Reduced Motor Nerve Conduction Velocity Research Articles

Effect of the dietary supplementation with a phosphatidyl-inositol metabolite, glycerophosphorylinositol, on Na +/K + ATPase activity and body weight in normal rats

Among the functions related to the inositol-containing phospholipids in the mammalian cells there is the activation of the Na +/K + ATPase. A reduction of the activity of this enzyme is implicated in the reduced motor nerve conduction velocity observed in diabetic rats, in which concentration of free inositol in the peripheral nerve is lower than in normal rats. Even erythrocytes from diabetics have fewer sodium pumps than do erythrocytes from age-matched controls. Feeding normal, weaning rats glycerophosphorylinositol (GPI), a metabolite of myo-inositol, we investigated the connections among inositol availability, sodium pump activity, and development. Unexpectedly, GPI supplementation determined a reduction in the Na +/K + ATPase activity and a decrease in the phosphatidylinositol content in the erythrocyte membranes, without altering the phosphatidylinositol fatty acid composition. Apart from all considerations about the mechanism of action of GPI, these data clearly state the relationship between sodium pump activity and phosphatidylinositol levels.

Aldose reductase inhibition with imirestat-effects on impulse conduction and insulin-stimulation of Na+/K(+)-adenosine triphosphatase activity in sciatic nerves of streptozotocin-diabetic rats.

This study describes reduced motor nerve conduction velocity and increased resistance to hypoxia-induced conduction failure in sciatic nerves of rats after four weeks of streptozotocin-induced diabetes (both effects were significant at p less than 0.05). These changes occurred in the absence of any deficit in the steady-state ouabain-sensitive adenosine triphosphatase (ATPase) activity of sciatic nerve endoneurial homogenates. The addition of 10 nmol/l insulin to endoneurial homogenates from control animals resulted in a 34% increase in ouabain-sensitive ATPase activity and a 19% reduction in ouabain-insensitive ATPase activity (both p less than 0.01). This stimulation of ouabain-sensitive ATPase activity by insulin did not occur in homogenates from diabetic rats. Treating diabetic rats daily with the aldose reductase inhibitor, imirestat (1 mg/kg) improved nerve conduction velocity (p less than 0.05) but was without effect upon the resistance to hypoxic conduction blockade or the deficit in insulin-stimulated ouabain-sensitive ATPase activity. These data suggest that in streptozotocin-diabetic rats the functional disorders of reduced motor nerve conduction velocity and increased resistance to hypoxic conduction blockade do not share a common aetiology and that impaired nerve conduction is not related to reduced maximal potential ouabain-sensitive ATPase activity.

Characterization of a novel aldose reductase inhibitor, FR74366, and its effects on diabetic cataract and neuropathy in the rat

FR74366 (FK366) {[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin- 1-yl] acetic acid} is a chemically novel aldose reductase (AR) inhibitor. It exhibited a highly potent, reversible, and mixed type inhibition of partially purified AR from the rat sciatic nerve (IC 50 = 3.6 nmol/L) and rat lens (IC 50 = 4.4 nmol/L). FR74366 inhibited sorbitol accumulation in the isolated human erythrocyte (IC 50 = 1.6 μmol/L), rat lens (IC 50 = 39 μmol/L), and rat sciatic nerve (IC 50 = 17 μmol/L) incubated with high glucose concentrations. The oral administration of FR74366 to streptozotocin (STZ)-induced diabetic rats for 2 weeks decreased sorbitol levels (ED 50 = 3.7 mg/kg for sciatic nerve, 23 mg/kg for lens, 52 mg/kg for retina, and 62 mg/kg for renal cortex). Administration of FR74366 to diabetic rats for 17 weeks delayed cataract formation and admixture of 0.028% FR74366 in the diet completely inhibited the cataract formation. Moreover, the recovery of reduced motor nerve conduction velocity by FR74366 in diabetic rats was demonstrated in prevention and reversal experiments. This recovery effect correlated well with reduction of accumulated sorbitol and fructose levels and normalization of decreased myoinositol levels. The duration and tissue specificity of inhibitory effects of FR74366 on sorbitol accumulation also correlated well with the levels of FR74366 in various tissues of diabetic rats. These data indicate that both decreases in tissue sorbitol levels and improvement of functional defects reflect FR74366 levels in tissue rather than plasma in diabetic rats. These results, taken together, suggest that FR74366, which is currently undergoing clinical trials in Japan and the United States, will be a useful therapeutic agent for diabetic complications.

