Brain, Vol. 124, No. 6, 1149-1155,
June 2001
© 2001 Oxford University Press
Abnormal axonal inward rectifier in streptozocin-induced experimental diabetic neuropathy
1 Departments of Neurology and 2 Diabetology, Kyoto University Graduate School of Medicine, Kyoto, 3 Department of Clinical Neuroscience, Hospital of The University of Tokushima, Tokushima, Japan and 4 Sobell Department of Neurophysiology, Institute of Neurology, London, UK
Correspondence to:
Ryuji Kaji, MD, Department of Clinical Neuroscience, Hospital of the University of Tokushima, 2 chome 5-1, Kuramotocho, Tokushima City, Tokushima 770-8503, Japan E-mail: rkaji{at}clin.med.tokushima-u.ac.jp
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Abstract |
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In order to explore the pathophysiology of diabetic neuropathy, we studied serial changes of axonal excitability in 20 adult Wistar rats with streptozocin-induced diabetes using the technique of threshold electrotonus (TE). After persistent hyperglycaemia had developed, rats were divided into two groups: nine were fed a diet containing aldose reductase inhibitor (Epalrestat 30 mg/kg/day) (ARI+ group) and 11 were fed a diet without the inhibitor (ARI– group). Eight normal control rats of similar age (NC group) were also studied. We monitored membrane properties of motor axons in the tail for 3 months using TE to measure the changes in excitability induced by subthreshold polarizing currents while recording compound muscle action potentials (CMAPs) in the tail muscle. The ARI– group showed a significant increase in CMAP latency 1 month after streptozocin injection, and by 3 months there was significantly lower excitability after hyperpolarization for 100 ms compared with the NC group. A similar change in TE was reproduced by injection of caesium chloride, an inhibitor of inward rectification. By contrast, the ARI+ group exhibited no significant change in TE or latency at 3 months, although they showed significant body weight loss and hyperglycaemia. These findings indicate that inward rectification is reduced in an experimental model, as in human diabetes, and that blocking the polyol pathway with an ARI prevents this reduction. Reduced inward rectification potentiates conduction block caused by activity-dependent hyperpolarization and may underlie the decreased vibratory sensation seen in the early stage of diabetic neuropathy.
diabetic neuropathy; threshold electrotonus; inward rectifier; activity-dependent hyperpolarization; pathophysiology
ARI = aldose reductase inhibitor; CMAP = compound muscle action potential; NC = normal control; TE = threshold electrotonus
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Introduction |
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Diabetic neuropathy is characterized by an early decrease in motor conduction velocity and loss of vibratory sense (Mackel, 1989
). Autonomic dysfunction may also be present in the early stage. Demyelination or Wallerian degeneration does not explain these clinical features fully (Thomas, 1997). The mechanisms involved in diabetic neuropathy are complicated and a variety of hypotheses, involving metabolic and vascular factors, have been proposed (Greene et al., 1992; Cameron and Cotter, 1993). Hyperactivity of the polyol pathway induced by hyperglycaemia has been a leading metabolic contender for the last two decades, and decreased conduction velocity in animal models of diabetes has been corrected successfully by inhibiting aldose reductase, which catalyses the critical step in the polyol pathway (Greene et al., 1987; Sima et al., 1990).
Threshold electrotonus (TE) is a new technique that has been developed to explore the function of axonal ion channels non-invasively (Bostock et al., 1998). This clinical test of axonal function is expected to provide physiological information that cannot be obtained from conventional nerve conduction studies. Using this method, Horn and colleagues have shown decreased excitability following the application of hyperpolarizing current to the median nerves in diabetic patients compared with normal subjects (Horn et al., 1996). They ascribed this finding to a deficiency in the inward rectifier, which counteracts the membrane hyperpolarization. They did not, however, examine the mechanism of this abnormality or the clinical stage at which it occurs in diabetes.
To facilitate the interpretation and the clinical use of TE, we have developed a rat model which allows pharmacological manipulation (Yang et al., 2000). In the present study, we used this model to examine serial changes in axonal excitability in streptozocin-induced diabetes. Findings were compared among normal controls and diabetic rats that had been treated or not treated with an aldose reductase inhibitor (ARI).
