The impact of exaggerated polyol pathway flux on ciliary neurotrophic factor (CNTF)-like bioactivity and expression of CNTF in rat sciatic nerve was examined after 2 months of galactose intoxication. Polyol content was elevated (P < 0.001) and motor nerve conduction velocity reduced (P < 0.05) in galactose-fed rats compared with control animals or control and galactose-fed rats treated with the aldose reductase inhibitor (ARI) Ponalrestat. CNTF-like bioactivity in the galactose-fed group was reduced to 30% of that assayed in the control group (P < 0.001). ARI treatment significantly increased CNTF-like bioactivity by 60% compared with the untreated galactose group (P < 0.05) but did not restore it to control levels. Unexpectedly, bioactivity in ARI-treated control animals was increased by nearly 250% compared with untreated controls (P < 0.005). In addition to the deficit in CNTF bioactivity in untreated galactose rats, the expression of protein, but not of mRNA, was reduced (P < 0.05). In ARI-treated control and galactose-fed rats, the expression of CNTF peptide was significantly enhanced above control levels (both P < 0.05). Concomitant with the reduction in CNTF levels, there was a shift in the axonal size-frequency distribution of myelinated fibers toward smaller axons in galactose-fed rats that was prevented by ARI treatment. Since galactose feeding has little impact on levels of CNTF mRNA, these observations suggest that deficits in CNTF-like bioactivity may result from a posttranscriptional modification of neurotrophic protein expression or turnover. Unlike other functional and structural disorders in galactose neuropathy, factors other than polyol accumulation may contribute to the deficit in CNTF-like bioactivity.
Aldose Reductase Inhibition Increases CNTF-Like Bioactivity and Protein in Sciatic Nerves From Galactose-Fed and Normal Rats
ANOVA, analysis of variance; AR, aldose reductase; ARI, aldose reductase inhibitor; CNTF, ciliary neurotrophic factor; E8CG, embryonic chick ciliary ganglia; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde phosphate dehydrogenase; LIF, leukemia inhibitory factor; MNCV, motor nerve conduction velocity.
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Andrew P Mizisin, Nigel A Calcutt, Peter S DiStefano, Ann Acheson, Frank M Longo; Aldose Reductase Inhibition Increases CNTF-Like Bioactivity and Protein in Sciatic Nerves From Galactose-Fed and Normal Rats. Diabetes 1 April 1997; 46 (4): 647–652. https://doi.org/10.2337/diab.46.4.647
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