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 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.
Mizisin
A P
AP
Department of Pathology, University of California, San Diego, La Jolla 92093-0612, USA. amizisin@ucsd.edu
Calcutt
N A
NA
DiStefano
P S
PS
Acheson
A
A
Longo
F M
FM
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001681:Biological Assay; D015152:Blotting, Northern; D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005690:Galactose / Q000633:toxicity*; D009414:Nerve Growth Factors / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D010793:Phthalazines; D012333:RNA, Messenger; C042829:ponalrestat; D000449:Aldehyde Reductase; D005690:Galactose