A new prostaglandin E 1 analogue (TFC-612) improves the reduction in motor nerve conduction velocity in spontaneously diabetic GK (Goto-Kakizaki) rats

A new prostaglandin E 1 analogue, TFC-612, was given orally to 2 month-old spontaneously diabetic GK (Goto-Kakizaki) rats for 3 months to ascertain its effects on reduced motor nerve conduction velocity (MCV). A high dose of this compound (0.3 mg/kg body weight) sifnificantly restored MCV after 2 and 3 months of administration, although the low dose (0.03 mg/kg body weight) did not. In addition, 1 month administration of TFC-612 significantly improved the reduced MCV in aged (5 month-old) GK rats only in the high dose group (0.3 mg/kg body weitht), but not in the low dose group (0.03 mg/kg body weight). Although TFC-612 significantly suppressed sorbitol accumulation in the sciatic nerves of GK rats in a dose dependent manner after 3 months administration, this suppression was not observed after either 2 months administration to 2 month-old GK rats or after 1 month administration to 5 month-old GK rats. Fasting blood glucose levels of all GK rats remained high throughout the experiments, regardless of TFC-612 administration. TFC-612's improvement on reduced motor nerve conduction velocity was related partly to suppression of sorbitol accumulation, but other factors, including microcirculation, may contribute significantly to this effect. These results suggest that TLC-612 may be beneficial in the treatment of diabetic nerve impairment.

Relation of Na +, K +-ATPase to delayed motor nerve conduction velocity: Effect of aldose reductase inhibitor, ADN-138, on Na +, K +-ATPase activity

The role of sorbitol, myo-inositol, and Na +, K +-adenosine triphosphatase (ATPase) activity on motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-diabetic rats was studied. Reduction of MNCV and Na +, K +-ATPase in caudal nerves appeared after 3 weeks of diabetes, and at this time treatment with aldose reductase inhibitor (ARI), ADN-138 and 1% myo-inositol supplement was begun. One percent myo-inositol supplement for 3 weeks resulted in a significant increase in myo-inositol levels in diabetic nerves, but left MNCV and sorbitol levels unchanged. In contrast, treatment with ADN-138 for 3 weeks reduced sorbitol levels in diabetic nerves and resulted in significant increases in MNCV and Na +,K +-ATPase in the nerves. Since ADN-138 did not restore myo-inositol levels, the increase in Na +, K +-ATPase levels by ADN-138 treatment was independent of myo-inositol levels. Also, nerve Na + levels in ADN-138-treated rats were reduced and the ratio of K + to Na + was raised, while 1% myo-inositol supplement did not affect them. These results suggest that treatment with ADN-138 elevates MNCV through a series of processes: ARI → reduction of sorbitol level → increase in Na +, K +-ATPase activity → correction of K +, Na + imbalance → increase in MNCV.

Essential fatty acid treatment ? effects on nerve conduction, polyol pathway and axonal transport in streptozotocin diabetic rats

This study was designed to examine the effect of dietary supplementation with essential fatty acids (evening primrose oil--5% weight:weight added to the diet) on acute neurophysiological and neurochemical defects in streptozotocin-diabetic rats. Diabetic rats, which were not given evening primrose oil, showed highly significant elevations of nerve sorbitol and fructose combined with a depletion of nerve myo-inositol. In those animals there was also a 40% reduction (p less than 0.02) in the accumulation of axonally transported substance P-like immunoreactivity proximal to a 12 h sciatic nerve ligature together with reduced motor nerve conduction velocity (13% [p less than 0.001] and 20% [p less than 0.001] in two separate experiments). Treatment of other diabetic rats with evening primrose oil prevented completely the development of the motor nerve conduction velocity deficit without affecting sorbitol, fructose or myo-inositol levels or the deficit in axonal transport of substance P. In a second experiment, treatment of diabetic rats with evening primrose oil was associated with significant attenuation of the conduction velocity deficit, but not complete prevention.

