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Brain stem auditory evoked potentials and myelin changes in triethyltin-induced edema in young adult rats
EXPERIMENTAL
NEUROLOGY
66, 629-635 (1979)
Brain Stem Auditory Evoked Potentials and Myelin Changes in Triethyltin-Induced Edema in Young Adult Rats A. AMOCHAEV, Brain-Behavior
R.C.
Research Center. Francisco at Sonoma
JOHNSON,
A. SALAMY,
Langley Porter State Hospital, Received
June
Institute, Eldridge,
AND S.N.SHAH~*~ University Cahyornia
of California-San 95431
6. 1979
The effect of white matter edema induced by triethyltin (TET) intoxication on the brain stem auditory evoked potentials was examined in young adult rats. Results show that animals which received TET had lower body weight, increased brain weight, and increased water content in brain tissue. The amount of myelin (normal flotation density) recovered was reduced in TET-treated rats by approximately 45%, however, the recovery of synaptosomes was normal. The decrease in myelin content in the central nervous system of the TET-treated rats was accompanied by a significant increase in the peak latencies of all brain stem auditory evoked potentials (waves I, II, III, IV) as well as the interpeak (IV - I) difference. The potential latencies and the amount of myelin recovered became normal within 2 weeks after discontinuing TET treatment. These results demonstrate the relationship between the amount of myelin in the central nervous system and the latencies of the brain stem auditory evoked potentials and suggest that they may serve as a noninvasive measure of myelin defect.
INTRODUCTION The brain stem evoked potential to acoustic stimulation represents activation of the pathways in the auditory system from the peripheral nerve (VIIIth) to the level of the inferior colliculi (2,5). At fixed intensity and rate of presentation, click stimuli produce short-latency evoked potentials that show, during brain development, a monotonic decrease in latency with increasing age (12). In normal matured animals, however, this response is remarkably stable. The developmental period during which the decline in Abbreviations: TET-triethyltin, BAEP-brain stem auditory evoked potential I This investigation was supported by National Institutes of Health Grant NS 14938. 2 To whom all correspondence should be addressed. 629 0014-4886/79/120629-07$02.00/O Copyright 0 1979 by Academic Press, Inc. All rights of reproductmn in any form reserved
630
AMOCHAEV
ET AL.
latency occurs coincides with the period of rapid myelination (12), thereby suggesting that age-dependent changes in the brain stem auditory evoked potential (BAEP) latency may be related to changes in myelin content. The aim of the present investigation was to establish in adult animals the correlation between BAEP latency and meylin content. The administration of triethyltin (TET) in drinking water is known to produce widespread edema in the white matter of the central nervous system due to splitting of myelin (1,7,8, 10). Histological examination of the edema revealed that (i) TET produced interstitial edema of the white matter without obvious damage to the neurons, (ii) the splitting of myelin occurred in white matter but not in gray matter, and (iii) no structural changes occurred in the synapses, mitochrondria, or clear glia cell process (7, 8). We therefore investigated the effect of triethyltin intoxication on the BAEP in young adult rats and related the changes to the myelin content of the central nervous system. MATERIALS
AND METHODS
Female Sprague-Dawley rats weighing approximately 250 g were divided into two groups and housed in individual cages. One group received triethyltin (TET) sulfate dissolved in tap water (20 mg/liter), and the other group drank regular tap water for 2 weeks. This dose schedule and time period were selected on the basis of studies by Graham et al. (4). After weakness and mild paralysis developed among TET-treated rats (within approximately 1 week), solid food was replaced with a paste of pulverized chow mixed with water containing TET. Auditory brain stem evoked potentials were recorded at the end of the 2-week (1Cday) period. To examine if the effects of TET were reversible, several rats which had received TET for 2 weeks drank normal tap water for another 2 weeks prior to testing. The animals were anesthetized with a-chloralose (65 mg/kg, i.p.). Recordings were obtained with platinum-needle electrodes (Grass E2) inserted subcutaneously at the vertex of the scalp (active lead) and at the anterior border of the pinna of the stimulated ear (reference lead). The stimulus consisted of 20-ps, 40-V positive pulses (60 dBHL above experimenter’s threshold) which activated a miniature hearing aid-type receiver (M-98 Radioear) connected to a plastic tube fitted snugly into the ear canal. Stimuli were delivered monaurally at a rate of 20 per s. Bioelectric activity was amplified by a Grass P511 preamplifier set to pass a lOO- to 3000-Hz signal (l/2 amplitude range) and led to a computer of average transients (Technical Measurements Corp. C400). Four hundred responses (sweep 32-ms duration) were summated to establish the brain
