axon regeneration in the mature optic nerve by intravitreal application of the toll-like receptor 2 agonist Pam3Cys.
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Hauk Thomas G, Leibinger Marco, Müller Adrienne, Andreadaki Anastasia, Knippschild Uwe, Fischer Dietmar
Аннотация
PURPOSE: 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.
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.
Предметные рубрики MeSH
AnimalsAxonsAxotomyBlotting, WesternCell SurvivalCells, CulturedCiliary Neurotrophic FactorCysteineFemaleFluorescent Antibody Technique, IndirectGlial Fibrillary Acidic ProteinInjectionsJanus KinasesLipoproteinsNerve RegenerationNeuroprotective AgentsOptic NerveRatsRats, Sprague-DawleyRetinal Ganglion CellsSTAT3 Transcription FactorToll-Like Receptor 2Up-RegulationVitreous Body