The effect of ulinastatin on reduced nerve conduction velocity and blood pressure.

Application of a pneumatic tourniquet in orthopedic surgery is sometimes followed by hypotension and paralysis. Seventy-five patients scheduled for knee joint surgery were examined to evaluate the effects of ulinastatin on changes in blood pressure, venous pH and motor nerve conduction by pneumatic tourniquet application above the knee joint. In fifty-five of the patients, the femoral vein of the operating side was cannulated with a catheter to obtain venous blood samples before and after tourniquet application. 300,000 Unit of ulinastatin (UST) was administered intravenously before inflation of the tourniquet in 10 patients. In the other sixteen patients, the motor nerve conduction velocity (MNCV) of the peroneal nerve was measured before inflation and after release of the tourniquet. In the UST-free group, the reduced blood pressure and pH persisted for more than 15 min, while in the UST-treated group, the reduced blood pressure returned to the normal leven in 15 min. In the control group, femoral venous P(O)(2) continued to increase after 10 min, but that in the UST-treated group returned to the normal range. Tourniquet application significantly reduced peroneal MNCV. Pre-and post-treatment with UST significantly lessened the reduction of MNCV induced by the tourniquet. It is concluded that UST may have protective and therapeutic effects on ischemic nerve injury, induced by the application of a turniquet.

Antibodies against acetylcholinesterase and low levels of cholinesterases in a patient with an atypical neuromuscular disorder

Antibodies against acetylcholinesterase were found in the serum of a patient presenting dyspnea, generalized muscle paresis, diminished tendon reflexes, and fasciculations. Electrodiagnostic studies showed a decremental response, an incomplete interference pattern, and reduced motor nerve conduction velocity. Edrophonium administration resulted in extreme cholinergic crisis. Biopsies displayed muscle atrophy and nervous tissue degeneration. Recurrent acute respiratory failure ended in death. The patient's serum pseudocholinesterase and red blood cells acetylcholinesterase levels were generally very low, with periodical fluctuations. Minute quantities of the patient's serum inhibited the activity of cholinesterases from normal human serum and from various fetal tissues. Enzyme inhibition was abolished following preadsorption of the serum immunoglobulins with goat antihuman Fab, and radioiodinated acetylcholinesterase from human erythrocytes was precipitated by the patient's serum, confirming that anticholinesterase antibodies were present. Acetylcholinesterase extracted from fetal striated muscle with detergent and salt was inhibited to a larger extent than the enzymes similarly prepared from other fetal tissues and more efficiently than buffer-soluble muscle enzyme. These findings suggest that the patient's serum contained antibodies which interacted preferentially with the membrane-associated forms of muscle acetylcholinesterase and indicate that autoantibodies against acetylcholinesterase could play a role in the pathogenesis of the disease.

Studies on peripheral nerve and lens in long-term experimental diabetes: Effects of the aldose reductase inhibitor statil

