Biomedical subjects

J D Schmelzer

Publications and source records attributed to J D Schmelzer.

At least 37 records · Page 2Linked to original sources

PubMed1995

Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy.

OBJECTIVE: To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS: We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS: NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS: These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.

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PubMed1994

Different reinnervation patterns in the celiac/mesenteric and superior cervical ganglia following guanethidine sympathectomy in adult rats.

We sought to determine whether chronic guanethidine (Gu) treatment in adult rats produces depletion of sympathetic neurons and hyperinnervation by sensory neuropeptides in the celiac/superior mesenteric (C/SMG) ganglion. Rats received Gu 40 mg/kg per day i.p or saline for 5 weeks. Upon completion of treatment, the C/SMG and the superior cervical ganglion (SCG) were examined for neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP), both by immunocytochemistry (ICC) and radioimmunoassay (RIA). Gu produced marked depletion of NPY-containing neurons and NPY content in the C/SMG, similar to that in the SCG (-89 +/- 2 vs. -92 +/- 4%, respectively). SP and CGRP immunoreactivities were significantly higher in control C/SMG as compared with SCG; after Gu treatment, there was no significant increase in either SP or CGRP in the C/SMG, however, both increased in the SCG. In contrast, VIP levels were similar in the SCG and C/SMG in controls and increased in the C/SMG but not in the SCG after Gu treatment. Thus, in adult rats, the C/SMG is as susceptible as the SCG to Gu treatment; the different pattern of hyperinnervation by SP, CGRP and VIP of the C/SMG as compared with the SCG may reflect the different sources for these neuropeptides in prevertebral as compared with paravertebral ganglia.

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PubMed1994

Effect of alpha-tocopherol deficiency on indices of oxidative stress in normal and diabetic peripheral nerve.

We tested the hypothesis that oxidative stress can cause neuropathy by evaluating the effect of alpha-tocopherol depletion in normal and streptozotocin (STZ) diabetic peripheral nerve (known to be subject to oxidative stress). The end points were nerve electrophysiology and indices of oxidative stress. Studies were done on 6 groups of rats at 1 and 3 months: (1) Controls, normal alpha-tocopherol (Con[N]). (2) Controls, alpha-tocopherol-deficient (Con[-]) (3) Controls, alpha-tocopherol supplemented (Con[+]); (4) Diabetic, normal alpha-tocopherol (STZ[N]); (5) Diabetic, alpha-tocopherol-deficient (STZ[-]) (6) Diabetic, alpha-tocopherol supplemented (STZ[+]). An alpha-tocopherol-deficient diet resulted in a rapid depletion of the vitamin in plasma and sympathetic neurones (superior cervical ganglion), and a slower depletion in sensory neurones (dorsal root ganglion) and nerve. The depletion was associated with a reduction in reduced glutathione and an increase in conjugated dienes and hydroperoxides in normal rats, and resulted in similar changes, or accentuated the abnormalities, in diabetic nerves. Changes were more pronounced at 1 than 3 months and alpha-tocopherol supplementation, for the most part, did not prevent the abnormalities. alpha-Tocopherol depletion induced or worsened nerve conduction abnormalities in both sciatic-tibial and caudal nerves. Sensory fibers were more affected than motor fibers and the changes were more pronounced at 3 than 1 month. These findings support the notion that oxidative stress may cause neuropathy and that it might be mechanistically implicated in experimental diabetic neuropathy (STZ-EDN).

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PubMed1994

Motor and somatosensory evoked potentials in mice infected with Theiler's murine encephalomyelitis virus.

We used an in vivo technique to record spinal motor and somatosensory evoked potentials in SJL/J and B10 mice chronically (4-10 months) infected with Daniel's strain of Theiler's murine encephalomyelitis virus (TMEV). SJL/J mice demonstrated primary spinal cord demyelination with chronic TMEV infection, whereas B10 mice were resistant to TMEV induced demyelination. Analysis based on the velocity of the initial peak of evoked responses demonstrated significantly slower conduction velocities in infected SJL/J mice as compared to age-matched uninfected SJL/J controls (p < 0.01) and infected B10 mice (p < 0.01). We noted no significant differences in conduction velocities of spinal evoked potentials recorded between uninfected SJL/J mice, uninfected B10 mice and infected B10 mice. Chronic infection with TMEV in susceptible SJL/J mice is associated with slowed conduction of spinal motor and somatosensory evoked potentials. This sensitive electrophysiologic assay will provide an in vivo method to test therapeutic regimens to inhibit demyelination or promote remyelination.

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PubMed1993

The influence of dose of microspheres on nerve blood flow, electrophysiology, and fiber degeneration of rat peripheral nerve.

