title: Transition metals and polyol pathway in the development of diabetic neuropathy in rats.
abstract: BACKGROUND
  The transition metal-catalyzed reaction is a major source of oxygen free radicals, which play an important role in vascular dysfunction leading to ischemia in diabetic tissues. The inhibition of polyol pathway hyperactivity has been reported to ameliorate neurovascular abnormalities in diabetic rats and has been proposed to improve the oxygen free radical scavenging capacity. The present study was conducted to compare the effect of a transition metal chelating agent, trientine (TRI), on diabetic neuropathy with that of an aldose reductase inhibitor, NZ-314 (NZ).
  
  
  METHODS
  Diabetic rats were divided into three groups: (1). untreated, (2). TRI-treated, and (3). NZ-treated. TRI (20 mg/kg) or NZ (100 mg/kg) was administered by gavage or chow containing NZ, respectively, for 8 weeks. Motor nerve conduction velocity (MNCV), coefficient of variation of the R - R interval on electrocardiogram (CVr-r), sciatic nerve blood flow (SNBF), platelet aggregation activities, and serum concentrations of malondialdehyde were measured.
  
  
  RESULTS
  Untreated diabetic rats showed delayed MNCV, decreased CV(R-R), and reduced SNBF compared to normal rats. TRI or NZ completely prevented these deficits. Platelet hyperaggregation activities in diabetic rats were prevented by NZ, but not by TRI. Increased concentrations of malondialdehyde in diabetic rats were partially but significantly ameliorated by either TRI or NZ.
  
  
  CONCLUSIONS
  These observations suggest that increased free radical formation through the transition metal-catalyzed reaction plays an important role in the development of diabetic neuropathy and that the preventive effect of an aldose reductase inhibitor on diabetic neuropathy may also be mediated by decreasing oxygen free radicals.
authors.affiliation: The Third Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan. jiro@tsuru.med.nagoya-u.ac.jp
authors.forename: Jiro
authors.initials: J
authors.lastname: Nakamura
authors.forename: Yoji
authors.initials: Y
authors.lastname: Hamada
authors.forename: Sadao
authors.initials: S
authors.lastname: Chaya
authors.forename: Eitaro
authors.initials: E
authors.lastname: Nakashima
authors.forename: Keiko
authors.initials: K
authors.lastname: Naruse
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamiya
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Sakakibara
authors.forename: Naoki
authors.initials: N
authors.lastname: Koh
authors.forename: Nigishi
authors.initials: N
authors.lastname: Hotta
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology*; D004562:Electrocardiography; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008670:Metals / Q000037:antagonists & inhibitors / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014266:Trientine / Q000494:pharmacology
chemical_list: C105123:3-((5-chlorobenzothiazol-2-yl)methyl)-1,2,3,4-tetrahydro-2,4-dioxopyrimidine-1-acetic acid; D001786:Blood Glucose; D002614:Chelating Agents; D008670:Metals; D011108:Polymers; D011744:Pyrimidinones; D013844:Thiazoles; C024617:polyol; D008315:Malondialdehyde; D000449:Aldehyde Reductase; D014266:Trientine