Functional regeneration in the CNS is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. A principal, yet unresolved question is the interaction between these two major factors. We thus evaluated the role of pharmacological inhibition of rho kinase (ROCK), a key mediator of myelin-derived axonal growth inhibition and CNTF, a potent neurotrophic factor for retinal ganglion cells (RGC), in models of retinal ganglion cell apoptosis and neurite outgrowth/regeneration in vitro and in vivo. Here, we show for the first time that the ROCK inhibitor Y-27632 significantly enhanced survival of RGC in vitro and in vivo. In vitro, the co-application of CNTF and Y-27632 potentiated the effect of either substance alone. ROCK inhibition resulted in the activation of the intrinsic MAPK pathway, and the combination of CNTF and Y-27632 resulted in even more pronounced MAPK activation. While CNTF also induced STAT3 phosphorylation, the additional application of ROCK inhibitor surprisingly diminished the effects of CNTF on STAT3 phosphorylation. ROCK activity was also decreased in an additive manner by both substances. In vivo, both CNTF and Y-27632 enhanced regeneration of RGC into the non-permissive optic nerve crush model and additive effects were observed after combination treatment. Further evaluation using specific inhibitors delineate STAT3 as a negative regulator of neurite growth and positive regulator of cell survival, while MAPK and Akt support neurite growth. These results show that next to neurotrophic factors ROCK inhibition by Y-27632 potently supports survival of lesioned adult CNS neurons. Co-administration of CNTF and Y-27632 results in additive effects on neurite outgrowth and regeneration. The interaction of intracellular signalling pathways may, however, attenuate more pronounced synergy and has to be taken into account for future treatment strategies.

The X-ray diffraction analysis of crystals of {[Me2N(CH2)3]2SnF2·2H2O (3a) obtained by reaction of [Me2N(CH2)3]2SnR2 (R = Me, Ph) with Pr3SnF reveals a six-coordinate, distorted octahedral geometry at tin with the pairs of fluorine, nitrogen and carbon atoms bound to the metal atom being all in a mutual trans configuration. Room-temperature 119Sn, 19F, 1H, and 13C NMR spectra of 3a reveal exchange averaging with loss of the 1 J(119Sn−19F) coupling on the 119Sn and 19F NMR time scales. Below −50 °C, 119Sn and 19F NMR coupling data evidence the existence of only two isomers among the five a priori possible ones, a major (ca. 80%) and a minor species (ca. 20%). The methyl 13C resonance as well as the 1 J(119Sn−19F), 1 J(119Sn−13C), and 2 J(19F−13C) coupling patterns reveal the major species to have the same all-trans structure as in the crystal state, while the minor species has a cis arrangement for its fluorine and nitrogen atoms and the trans one for its carbon atoms. Gradient assisted 1H−119Sn HMQC spectroscopy establishes 3 J(119Sn−1H) correlations through the Me2N→Sn bond to exist in both slow- and fast-exchange ranges. Together with the loss of the 1 J(119Sn−19F) coupling at high temperature, this evidences the Me2N→Sn coordination to be maintained during the cis−trans isomerization and the latter to occur through a dissociative mechanism involving tin−fluorine bond rupture. Addition of Bu4N+F-·3H2O in CH2Cl2 yields under quaternization of one nitrogen zwitterionic {[Me2(ClCH2)N+(CH2)3][Me2N(CH2)3]SnF3 -}·H2O (3b).

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The syntheses of [Me2N(CH2)3]2Sn(EAr)2 (1, E = O, Ar = C6H5; 2, E = O, Ar = p-t-BuC6H4; 3, E = O, Ar = p-NO2C6H4; 4, E = O, Ar = o-FC6H4; 7, E = S, Ar = C6H5), [Me2N(CH2)3]2Sn(o-O2C6H3R-3) (5, R = H; 6, R = OCH3), and {[Me2N(CH2)3]2SnPh}+I- (8) are reported. X-ray diffraction analyses reveal distorted-octahedral geometries for the tin atoms in compounds 1−7 with, except for the stannaindane derivative 5, the carbon atoms in mutually trans positions, while the nitrogen and oxygen atoms are cis. In compound 5, the carbon atoms are cis, whereas the nitrogen atoms are trans. Compound 8, in contrast, is ionic and consists of an intramolecularly pentacoordinated triorganotin cation and an iodide anion. Variable-temperature 1H, 13C, and 119Sn NMR investigations reveal the compounds to have similar structures in solution. The coalescence phenomena observed in the 1H and 13C NMR spectra are explained both in terms of Sn−O bond cleavage (1−4) and chirality inversion through a sequence of five intramolecular Berry-type pseudorotations (1−4, 8), interconverting the enantiomers with propeller-like geometry. The dynamic behavior in solution of the stannaindane derivatives 5 and 6 and of the thiophenolate derivative 7 is interpreted in terms of intramolecular Sn−N bond dissociation.

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