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Animals
We found previously that mature rats (body weight >400 g) provide a useful experimental model of human TE (Yang et al., 2000
). In this study we used male Wistar rats at 18–20 weeks of age (body weight >400 g). Diabetic rats were produced by injecting 40–45 mg/kg of streptozocin intraperitoneally in 0.05 M citrate buffer, pH 4.5. These rats had a non-fasting plasma glucose concentration >350 mg/dl (measured by GluTest EII; SRL, Tokyo, Japan) in tail vein blood 48–96 h after streptozocin injection. All rats were fed a standard laboratory diet. Plasma glucose concentration and TE were monitored at regular intervals. After 1 week of streptozocin administration, the diabetic rats (blood glucose >350 mg/dl) were divided randomly into two groups. The ARI+ group (n = 9) was fed an ARI (Epalrestat; Ono Pharmaceuticals, Osaka, Japan) at 30 mg/kg/day. The ARI– group (n = 11) was a diabetes control group that did not receive the ARI. We did not select the animals to be assigned for medication before the administration of streptozocin, because some failed to develop significant hyperglycaemia. A group of 8 normal rats, the normal control (NC) group, had free access to laboratory chow and water only. All these groups underwent TE recording and measurement of compound muscle action potential (CMAP) latency (see below), plasma glucose concentration and body weight (i) at the start of the study (0 month), (ii) 28–32 days after the start (1 month) and (iii) 84–96 days after the start (3 months). The same animals were used for testing at each time point.
A group of three mature normal rats was used for pharmacological manipulation by systemic administration of caesium cloride (500 mg/kg intraperitoneally), which blocks the inward rectifier. Because caesium is associated with cardiovascular complication, we monitored the electrocardiogram throughout the experiment. Part of the latter experiment has been published previously (Yang et al., 2000).
Threshold electrotonus recording
The principle of TE has been described in detail by Bostock and colleagues (Bostock et al., 1995, 1998). In brief, threshold tracking was used to monitor the excitability of the tail nerve during the application of long-lasting subthreshold de- or hyperpolarizing currents at the same sites. The target response was set at 40% of the CMAP obtained with supramaximal stimulation, and a computer was used to control the strength of a 1 ms test stimulus in order to maintain the response close to the target. The program QTRAC (Institute of Neurology, London) was used on a 486 IBM PC computer to record muscle action potentials, to generate the stimuli and to display the results (Fig. 1A). The nerve was stimulated at 1 Hz and five stimulus conditions were tested in turn: a 1 ms test stimulus alone (control) and test stimuli superimposed on 100 ms polarizing currents set to 20, –20, 40 and –40% of the last control stimulus (conditioning A–D in Fig. 1B). The starting time of the conditioning currents was stepped from 2 ms after the test stimulus backwards in time to 198 ms before it, over a period of 10–15 min.
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A Wistar rat was anaesthetized with sodium pentobarbital (50 mg/kg intraperitoneally) and its tail was placed on a heating plate, the temperature of which was controlled automatically at 35°C (Fig. 1A
). We used a disposable Ag–AgCl electrode with a saline-soaked pad (30x22 mm) to stimulate the caudal nerve. The cathode was attached to the lateral side of the tail 1.5 cm from its base. The same side of the tail was used for the cathode in each animal unless local injury to the tail unrelated to the experiment prevented this. The anode was attached to the skin of the hip from which the hair had been removed. We recorded CMAPs from the caudal muscle with stainless steel needle electrodes. The recording electrode for pickup was inserted into the ipsilateral side of the tail 6 cm distal to the stimulating cathode. The reference electrode was inserted into the ipsilateral side of the tail 2 cm distal to the pickup electrode. The ground electrode was placed on the contralateral side of the tail 2 cm proximal to the pickup electrode. The latencies to the onset of the CMAPs thus recorded were measured as an index of conduction velocity. All the experimental procedures were approved by the Institutional Review Board of Animal Experimentation of Kyoto University.
Analysis of threshold electrotonus findings
We used the method of TE analysis described previously (Fig. 1B) (Yang et al., 2000). To quantify the early response to depolarization, we measured the mean threshold decrease from 10–20 ms after the onset of the depolarizing conditioning pulse at 40% of threshold intensity (TEd10–20). This measure is strongly dependent on voltage-dependent fast potassium channel activity (Yang et al., 2000). We also measured the corresponding decrease in threshold on hyperpolarization (TEh10–20). Because the threshold always increased after hyperpolarization, TEh10–20 had a negative value. This measure depends primarily on the passive membrane properties of the axon (Yang et al., 2000). TEd90–100 was the mean threshold decrease 90–100 ms after the onset of the depolarizing conditioning pulse (40%), after activation of slow potassium channels (Yang et al., 2000). TEh90–100 was the corresponding threshold decrease on hyperpolarization. Again, this had a negative value. The absolute value of this depends in part on the cation channel (Ih) or the inward rectifier, which opens to counteract excessive hyperpolarization (Yang et al., 2000). Statistical analysis of group differences was performed using MANOVA (multivariate analysis of variance) or repeated measures ANOVA (analysis of variance) (Statistica; StatSoft, Tulsa, Okla., USA) with group (NC, ARI+, ARI–)xtime (0, 1, 3 months)xfactor (body weight, latency, TE measures). We also used ANOVA and Fisher's PLSD for post hoc analysis (StatView; Abacus Software, Berkeley, Calif., USA).
