Transition metals and polyol pathway in the development of diabetic neuropathy in rats.
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.
Nakamura
Jiro
J
The Third Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan. jiro@tsuru.med.nagoya-u.ac.jp
Hamada
Yoji
Y
Chaya
Sadao
S
Nakashima
Eitaro
E
Naruse
Keiko
K
Kato
Koichi
K
Yasuda
Yutaka
Y
Kamiya
Hideki
H
Sakakibara
Fumihiko
F
Koh
Naoki
N
Hotta
Nigishi
N
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
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