Prevention of some electrophysiologic and biochemical abnormalities with oxygen supplementation in experimental diabetic neuropathy.

Low, Phillip A.; Tuck, R. R.; Dyck, Peter J.; Schmelzer, James D.; Yao, Jeffrey

doi:10.1073/pnas.81.21.6894

Cited by 108 publications

(44 citation statements)

References 37 publications

(45 reference statements)

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“…The normalization of NBF before electrophysiologic abnormalities would be the correct sequence if the late electrophysiologic abnormalities were due to ischemia. This information could provide further support to earlier data on the prevention of electrophysiologic abnormalities with ox- ygen supplementation (8) and normalization of CNAP with hyperbaric oxygenation (9).…”

Section: Discussionsupporting

confidence: 75%

“…Platelet thromboxane B2 is increased (3)(4)(5)(6), resulting in a reduced prostacyclin/ thromboxane ratio and resultant vasoconstriction. Improvement in blood flow by chemical sympathectomy (7) or an increase in the oxygen supply by supplementation (8) or hyperbaric oxygenation (9) has been shown to improve nerve electrophysiology. Although these findings implicate perturbed microvascular physiology, the mechanism(s) by which chronic hyperglycemia results in a reduction in NBF is uncertain.…”

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confidence: 99%

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Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

Kihara

Schmelzer

Poduslo

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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189

110

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Since advanced glycosylation end products have been suggested to mediate hyperglycemia-induced microvascular atherogenesis and because aminoguanidine (AG) prevents their generation, we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. Four groups of adult Sprague-Dawley rats were studied: group I received STZ plus AG (25 mg kg'1 day-1), group II received STZ plus AG (50 mg-kg'1day-1), group HI received STZ alone, and group IV was a control. We monitored conduction and action potential amplitudes serially in sciatic-tibial and caudal nerves, nerve blood flow, oxygen free radical activity (conjugated dienes and hydroperoxides), and the product ofthe permeability coefficient and surface area to 125I-labeled albumin. STZ-induced diabetes (group HI) caused a 57% reduction in nerve blood flow and in abnormal nerve conduction and amplitudes and a 60% increase in conjugated dienes. Nerve blood flow was normalized by 8 weeks with AG (groups I and II) and conduction was significantly improved, in a dosedependent manner, by 16 and 24 weeks in sciatic-tibial and caudal nerves, respectively. The permeability coefficient was not impaired, suggesting a normal blood-nerve barrier function for albumin, and the oxygen free-radical indices were not ameliorated by AG. We suggest that AG reverses nerve ischemia and more gradually improves their electrophysiology by an action on nerve microvessels. AG may have potential in the treatment of diabetic neuropathy.In chronic experimental diabetic neuropathy, nerve blood flow (NBF) is reduced and the oxygen tension histogram is shifted into the hypoxic range (1). Nerve biosynthesis of 6-keto-prostaglandin Fia, the stable metabolite of prostacyclin, is significantly reduced in chronic, but not in acute, experimental diabetic neuropathy (2). Platelet thromboxane B2 is increased (3-6), resulting in a reduced prostacyclin/ thromboxane ratio and resultant vasoconstriction. Improvement in blood flow by chemical sympathectomy (7) or an increase in the oxygen supply by supplementation (8) or hyperbaric oxygenation (9) has been shown to improve nerve electrophysiology. Although these findings implicate perturbed microvascular physiology, the mechanism(s) by which chronic hyperglycemia results in a reduction in NBF is uncertain. It has been suggested that advanced glycosylation end products (AGE) may mediate hyperglycemiainduced microvascular atherogenesis (10, 11). Since aminoguanidine (AG) prevents AGE generation and has been reported to prevent basal lamina thickening in diabetic rats (10, 11), we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. METHODS Experimental Diabetic Neuropathy. We used male SpragueDawley rats weighing -250 g. They were separated into four groups of 16 animals each: group I or AG25 received STZ plus AG (25 mg kg-1-day-1), group II or AG50 received STZ plus AG...

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

Kihara

Schmelzer

Poduslo

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

189

110

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“…In experimental diabetic rats, reduction in nerve blood flow and decrease in endoneurial oxygen tension in the sciatic nerve have been attributed to ischemia in the endoneurium (1). Electrophysiological and biochemical abnormalities were improved with oxygen supplementa tion in these animals (2). Furthermore, involvement of the ischemic process in the development of neuropathy has been demonstrated by morphological studies with biopsied human nerve samples (3,5).…”

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confidence: 87%

Effects of Beraprost Sodium, a Prostacyclin Analogue, on Diabetic Neuropathy in Streptozotocin-Induced Diabetic Rats

