Polyol pathway hyperactivity is closely related to carnitine deficiency in the pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats.
To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.
Nakamura
J
J
The Third Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan.
Koh
N
N
Sakakibara
F
F
Hamada
Y
Y
Hara
T
T
Sasaki
H
H
Chaya
S
S
Komori
T
T
Nakashima
E
E
Naruse
K
K
Kato
K
K
Takeuchi
N
N
Kasuya
Y
Y
Hotta
N
N
D000108:Acetylcarnitine / Q000627:therapeutic use; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D002331:Carnitine / Q000032:analysis / Q000172:deficiency*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications; D003929:Diabetic Neuropathies / Q000097:blood / Q000188:drug therapy / Q000209:etiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D011108:Polymers / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000098:blood supply; D013777:Tetrazoles / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D011108:Polymers; D013777:Tetrazoles; D013876:Thiophenes; C024617:polyol; C080974:(5-(3-thienyl)tetrazol-1-yl)acetic acid; D000108:Acetylcarnitine; D000449:Aldehyde Reductase; C023142:polyol dehydrogenase (NADP); D002331:Carnitine