DEMYELINATION
AND
EVOKED
POTENTIAL
LATENCIES
631
stem auditory evoked potential. Three averages were obtained from each rat and written out on an X-Y plotter (Hewlett Packard 7004b). The latencies and amplitudes of the first four positive-going peaks were measured and averaged to represent each rat’s evoked potential. In addition, the latency difference between peaks IV and I was computed. This measure provides an index of central conduction from the VIIIth nerve (peak I) to the level of the inferior colliculi (peak IV). A two-way, repeated measures analysis of variance was carried out separately for latency and amplitude. After stimulation, body weights were noted, the animals in each group were killed, and their brains were removed and weighed. Brains from several rats in each group were dissected to separate the brain stem. Half cortices from the remaining rats in each group were used for the preparation of myelin and synaptosomes by sucrose density gradient centrifugation (6). The other half of the cortices and the brain stems were weighed, frozen, and lyophilized for determination of moisture content. RESULTS Typical recordings from four representative rats of the control (A) and TET-treated (B) groups are shown in Fig. 1. TET produced an increase in response latency of all peaks and a decrease in amplitude of peaks I, II, and III. The means and standard deviations for peak latencies and amplitudes are presented in Table 1. The results of the two-way analysis of variance on the peak latencies showed a significant difference between groups (F[l/25] = 698, P < 0.001) as well as a significant group x peak interaction (F[3/75] = 27.5, P < 0.001). An analysis of specific contrasts (Newman-Keul’s) showed a significant difference between all four peaks as well as the peak IV - I latency difference (P < 0.01). Similar results were observed for peak amplitudes (F[l/25] = 12.8, P < 0.001). Again a significant group x peak interaction (F[3/75] = 3.28, P < 0.02) emerged. Specific contrasts revealed that the amplitude of the first three peaks (P < O.Ol), but not peak IV, differed among groups. When TET-treated rats were recovered, the peak latencies returned to normal within the 2-week period. Although the amplitude of peak III was normal, the amplitude of peaks I and II remained lower. The results presented in Table 2 indicate that rats receiving TET had reduced body weights and brain weights were higher as a result of increased moisture content (Student’s t = 2.46, P < 0.05) with respect to the controls. The increase in moisture was most evident in the brain stem (t = 7.82, P < 0.01). The yield of myelin was reduced approximately 45% as a result of TET administration, whereas synaptosomal yield was un-
632
AMOCHAEV
ET AL.
A
FIG. 1. Effect of triethyltin administration on brain stem auditory evoked potentials. Each trace represents an average of 400 potentials obtained from a different rat. A-four control animals, B-four TET-treated animals. Upward deflection indicates positivity at the active electrode (vertex).
affected. Body and brain weights and water and myelin content of the central nervous system became normal within 2 weeks after discontinuing TET treatment. DISCUSSION It is well established that triethyltin produces an increase in the water content of the brain. This effect is apparent only in the white matter. Electron microscopic examination of triethyltin-induced edema also revealed that the water is intramyelinic and causes splitting of myelin at the intraperiod line (1). Eto et al. (3) and Smith (13) measured, by careful chemical analysis, the extent of myelin loss and the compositional changes
DEMYELINATION
AND EVOKED TABLE
Effect of Triethyltin
(TET) Intoxication
POTENTIAL
633
LATENCIES
1 on Brain Stem Auditory Potentials
Peak latencies (ms) Treatment
I
II
III
IV
IV - 1”
Control (14)” TET (13) Post-TET (4) 2 weeks
1.10 2 0.12’ 1.36* ? 0.21
1.98 + 0.08 2.37* r 0.13
2.62 k 0.13 3.15* 2 0.10
3.70 + 0.23 4.56* 2 0.20
2.61 + 0.24 3.21* + 0.27
1.10 + 0.21
1.98 it 0.23
2.60 + 0.22
3.60 ? 0.24
2.55 -t 0.17
Peak amplitudes (standardized Control (14) TET (13) Post-TET (4) 2 weeks
units)
14.5 2 3.6 5.6* r+ 2.3
16.8 ? 4.1 11.4 + 3.9*
13.9 r 4.6 7.2* 2 3.4
6.1 ? 2.3 5.0 i- 1.3
-
8.5 + 3.3
12.0 + 4.5
11.5 i- 6.4
5.1 t 1.0
-
D Difference in latencies of peaks IV and I is taken as a measure of central conduction. DNumbers in parentheses represent the number of rats tested. c Mean + S.D. * Significantly different from control: P < 0.01.