Microsphere embolization of peripheral nerve results in a variable degree of ischemic fiber degeneration. To enhance the utility of the model, we evaluated the relationship between dose of microspheres to the supplying arteries of the sciatic-tibial nerve to nerve blood flow (NBF), electrophysiology, morphology, and behavioral changes. There was considerable variability in the effect of embolization on nerve pathology in individual nerves. However, the dose of microspheres regressed with the degree of hindlimb paresis, reduction in NBF, degree of fiber pathology, and ischemic conduction failure of the tibial nerve, evaluated at day 7. All nerves with severe (grade 4) fiber degeneration had flows of < 3 mL x 100 g-1 x min-1. We conclude that it is possible to predict with a high degree of accuracy the severity of fiber degeneration by the degree of NBF reduction and by the electrophysiologic abnormalities.

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PubMed1992

Guanethidine sympathectomy increases substance P concentration in the superior sympathetic ganglion of adult rats.

Adult rats received intraperitoneal injections of guanethidine or saline for 5 weeks. Six to 8 weeks following completion of treatment, concentrations of substance P and neuropeptide Y (NPY) were measured by radioimmunoassay in the superior cervical ganglion (SCG) and thoracic spinal cord. The SCG was also immunostained for NPY and substance P. No differences were observed in thoracic spinal cord content of either NPY or substance P. We observed depletion of NPY immunoreactive neurons and NPY levels in the SCG, and pharmacologic evidence of postganglionic denervation in guanethidine-treated rats. In guanethidine-treated rats, there was a marked increase of substance P levels in the SCG, where substance P was localized in fibers, but not cell bodies. Thus, sprouting of substance P-containing sensory fibers in the sympathetic ganglia occurs following postganglionic sympathectomy in adult rats.

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PubMed1991

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

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-1.day-1), group III 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 of the permeability coefficient and surface area to 125I-labeled albumin. STZ-induced diabetes (group III) 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 dose-dependent 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.

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PubMed1991

Effect of ischemia and reperfusion in vivo on energy metabolism of rat sciatic-tibial and caudal nerves.

Our model of severe nerve ischemia consistently results in extinction of the compound nerve and muscle action potentials (NAP; CMAP) within 30 min. Since impulse transmission may depend on nerve energy metabolism (NEM), we studied the effects of ischemia with reperfusion on sciatic-tibial nerve NEM in vivo and compared these results with NEM of this nerve in deoxygenated Ringer's solution in vitro and postmortem. Ischemia for 30 min postmortem or in deoxygenated Ringer's solution resulted in marked depletion of adenosine triphosphate (ATP) and creatine phosphate (CP) and an increase in lactate (LAC) of sciatic-tibial nerve of adult male Sprague-Dawley rats. In vivo ischemia for up to 3 h to sciatic-tibial nerve was sufficient to extinguish CMAP but not NAP and did not deplete ATP, CP, or GLU nor did it increase LAC. Ischemia sufficient to extinguish NAP resulted in reduction of energy substrates to about 50% of resting. Muscle fails to conduct impulses before nerve and in vivo reductions of energy substrates are milder than in vitro changes. These changes are explainable in terms of energy requirements and supply. These findings support an energetic basis of ischemic conduction failure.

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PubMed1990

Noradrenergic and neuropeptide Y mechanisms in guanethidine-sympathectomized rats.

The cardiovascular responses to sympathomimetic agents, the norepinephrine (NE) content in peripheral tissues, and the tissue content and cardiovascular effects of neuropeptide Y (NPY) were examined in anesthetized adult rats with guanethidine-induced sympathectomy (GuSx). We observed blunted pressor responses to tyramine, exaggerated pressor responses to phenylephrine, and markedly reduced NE contents in the atrium, femoral artery, superior cervical ganglion (SCG), and sciatic and vagus nerves. When tyramine responses were corrected for the NE content in the SCG, GuSx rats were similar to controls. A depletion of NPY levels in tissue resulted in an increased sensitivity to the pressor effects of intravenous NPY administration. GuSx, therefore, reproduces findings of postganglionic adrenergic failure in humans. Responses to the administration of sympathomimetic agents may reflect the degree of noradrenergic denervation. NPY may be a potential marker of chronic postganglionic sympathetic denervation in cardiovascular tissue.

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PubMed1989

Comparison of nerve regeneration in vascularized and conventional grafts: nerve electrophysiology, norepinephrine, prostacyclin, malondialdehyde, and the blood-nerve barrier.