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Plasma glucose levels and body weight
All rats in the ARI+ and ARI– groups had a non-fasting plasma glucose concentration >350 mg/dl in tail vein blood 1 and 3 months after the start of the study. Body weights (mean ± SD) of the NC, ARI+ and ARI– groups at 3 months were 555 ± 48, 331 ± 40 and 308 ± 45 g, respectively. The diabetic rats (groups ARI+ and ARI–) had significantly lower body weights than the NC group [two-way ANOVA (groupxtime) of body weight, F(4,50) = 16.84, P < 0.000001; ANOVA and Fisher's PLSD, P < 0.02 at 1 and 3 months] (Fig. 4
).
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Threshold electrotonus findings
Tracking of TE in control rats resulted in voltage- and time-dependent changes in axonal excitability similar to those described previously (Yang et al., 2000
). Because TEs in the NC group changed slightly during the period 0–3 months, we compared TE values of ARI+ and ARI– animals with those of NC animals of the same age.
At 0 and 1 months after streptozocin treatment, tracking of TE in diabetic rats showed changes in excitability similar to those in the NC group (Figs 2 and 3).
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At 3 months, rats in the ARI– group exhibited a more negative average TEh90–100 than those in the NC and ARI+ groups; they showed more subexcitability during the application of long-duration (90–100 ms) hyperpolarizing currents than rats in the other groups, whereas the NC and ARI+ groups did not differ.
Three-way ANOVA showed significant interactions of groupxtimexfactor [F(8,100) = 15.24, P < 0.000001]. Two-way ANOVA of TEh90–100 showed a significant interaction between group and time [F(4,50) = 4.54, P = 0.003]. ANOVA and Fisher's PLSD at 3 months showed significant differences in TEh90–100 between the ARI– and NC groups (P = 0.005) and between the ARI– and ARI+ groups (P = 0.04) (Fig. 4). The same type of selective change in TEh90–100 was reproduced by systemic administration of caesium in three normal mature rats (Fig. 3). Caesium was tolerated without major cardiovascular complication until the recordings had been completed.
TEd10–20, TEd90–100 and TEh10–20 showed no significant differences among the three groups.
CMAP latency
We found differences in mean CMAP latency between the NC and ARI– groups and between the ARI+ and ARI– groups as early as 1 month, and also at 3 months (Fig. 4).
A two-way ANOVA of latency showed a significant interaction between group and time [F(4,50) = 5.93, P = 0.0005]. ANOVA and Fisher's PLSD showed significant differences in latency between the ARI– and NC groups at 1 month (P < 0.0001) and 3 months (P = 0.0001), and between the ARI– and ARI+ groups at 1 month (P = 0.006) and 3 months (P = 0.007).
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Discussion |
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In the present study, diabetic rats demonstrated early slowing of nerve conduction and subsequent development of TE findings suggestive of abnormal axonal inward rectification, whereas those treated with ARI showed no significant changes compared with normal control animals of similar age.
Diabetic neuropathy is characterized clinically by alterations in excitability which can lead to either positive (paraesthesia, dysaesthesia, pain) or negative (hypaesthesia, anaesthesia) symptoms. Factors possibly involved in the pathogenesis are increased protein glycation, accumulation of polyols, altered lipid metabolism, decreased myoinositol content, abnormal Schwann cell function, microangiopathy with hypoxia and lack of neurotrophic factors (Greene et al., 1997). One of the consequences of these is reduced activity of the sodium–potassium pump, which in turn leads to accumulation of sodium ions within the axon.
Slowing of nerve conduction has been documented early in the course of diabetes in humans and in experimental animals (hyperglycaemic neuropathy) (Thomas, 1997). This is rapidly reversed by normalizing the glucose level or by insulin therapy (Gregersen, 1968; Ward et al., 1971; Greene et al., 1975). A decreased sodium concentration gradient across the axonal membrane has been linked to the slowing of nerve conduction (Greene et al., 1997). Conduction slowing in animal models of diabetes is prevented by inhibiting aldose reductase, which catalyses the key step in the polyol pathway (Greene and Sima, 1993; Greene et al., 1999). The present study has confirmed the beneficial effect of ARI on conduction slowing. Because the ARI+ group showed body weight loss similar to that in the ARI– group, a simple maturational deficit of myelinated fibres (Sharma et al., 1981, 1985) does not fully account for the conduction slowing in our model.
