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of RGCs by intravitreal injection of Ad CNTF was reported 7, 14, and 21 days following optic nerve axotomy. Long term CNTF delivery was achieved Dynasore by lentiviral or AAV vector mediated CNTF gene transfer. Considerable RGC survival was observed on day 14 and 21 following intravitreal injection of LV CNTF at the time of optic nerve transaction. Long term survival of RGCs following optic nerve crush or crush plus ischemia was also observed in experiments with AAV CNTF. The number of RGCs in the treated retinas was four times greater than those in the manage retinas when RGCs were counted 7 weeks following optic nerve crush. In experiments with optic nerve crush plus ischemia, the RGC survival in AAV CNTF treated retinas was virtually 6 times greater Dynasore than in controls.
A study utilizing AAV CNTF in laser Ponatinib induced glaucoma in rats demonstrated that the loss of ganglion cell axons was considerably lower in treated retinas than in controls. A recent study showed that in an optic nerve transaction rat model, delivery of AAV CNTF in combination with CNTF protein and CPT cAMP following transaction provided greater RCG protection and axon regeneration than administration of AAV CNTF or CNTF protein plus CPT cAMP alone. The injection of CNTF protein plus CPT cAMP gives instant protection to the RCGs whereas the AAV CNTF, with a delay in the transgene expression, gives long term protection. 7. 2. Axogenesis CNTF is additionally an axogenesis element. In the presence of CNTF inside a serum free medium, purified rat RGCs showed substantial long neurite outgrowth. CNTF treatment also promotes axon regeneration in vivo.
Enhanced RGC axon regeneration into peripheral nerve grafts following axotomy occurs with intravitreal CNTF injection in hamsters, mice, and rats. CNTF secreting Schwann cells carrying Haematopoiesis lentiviral mediated CNTF cDNA were utilized to reconstruct peripheral nerve grafts by seeding them to peripheral nerve sheaths. Such grafts induced significant improve in survival and axonal regeneration in rat RGCs when sutured to the proximal stumps following optic nerve transaction. Furthermore, Ponatinib endogenous CNTF has been shown to be among the important variables that mediate lens injury induced axon regeneration. Working with CNTF knock out and CNTF/LIF double knock out mice, Leibinger and colleagues demonstrated that lens injury induced axon regeneration and neuroprotection following optic nerve crush depend on endogenous CNTF and LIF.
In the study discussed in section 7. 1, delivery of AAV CNTF in combination with CNTF protein and CPT cAMP following optic nerve transaction also resulted in greater RCG axon regeneration Dynasore than AAV CNTF or CNTF protein plus CPT cAMP alone. The findings that intravitreal injection of CNTF induces phosphorylation of STAT3 in RGCs, and that CNTF protects RGCs and promotes neurite outgrowth in culture RGCs indicate that CNTF acts directly on RGCs. A study in the optic nerve crush model showed that CNTF stimulated axon regeneration is significantly enhanced when the SOCS3 gene is deleted in RGCs, providing additional evidence that CNTF directly acts on RGCs.
These experiments, indicating that CNTF promotes the survival of RGCs and also stimulates axon regeneration, give experimental evidence for taking into consideration the clinical application of CNTF for ganglion cell degeneration, like in glaucoma, retinal ischemia, as well as other optic nerve injuries. 8. CNTF and RPE cells The effects of CNTF on the RPE cells have recently Ponatinib been studied by Li and colleagues. Working with primary cultures of human fetal RPE cells that were physiologically and molecularly comparable to native human tissue, they confirmed that all three receptor subunits for CNTF binding, CNTFR, gp130, and LIFB, are present on the apical membrane of RPE cells and that CNTF administration induces a significant improve in STAT3 phosphorylation. An important locating in the study was that CNTF considerably increases the active ion linked fluid absorption across the RPE via cystic fibrosis transmembrane conductance regulator, which is specifically blocked by an CFTR inhibitor.
Furthermore, administration of CNTF increases the survival of RPE cells and modulates Dynasore the secretion Ponatinib of a number of neurotrophic variables and cytokines from the apical side, including an increase in NT3 secretion, and decreases in VEGF, TGFB2, and IL 8 secretion. The improve in RPE cell survival observed in this study is consistent with the prior locating in rat RPE cells, in which significant improve in cell survival was noticed in primary culture of rat RPE cells and an immortalized rat cell line BPEI 1 in the presence of CNTF or LIF. RPE is often a monolayer of polarized epithelial cells situated among the neuronal retina and also the choroidal blood supply, an essential component from the blood retinal barrier. Ions, fluid, nutrients, and metabolic waste merchandise are selectively transported among the neuronal retina and also the choriocapillaris. The improve in fluid transport from the apical to the basal side suggests that additionally to neuroprotection, CNTF could support t