Strain-specific differences in the effects of cyclosporin A and FK506 on the survival and regeneration of axotomized retinal ganglion cells in adult rats

• Published in: Neuroscience 2007-05, Vol.146 (3), p.986-999
• Main Authors: Cui, Q, Hodgetts, S.I, Hu, Y, Luo, J.-M, Harvey, A.R
• Format: Article
• Language: English
• Subjects: Animals; autoimmune disease; axonal regeneration; Axotomy; Biological and medical sciences; CD4-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - drug effects; Cell Survival - drug effects; Cyclosporine - pharmacokinetics; Cyclosporine - pharmacology; Eye and associated structures. Visual pathways and centers. Vision; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; Lymphocyte Count; Macrophages - drug effects; Macrophages - immunology; Nerve Regeneration - drug effects; Neurology; neuronal survival; peripheral nerve grafts; Rats; Rats, Inbred F344; Rats, Inbred Lew; retina; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - transplantation; Species Specificity; Tacrolimus - pharmacokinetics; Tacrolimus - pharmacology; Tubulin - biosynthesis; Vertebrates: nervous system and sense organs; visual system
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2007.02.034

Abstract The immune response can influence neuronal viability and plasticity after injury, effects differing in strains of rats with different susceptibility to autoimmune disease. We assessed the effects of i.p. injections of cyclosporin A (CsA) or FK506 on adult retinal ganglion cell (RGC) survival and axonal regeneration into peripheral nerve (PN) autografted onto the cut optic nerve of rats resistant (Fischer F344) or vulnerable (Lewis) to autoimmune disease. Circulating and tissue CsA and FK506 levels were similar in both strains. Three weeks after autologous PN transplantation the number of viable β-III tubulin-positive RGCs was significantly greater in CsA- and FK506-treated F344 rats compared with saline-injected controls. RGC survival in Lewis rats was not significantly altered. In F344 rats, retrograde labeling of RGCs revealed that CsA or FK506 treatment significantly increased the number of RGCs that regenerated an axon into a PN autograft; however these agents had no beneficial effect on axonal regeneration in Lewis rats. PN grafts in F344 rats also contained comparatively more pan-neurofilament immunoreactive axons. In both strains, 3 weeks after transplantation CsA or FK506 treatment resulted in increased retinal macrophage numbers, but only in F344 rats was this increase significant. At this time-point PN grafts in both strains contained many macrophages and some T cells. T cell numbers in Lewis rats were significantly greater than in F344 animals. The increased RGC axonal regeneration seen in CsA- or FK506-treated F344 but not Lewis rats shows that modulation of immune responses after neurotrauma has complex and not always predictable outcomes.