More importantly, we found that the decrease in nerve excitability produced by a long-duration hyperpolarizing current is greater than normal in diabetic rats. This finding is in agreement with a previous study of TE in human diabetics (Horn et al., 1996). By reproducing this phenomenon in an experimental model, we have been able to show that it develops relatively early in the course of the disease and that it is mediated by the polyol pathway, because it was prevented by treatment with an ARI. As in the previous study (Horn et al., 1996), we found that the change in TE caused by diabetes is restricted to the responses to hyperpolarizing currents, suggesting a selective deficit in inward rectification. We were able to confirm this interpretation in our experimental model by blocking inward rectification in some animals with caesium, which produced a change very similar to that occurring in diabetes. Since inward rectification has been found in other neuronal cells to depend on the level of intracellular cAMP (cyclic adenosine monophosphate) (Akasu and Shoji, 1994; Ingram and Williams, 1996), this change may be related to the lack of cAMP reported in diabetic nerves (Ito et al., 1990). As is true for conduction slowing, this abnormality in inward rectification cannot be explained by the simple maturational deficit, because a previous study (Yang et al., 2000) demonstrated the opposite TE finding—prominent inward rectification as the hallmark of immaturity.
It is not yet clear what contribution a reduction in inward rectification makes to the symptoms of diabetic neuropathy. Impairment of vibration perception is an early sign of the disease (Thomas, 1993), and there is evidence from microneurography that this is due to a high level of fatigability of cutaneous afferents on repetitive stimulation (Mackel, 1989). Cutaneous afferents appear to express more inward rectification than motor fibres (Bostock et al., 1994). By counteracting the axonal hyperpolarization induced by the electrogenic sodium pump and the slow potassium channel, the inward rectifier limits the subexcitability that develops on high-frequency stimulation (Baker et al., 1987) and which may be responsible for the fatigue. Sensory nerves in diabetes may lose this important ability of the inward rectifiers to allow high-frequency impulse transmission. However, although there is evidence that hyperpolarization by the sodium pump causes activity-dependent conduction failure in demyelinated axons (Bostock and Grafe, 1985), this has not yet been shown to be true in diabetes, in which the pump activity seems to be compromised.
Alternatively, the slowing of conduction in diabetic nerves may be due to reduced activity of the sodium pump, intracellular sodium accumulation and membrane depolarization (Ritchie, 1985). As in a previous study in humans (Strupp et al., 1990), our data suggest the contrary: the TE changes we observed in the ARI– group were not consistent with depolarization of the whole nerve, because TE is exquisitely sensitive to membrane depolarization in that it shows a decreased change in excitability after both depolarizing and hyperpolarizing conditioning currents (Bostock et al., 1998; Yang et al., 2000). As a corollary, the impairment of inward rectification shown in the present study cannot be explained by depolarization of the resting membrane, which makes the inward rectifier less responsive to applied hyperpolarizing currents. The possibility remains, however, that activity-dependent hyperpolarization is impaired in experimental diabetes, and that sodium accumulation, rather than hyperpolarization, is responsible for the conduction failure.
The present findings may also be relevant to our understanding of the mechanism of the positive symptoms in diabetic neuropathy. The deficiency of intracellular cAMP was found to decrease the number of inward-rectifying potassium channels (Kir) in Schwann cells, which re-uptake extracellular potassium ions (Konishi, 1992, 1994). If the inward rectification of Schwann cells (Kir) is also abnormal in diabetes, deficient inward rectifiers of the Schwann cells might topically accumulate potassium ions extracellularly and adjacent to the axon, which in turn will generate ectopic impulses at depolarized segments.
Detailed physiological studies, such as the investigations of experimental demyelination that have been performed previously (Bostock and Grafe, 1985), will probably be required to resolve these issues and to demonstrate clearly the functional consequences of reduced axonal inward rectification in diabetes. If changes in inward rectification are functionally important, the ability to monitor this conductance in animals and non-invasively in humans could prove useful in the evaluation of potential treatments for diabetic neuropathy. In addition, pharmacological agents that upregulate cAMP might be useful for the treatment of patients with diabetic neuropathy.
In conclusion, we have used the rat streptozocin model of diabetes to investigate the early changes in axonal excitability in diabetic neuropathy. The evidence for reduced inward rectification, previously described in human diabetics, was reproduced in rats and was found to depend, like the reduction in conduction velocity, on the polyol pathway.
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The authors wish to thank Professor Hiroshi Shibasaki for editing and critical review of the manuscript. This work was supported by grants-in-aid from the Japanese Ministry of Science, Culture and Sports, from the Japanese Ministry of Health and Welfare and a grant from Ono Pharmaceutical Company.
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Received July 12, 2000. Revised February 2, 2001. Accepted February 9, 2001.
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