Ueno

Koike

Nakamura

et al. 1996

Japanese Journal of Pharmacology

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ABSTRACT-The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on motor nerve con duction velocity and nerve blood flow of the sciatic nerve were investigated in streptozotocin-induced dia betic rats, and they were compared with the effects of epalrestat (aldose reductase inhibitor). Treatment with BPS for 4 weeks significantly inhibited the decrease in motor nerve conduction velocity and nerve blood flow dose-dependently, but epalrestat had no effect on nerve blood flow. Morphological changes of the myelinated fibers of the sciatic nerve were observed macroscopically. The mean axonal area and the mean circularity index of diabetic control rats were significantly less than that of normal rats, while after 6 weeks of BPS treatment, these decreases of the axonal area and the circularity index were inhibited. The enlarge ment of the mean lumen area of microvessels in the diabetic rats was significantly inhibited after 6 weeks of BPS treatment. Additionally, augmentation of the washed platelet aggregation in diabetic rats was sig nificantly normalized by BPS. It was suggested that BPS is effective on diabetic neuropathy via amelioration of the decrease of blood supply to the structure. The effects of BPS on platelets might also contribute to the improvement of neuronal circulatory deficiency.

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“…However, clinically significant DAN takes months to develop in rodents (28,30) and years to decades in humans (24). Because the glucagon response to insulin-induced hypoglycemia in the BB rat is severely impaired far earlier than the development of DAN (7), we considered it unlikely that DAN was the mediator of this specific, early glucagon impairment.…”

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confidence: 99%

Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy

Mundinger¹,

Mei²,

Figlewicz³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy. Am J Physiol Endocrinol Metab 285: E1047-E1054, 2003. First published July 22, 2003 10.1152/ajpendo.00136. 2003.-We investigated the functional impact of a recently described islet-specific loss of sympathetic nerves that occurs soon after the autoimmune destruction of ␤-cells in the BB diabetic rat (35). We found that the portal venous (PV) glucagon response to sympathetic nerve stimulation (SNS) was markedly impaired in newly diabetic BB rats (BB D). We next found a normal glucagon response to intravenous epinephrine in BB D, eliminating the possibility of a generalized secretory defect of the BB D ␣-cell as the mediator of the impaired glucagon response to SNS. We then sought to determine whether the glucagon impairment to SNS in BB D was due solely to their loss of islet sympathetic nerve terminals or whether other effects of autoimmune diabetes contributed. We therefore reproduced, in nondiabetic Wistar rats, an islet nerve terminal loss similar to that in BB D with systemic administration of the sympathetic neurotoxin 6-hydroxydopamine. The impairment of the glucagon response to SNS in these chemically denervated, nondiabetic rats was similar to that in the spontaneously denervated BB D. We conclude that the early sympathetic islet neuropathy of BB D causes a functional defect of the sympathetic pathway to the ␣-cell that can, by itself, account for the impaired glucagon response to postganglionic SNS. norepinephrine; 6-hydroxydopamine; neuropathy HUMAN AUTOIMMUNE TYPE 1 DIABETES is characterized by a major impairment of the glucagon response to insulininduced hypoglycemia (15) that is evident early in the course of the disease (6). BioBreeder diabetic rats (BB D), one of the best animal models of human autoimmune diabetes, exhibit this specific glucagon impairment after only 1 wk of diabetes (25). Defects in several mechanisms have been proposed to mediate the impairment (15,40,44). We have favored the hypothesis of autonomic defects, because an important role of autonomic inputs to the islet in mediating the glucagon response to hypoglycemia has been demonstrated in both nondiabetic animals (5,19,20,22) and humans (17). We have focused specifically on damage to sympathetic nerves of the islet because central glucopenia results in activation of pancreatic sympathetic nerves (10, 21), and this activation can, by itself, mediate most of the glucagon response to insulin-induced hypoglycemia (18). We hypothesized that, early in autoimmune type 1 diabetes, there is damage to the sympathetic pathway to the islet that contributes to the early impairment of the glucagon response to hypoglycemia seen in this disease.Diabetic autonomic neuropathy (DAN), a wellknown complication of type 1 diabetes, impairs several classes of nerves (3, 11, 43), including peripheral sympathetic nerves (31, 45). However, clinically significant DAN takes months to develop in rodents (28, 30) and years to d...

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Prevention of some electrophysiologic and biochemical abnormalities with oxygen supplementation in experimental diabetic neuropathy.

Cited by 108 publications

References 37 publications

Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals.

Effects of Beraprost Sodium, a Prostacyclin Analogue, on Diabetic Neuropathy in Streptozotocin-Induced Diabetic Rats

Impaired glucagon response to sympathetic nerve stimulation in the BB diabetic rat: effect of early sympathetic islet neuropathy

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