ALDOSE REDUCTASE INHIBITION INCREASES CNTF-LIKE BIOACTIVITY AND PROTEIN IN SCIATIC-NERVES FROM GALACTOSE-FED AND NORMAL RATS

The impact of exaggerated polyol pathway flux on ciliary neurotrophic factor (CNTF)-like bioactivity and expression of CNTF in rat sciatic n erve was examined after 2 months of galactose intoxication. Polyol con tent was elevated (P < 0.001) and motor nerve conduction velocity redu ced (P < 0.05) in galactose-fed rats compared with control animals or control and galactose-fed rats treated with the aldose reductase inhib itor (ARI) Ponalrestat. CNTF-like bioactivity in the galactose-fed gro up was reduced to 30% of that assayed in the control group (P < 0.001) . ARI treatment significantly increased CNTF-like bioactivity by 60% c ompared with the untreated galactose group (P < 0.05) but did not rest ore it to control levels. Unexpectedly, bioactivity in ARI-treated con trol animals was increased by nearly 250% compared with untreated cont rols (P < 0.005). In addition to the deficit in CNTF bioactivity in un treated galactose rats, the expression of protein, but not of mRNA, wa s reduced (P < 0.05). In ARI-treated control and galactose-fed rats, t he 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 myeli nated fibers toward smaller axons in galactose-fed rats that was preve nted by ARI treatment. Since galactose feeding has little impact on le vels of CNTF mRNA, these observations suggest that deficits in CNTF-li ke bioactivity may result from a posttranscriptional modification of n eurotrophic protein expression or turnover. Unlike other functional an d structural disorders in galactose neuropathy, factors other than pol yol accumulation may contribute to the deficit in CNTF-like bioactivit y.