Coexistence of nerve conduction deficit with increased Na(+)-K(+)-ATPase activity in galactose-fed mice. Implications for polyol pathway and diabetic neuropathy.
We measured motor nerve conduction velocity (MNCV), Na(+)-K(+)-ATPase activity, polyol-pathway metabolites, and myo-inositol in sciatic nerves from control mice, galactose-fed (20% wt/wt diet) mice, and galactose-fed mice given the aldose reductase inhibitor ponalrestat (300-mg/kg diet). Treatments were maintained for 4 wk. Galactose feeding was associated with a 21.5% reduction in MNCV (P less than 0.001), which was almost completely prevented by ponalrestat. Galactose-fed mice showed an 81% increase in Na(+)-K(+)-ATPase (P less than 0.01), an effect completely prevented by aldose reductase inhibition. Treatment of a separate galactose-fed group with sorbinil (300 mg/kg diet) also attenuated the MNCV deficit and prevented the increased Na(+)-K(+)-ATPase activity associated with galactosemia. Accumulation of galactitol in the nerves of galactose-fed mice was prevented by aldose reductase inhibition, but there were no alterations in myo-inositol levels in the sciatic nerves of any group. These data show that exaggerated flux through the polyol pathway can cause an MNCV deficit that is unrelated to either myo-inositol levels or NA(+)-K(+)-ATPase activity.
Calcutt
N A
NA
Department of Pharmacology, St. Bartholomew's Hospital Medical College, London, United Kingdom.
Tomlinson
D R
DR
Biswas
S
S
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D003929:Diabetic Neuropathies / Q000209:etiology*; D004032:Diet; D005260:Female; D005690:Galactose / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009132:Muscles / Q000187:drug effects / Q000294:innervation; D009420:Nervous System / Q000187:drug effects / Q000201:enzymology; D009424:Nervous System Physiological Phenomena; D009431:Neural Conduction; D010793:Phthalazines / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D010793:Phthalazines; D011108:Polymers; C024617:polyol; C042829:ponalrestat; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; D005690:Galactose