This study determined the axonal transport of choline acetyltransferase (ChAT) activity and its content in several tissues in nondiabetic control rats and in four groups of rats with streptozotocin-induced diabetes of 6-months duration. Diabetic rats were either untreated, treated only with either the aldose reductase inhibitor Statil (Imperial Chemical Industries, Pharmaceuticals Division, Macclesfield, UK) or insulin, or were given the two in combination. Insulin treatment consisted of a single weekly injection of a long-acting insulin, a regime designed not to control the diabetes, but to provide regular respite from the catabolic dominance of uncontrolled diabetes. Elevated levels of sugars and polyols in the sciatic nerves of untreated diabetic animals were markedly attenuated by Statil. The reduced myo-inositol content and reduced axonal transport of ChAT activity also seen in these nerves were prevented by Statil, but a reduced motor nerve conduction velocity was attenuated only by Statil and insulin in combination. The presence of cataracts in all diabetic animals was associated with hyperhydration of the lens. The level of hydration and presence of cataracts were reduced by Statil, particularly in combination with insulin. ChAT activities of the iris, adrenal gland, and superior cervical ganglion were similar in all groups. Skeletal muscles showed wasting while the ileum showed an increased weight per unit length in diabetic rats. These tissues also displayed alterations in ChAT activities, particularly when referenced to unit weight of tissue, which may have been a consequence of the weight changes rather than diabetes per se. Thus, biochemical and functional defects of sciatic nerve previously reported in short-term experimental diabetes, preventable by aldose reductase inhibition, persist in rats with long-term experimental diabetes. Several of these defects were related to enhanced polyol pathway activity as demonstrated by their prevention or attenuation by Statil.

Ganglioside Treatment of Streptozotocin‐Diabetic Rats Prevents Defective Axonal Transport of 6‐Phosphofructokinase Activity

This study measured axonal transport of 6-phosphofructokinase (PFK) and aldolase activities in the sciatic nerves of rats with short-term streptozotocin-induced diabetes. The diabetic rats showed deficits in anterograde (69% of controls; p less than 0.001) and retrograde (33% of controls; p less than 0.01) accumulations of PFK activity as well as its content per unit length of unconstricted sciatic nerve (86% of controls; p less than 0.05). There were no accumulation deficits in aldolase activity in the nerves of the diabetic rats, although the activity per unit length of unconstricted nerve was deficient (81% of controls; p less than 0.05). Treatment of diabetic rats with mixed bovine brain gangliosides (10 mg/kg of body weight/day, i.p.) did not affect the deficit in PFK activity in unconstricted nerve (84% of ganglioside-treated controls; p less than 0.01), but all the other defects in enzyme activities were prevented completely. The diabetic rats also showed a reduction of 7% (p less than 0.01) in sciatic nerve dry weight per unit length, which was prevented by ganglioside treatment. In contrast, the reduced motor nerve conduction velocity, accumulation of polyol pathway metabolites, and depletion of myo-inositol, characteristic of untreated short-term diabetes, were unaffected by ganglioside treatment.

Guillain-Barré syndrome. A clinical electrophysiological and biochemical study.

Fifty-six consecutive patients with Guillain-Barré syndrome representing 49% of all cases of peripheral neuropathy (except those due to diabetes mellitus and leprosy) admitted to the Postgraduate Institute of Medical Education and Research, Chandigarh over a period of three years were studied. All patients developed weakness of limbs within one day to three weeks. Attenuation of deep tendon jerks (98%) paresthesia (66%), cranial nerve involvement (41%) and antecedent infection (32%) were the common clinical features. The common patterns of motor weakness were predominantly proximal in all the four limbs (45%) or predominantly proximal in lower limbs along with distal muscles in upper limbs (29%). Electrodiagnostic studies revealed prolonged distal (motor) latency (82%), reduced motor nerve conduction velocity (74%), sensory nerve conduction abnormality (85%) and evidence of denervation (41%). Evoked motor response of median, ulnar, common peroneal and tibial nerves exhibited significant increase in duration and reduction in amplitude. The maximum incidence of electrophysiological abnormality occurred between four to 12 weeks after the onset of neurological symptoms. Four patients died and 11 showed poor recovery. Long intervals (greater than 3 weeks) between peak deficit and onset of recovery and coexistence of reduced motor nerve conduction velocity with evidence of denervation on EMG were found to be associated with poor recovery.