We compared the efficacy of vascularized (VASC) and conventional (CONV) sciatic nerve grafts in restoring nerve blood flow (NBF), conduction, the blood-nerve barrier, norepinephrine (NE), and 6-keto prostaglandin F1 alpha (6-KPGF; the stable prostacyclin metabolite) in the sciatic nerve of the rat. We also measured malondialdehyde (MDA) content. NBF was much greater in VASC grafts, but the increase was confined to non-nutritive flow. There was a statistically non-significant increase in nerve action potential amplitude in the grafted segments of VASC nerves at 1 and 2 months post graft. The [14C]sucrose permeability surface area (PA) product was increased in both CONV and VASC at 1 and 3 months and was not different to each other. NE and 6-KPGF, the major vasoconstrictor and dilator of nerve microvessels were better restored in VASC than CONV reaching statistically significance for 6-KPGF (P less than 0.001). MDA used as an index of oxygen free radical generation was not significantly different in the 3 groups. The better restoration of 6-KPGF and perhaps NE suggest that VASC grafts may be more effective in restoring vasoreactivity of peripheral nerve following graft.

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PubMed1989

Aortic occlusion and reperfusion and conduction, blood flow, and the blood-nerve barrier of rat sciatic nerve.

We studied the effect of ischemia and reperfusion on blood flow, electrophysiology, and the blood-nerve barrier of the sciatic nerve of the rat. Ischemia for 10 to 60 min, with up to 3 h of reperfusion, was produced by closure and then release of a noose around the abdominal aorta. Nerve blood flow and function were measured serially using microelectrode-hydrogen polarography and electrophysiologic recordings, respectively. The integrity of the blood-nerve barrier was assessed using the permeability surface area product to [14C]sucrose. Ischemia of up to 30 min did not impair reperfusion. One hour of ischemia resulted in reperfusion abnormalities that affected about half of the nerves. The ischemic and reperfusion stresses did not disrupt the blood-nerve barrier to [14C]sucrose nor produce conduction block. Possible mechanisms for this resistance to ischemic and reperfusion injury are discussed.

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PubMed1989

Ischemic and reperfusion injury of rat peripheral nerve.

A rat model of severe nerve ischemia was used to study the effects of ischemia and reperfusion on nerve conduction, blood flow, and the integrity of the blood-nerve barrier. Conduction failure was consistently found in the sciatic-tibial nerve during 1- and 3-hr ischemic periods. Recovery of the compound muscle action potential was prompt and complete upon reperfusion following 1 hr of ischemia. However, after 3 hr of ischemia, recovery in the proximal portion of the sciatic nerve was less than 10%, and conduction block occurred in the distal portion of the nerve. Nerve blood flow was restored to only 55% and 45% of resting values following 1 and 3 hr, respectively, of ischemia and did not recover even after 2 hr of reperfusion. The blood-nerve barrier was not statistically impaired to the passage of [14C]sucrose following 1 hr of ischemia but was significantly impaired after 3 hr of ischemia. The permeability-surface area product was consistently greater following 1 hr of reperfusion than during the immediate reperfusion period. These data indicate that severe ischemia of peripheral nerve results in reperfusion injury, conduction block, and blood-nerve barrier disruption. Microvascular events, which may occur during reperfusion, may be important in amplifying the nerve fiber damage that began during ischemia.

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PubMed1989

Prostacyclin and noradrenaline in peripheral nerve of chronic experimental diabetes in rats.

Noradrenaline levels in the superior cervical ganglion and sciatic nerve were significantly reduced in chronic streptozotocin-induced diabetes in rats. Sciatic nerve sheath in vitro biosynthesis of 6-keto prostaglandin F1 alpha (6KPGF1 alpha; the stable metabolite of prostacyclin) was significantly reduced but not in acute experimental diabetes. Nerves with reduced 6KPGF1 alpha had an excessive response to arachidonic acid stimulation. We suggest that the reduced endogenous biosynthesis of prostacyclin is due to reduced substrate availability, possibly due to the reduced noradrenaline. The implications of these findings on the pathogenesis of diabetic neuropathy are discussed. Neuropathy was found to involve all fibre populations studied (motor, sensory and sympathetic) and progressed with duration of diabetes.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

The effect of hyperbaric oxygenation and hypoxia on the blood-nerve barrier.

We measured the permeability coefficient--surface area product (PA) of peripheral nerve to [14C]sucrose in rat sciatic nerve in experimental chronic hypoxic hypoxia of up to 8 weeks and following hyperbaric oxygenation for 1 to 4 weeks. Chronic hypoxia caused an increase in PA presumably indicating impairment of the blood-nerve barrier at 4 weeks with restoration to normal by 8 weeks. Hyperbaric oxygenation (100% oxygen at 2.5 ata for 120 min/day 5 days per week) caused a mild but time dependent increase in PA reaching statistical significance by 4 weeks.

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PubMed1988

Effect of hyperbaric oxygenation on normal and chronic streptozotocin diabetic peripheral nerves.

Hyperbaric oxygenation is known to affect energy metabolism and endothelial cell structure and function, but its effects on peripheral nerve have not been reported. We investigated whether it would (i) reverse established streptozotocin-induced diabetic neuropathy, a condition in which endoneurial hypoxia exists; (ii) affect energy metabolism in nerve; and (iii) alter the blood-nerve barrier. Sprague-Dawley rats that had been diabetic for 3 months and age-matched controls were used in these studies. One diabetic group and one control group were treated with hyperbaric oxygenation (2 atm for 2 h, 5 days/week) for 4 weeks. Identical groups remained in room air. Sciatic nerve adenosine triphosphate (ATP), creatine phosphate, lactate, and glucose concentrations showed similar changes at rest in both room air and after hyperbaric oxygenation. Nerves of control and diabetic groups exhibited increased lactate production and increased utilization of glucose, ATP, and creatine phosphate after 15 min of anoxia. The albumin blood-nerve barrier index was increased in control and diabetic nerves after hyperbaric treatment. Nerve conduction velocity was reduced in the diabetic-room air group and not improved by hyperbaric oxygenation. Caudal nerve action potential, which was significantly reduced in this group, was normalized after hyperbaric treatment. Resistance to ischemic conduction failure was increased in untreated diabetic nerve but not significantly different from controls after hyperbaric exposure. These findings indicate that treatment with hyperbaric oxygenation will partially reverse the neuropathy encountered in chronic diabetes. The biochemical changes are suggestive of enhanced nerve energy metabolism induced by hyperbaric oxygenation. The altered albumin blood-nerve barrier index presumably results from the action of free radicals on endothelial cells.

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PubMed1987

Slow axonal transport in experimental hypoxia and in neuropathy induced by p-bromophenylacetylurea.

The slow axonal transport of proteins radiolabeled by incorporation of [35S]methionine was studied in motor nerves of rats subjected to chronic hypoxia. The conditions involved exposure to an atmosphere of 8-10% oxygen for periods of 3, 5, or 10 weeks. An experimentally verified computer model predicted a drop in mean endoneurial oxygen tension from 30.5 to 19 mm Hg, despite a measured increase in circulating hemoglobin from 16 to 22 g%. Nerve conduction velocity was unaffected during the early stages of hypoxia. After 10 weeks of hypoxia, conduction velocity still appeared normal in the sciatic nerve but was reduced in the caudal nerve by 2.5-4.5 m/s. At no time, however, was there evidence of impaired slow axonal transport, which proceeded with a mean velocity between 1 and 2 mm/day. Another set of experiments was performed to evaluate slow axonal transport in motor nerves of rats with peripheral neuropathy induced by the toxicant, p-bromophenylacetylurea. The results suggested a lower transport velocity in rats showing total hind-limb paralysis as compared with rats showing only mild to moderate motor dysfunction. The difference, however, could have reflected accelerated transport in mild neuropathy. In our view, the observations in experimental hypoxia- and toxicant-induced neuropathy are noteworthy for the resistance of slow transport to perturbation of the neuronal environment.

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PubMed1987

Electrophysiological studies on the effect of age on caudal nerve of the rat.

The effect of age on electrophysiologic parameters was studied on the caudal nerve of 374 male Sprague-Dawley rats (age 24 to 630 days) and on 83 Fischer 344 rats (age 29 to 900 days). For Sprague-Dawley rats nerve conduction velocity and nerve action potential amplitude were both a parabolic function of age, increasing to 1 year and then declining. For Fischer 344 rats the same parameters increased progressively to 1.5 years and then declined. In contrast, for both Sprague-Dawley and Fischer 344 rats, resistance to ischemic conduction failure was a hyperbolic function of age reaching an asymptote at 1.5 to 2 years of age. These age-related changes in caudal nerve parallel the electrophysiologic alterations with age in human peripheral nerve more closely than previous reports in rodent limb nerves.

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PubMed1986

The effect of age on energy metabolism and resistance to ischaemic conduction failure in rat peripheral nerve.

Caudal nerve conduction velocity and amplitude of nerve action potential increased progressively with age to 8 months after which time no further increases were demonstrated. Rat peripheral nerve was progressively more resistant to ischaemic-anoxic conduction failure with increasing age. This resistance to ischaemic conduction failure was paralleled by a progressive age-related decline in endoneurial O2 consumption. Endoneurial adenosine triphosphate and creatine phosphate values were also progressively reduced with age. 15 min of anoxia resulted in progressively smaller reductions in these nucleotide phosphates with increasing age to 8 months after which time little further change occurred. Nerve lactate response to anoxia was higher in young rats (1 and 2 months) than in older animals (8 and 21 months). High energy phosphate expenditure progressively declined with age to 8 months, then stabilized. These findings indicate that the major mechanism of resistance to ischaemic conduction failure is a progressive decline in energy requirements.

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