The primary role of the Erb's point-axilla segment in median and ulnar motor nerve conduction determinations in alcoholic neuropathy

Motor nerve conduction velocity (MNCV) was explored in the Erb's point-axilla (N-A) nerve segment of median and ulnar nerves, bilaterally, in 10 patients with a history of prolonged heavy drinking but in whom no other predisposing factors to peripheral neuropathy were found. For comparison, MNCV was determined also in the axilla-elbow (A-E), elbow-wrist (E-W) nerve segments, as well as the motor terminal latency (MTL) of the same nerves. A total of 140 nerve segments were tested but only 133 results were obtained. Abnormal MNCV or MTL was found in 36 or 27% of all tested nerve segments. From the latter, 38.9% were in the N-A nerve segments. Of all N-A nerve segments tested, reduction in MNCV was found in 46.7%. Our results are statistically significant.

Reversal of deficits in axonal transport and nerve conduction velocity by treatment of streptozotocin-diabetic rats with myo-inositol

This study examined the effects of myo-inositol treatment on the deficits of motor nerve conduction velocity and of axonal transport of choline acetyltransferase in rats with streptozotocin-induced diabetes. Motor nerve conduction velocity was measured in seven groups of male rats. Two groups formed nondiabetic controls; one survived for 3 and the other for 6 weeks, then motor nerve conduction velocity was again measured and the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction was estimated. The other five groups were rendered diabetic and subjected to similar measurements. Two diabetic groups were untreated and survived 3 or 6 weeks. The other three groups received myo-inositol for 1, 2, and 3 weeks, respectively, commencing 21 days after induction of diabetes. These groups survived for 4, 5, or 6 weeks, respectively. In all groups surviving for longer than 3 weeks an interim measurement of motor nerve conduction velocity was made 21 days after the start of the experiment (immediately before onset of treatment in the treated groups). In these groups a third measurement was made on the day before death. At death, choline acetyltransferase accumulation was measured and the remainder of the sciatic nerves was assayed for sorbitol and myo-inositol. In the two untreated diabetic groups we found reduced motor nerve conduction velocity, a deficit in the accumulation of choline acetyltransferase proximal to the sciatic nerve constriction, and a marked build-up of nerve sorbitol and a depletion of nerve myo-inositol. All three treated groups showed a reversal of this myo-inositol depletion without a reduction in the nerve sorbitol content. One week of treatment was without effect on nerve conduction velocity or axonal transport. In the 2-week treatment group axonal transport of choline acetyltransferase was similar to controls but the nerve conduction deficit was not reversed. After 3 weeks of treatment choline acetyltransferase accumulation was slightly greater than controls and the motor nerve conduction velocity had increased significantly from the pretreatment value (after 3 weeks' diabetes) and was not significantly less than the prediabetic value.

Quantitative analysis of myelin and axolemma particle distribution in C57BL/Ks diabetic mice and the effects of ganglioside treatment

By freeze-fracture technique we estimated myelin and axolemma intramembranous particle density in C57BL/Ks mice. A decrease in myelin particle content compared to controls is present in both 180 and 280 day old genetic diabetic mice. In addition, the axolemma of myelinated axons is affected in interparanodal regions while no modification was detected at nodal level. Such alterations of myelin membrane structure may also be responsible for the lower motor nerve conduction velocity (MNCV) observed in these diabetic mice; however this hypothesis cannot be taken into consideration for the reduction in MNCV at the early stage of the neuropathy (prior to 180 days of life). Therefore the structural changes of both myelin sheath and interparanodal axolemma as visualized by freeze-fracture are most likely related to late complications of the disease instead of being responsible for the changes in excitability. The low myelin and axolemma particle density of diabetic mice was found normal after 30 days' treatment with gangliosides. Such findings are in agreement with previous results on a significant effect of ganglioside treatment on MNCV and axonal area alterations in 180 and 280 day old genetic diabetic mice.

Prevention of peripheral nerve dysfunction by an aldose reductase inhibitor in streptozotocin-diabetic rats

A potent inhibitor of aldose reductase, (E)-3-carboxy-methyl-5-[(2E)-methyl-3-phenylpropenylidene]rhodanine (ONO-2235), was orally administered at a dose of 20 mg · kg −1 · d −1 for 2 weeks to streptozotocin-diabetic rats from the beginning of the diabetic state, ie, 24 hours after streptozotocin injection. The impairment of motor nerve conduction velocity (MNCV) of the tail nerve found in nontreated diabetic rats was apparently prevented by the treatment with the aldose reductase inhibitor (24.5 ± 0.4 v 29.0 ± 1.4 m/s on day 14, P < 0.005). Those diabetic rats treated with the compound actually showed an age-dependent increase in MNCV similar to that of normal control rats (25.5 ± 1.5 v 26.4 ± 1.0 m/s on day 7, 29.0 ± 1.4 v 29.4 ± 1.3 m/s on day 14, treated v normal, not statistically significant on both days). The sorbitol content of the sciatic nerve excised from ONO-2235-treated diabetic rats (0.067 ± 0.018 nmol/g wet weight) was significantly lower than that of the nontreated diabetic rats (1.309 ± 0.080 nmol/g wet weight, P < 0.001) but significantly higher than that of normal control rats (0.229 ± 0.015 nmol/g wet weight, P < 0.001). These results suggest that the reduction in MNCV noted in the experimental diabetic animals is not the result of retarded maturation of peripheral nerves but of metabolic derangement caused by the diabetic state, which can be prevented by suppressing sorbitol accumulation in nerve tissue. It also appears that there may be a threshold level of sorbitol accumulation that causes the impairment of nerve conduction velocity.

Reversal, by treatment with an aldose reductase inhibitor, of impaired axonal transport and motor nerve conduction velocity in experimental diabetes mellitus

Streptozotocin-diabetic rats showed reduced motor nerve conduction velocity, impaired orthograde axonal transport of choline acetyltransferase, and accumulated sorbitol in the sciatic nerve compared with age-matched controls. Another age-matched group, with diabetes of similar intensity, but treated daily with an aldose reductase inhibitor, showed none of these neurological defects. These findings implicate aldose reductase activity in the development of acute conduction and axonal transport defects in experimental diabetes.

Influence du controle glycemique sur la conduction nerveuse peripherique des diabetiques insulino-dependants

In order to better evaluate the influence of glycemic control on diabetic neuropathy, 73 diabetic patients were considered: 42 males and 31 females who had been treated with insulin during 9 years. Twenty-one subjects were examined during 2-12 months. Motor nerve conduction velocity (MCV) was measured on the external sciatic popliteus (ESP). The H reflex parameters from soleus were: latency time for H response (HL), the ratio between the maximum amplitude of the H reflex response and the M motor response: (formula: see text) was determined by a chromatographic method. The reduction of MCV, the rise in HL and the decrease of E in diabetics are more pronounced according to the duration of the disease and are significantly correlated with the rate of HbA1c (respectively MCV: r = -0.39, P less than 0.001; HL: r = 0.42, P less than 0.001; E: r = -0.37, P less than 0.01). There is a slight correlation between HbA1c level and the duration of diabetes. For the 21 diabetics observed during many months there is a very significant correlation between the slope of the evolution curves of HbA2c, MCV and HL.

Nerve Conduction Velocity in the Assessment of Hypertension

Motor nerve conduction velocity was measured in 52 hypertensive and 10 control subjects. Reduction of nerve conduction velocity paralleled elevation of blood pressure and retinal changes. No correlation was found between nerve conduction velocity and the duration of hypertension. Nerve conduction velocity can provide us with an objective measurable index of the severity of hypertension. Peripheral neuropathy may accompany a number of diseases of varying etiology. It is noted frequently in diabetes mellitus, uremia, and malignant tumors. Measurements of motor nerve conduction velocities in these conditions revealed that a functional conduction defect may precede the overt clinical manifestations of peripheral neuropathy.¹Reduced motor nerve conduction velocity is therefore an early indicator of subclinical nerve involvement. The exact nature and pathogenesis of the neural lesions is unknown. There is, however, some evidence, derived mainly from studies in diabetes, which suggests that degenerative vascular changes in the vasa nervorum may be