in the myelin membrane. In animals exposed to TET (5 to 10 mg/liter) for periods of 1 and 2 months, myelin loss approximated 39 and 46%, respectively (3). Smith (13), however, observed only 16% loss of myelin in male and 25% loss in the brains of female rats exposed to TET (10 mg/l) for 4 TABLE
2
Effect of Triethyltin (TET) Intoxication on Body Weight, Brain Weight, Moisture Content, and Myelin and Synaptosomal Yield Control Body weight (g) Brain weight (g) Moisture content (%) Cortex Brain stem Myelin yield (mg/g brain) Synaptosomal yield (mg/g brain)
TET
2 weeks post-TET
237.5 c 5.24 (14)” 156.6* k 6.05 (13) 1.8700 ? 0.193 (14) 2.0804* t 0.0832 (13)
223.0 2 6.7 (5) 2.033 ? 0.09 (5)
80.00 + 0.46 (8) 76.35 + 1.25 (6) 19.6 + 0.60 (8)
82.70** 2 0.64 81.15* k 0.82 10.38* 2 0.90
(7) (6) (7)
78.6 k 0.28 (5) 77.4 k 1.41 (5) 17.25 + 1.88 (5)
14.19 + 1.11 (8)
14.39* + 1.02
(7)
16.14 2 1.11 (5)
U Numbers in parentheses represent the number of rats or tissue samples analysed. Mean 2 SD. * Significantly different: P < 0.005. ** Significantly different: P < 0.025.
634
AMOCHAEV
ET AL.
weeks. Although the amount of TET in drinking water (20 mg/liter) used in the present study was relatively high, the animals received TET administration for the substantially shorter period of 2 weeks. Despite these methodologic differences, similar results in terms of myelin loss were obtained by us and by Eto et pl. (3). Further, under our experimental conditions, the recovery of synaptosomes (nerve ending particles) was not affected. This appears to be consistent with the electron microscopic studies (7,8) in which no structural changes were observed in the synapses. Triethyltin intoxication produced significant alterations in selected parameters of the surface-recorded brain stem auditory evoked potential. The effect of TET on response latencies was evident from the periphery to the level of the inferior colliculi (i.e., peaks I-IV). The increase in peak latency and its reversal within 2 weeks resemble the finding of Graham et al. (4) on the effect of TET on motor nerve conduction velocity. Because the reduction in myelin yield parallels the increase in potential latency, this change must be attributed to the disruption of myelin sheaths. This view is supported by the fact that when the recovery of myelin attains normality (after 2-week discontinuation of TET), peak latencies also approach their normal values. This association between experimentally induced myelin loss and latency prolongation in adult rats is consistent with the finding of our earlier studies in developing rats (11, 12). Support for the high correlation between latency changes and myelin abnormalities can also be derived from human studies of brain stem auditory evoked potentials in multiple sclerosis (9) and other demyelinating diseases. (14, 15). Patients with brain stem lesions showed increased latencies and interpeak differences. Triethyltin-treated rats may therefore be considered as a model for edema-associated demyelination or for diseases where spongy degeneration of white matter occurs such as in Canavan’s disease. The brain stem auditory evoked potential may hold diagnostic value for these and other types of demyelinating diseases. REFERENCES R. D. TERRY. 1%3. Fine structure and electrolyte analysis of cerebral edema induced by alkyl tin intoxication. J. Neuropathoi. Exp. Neurol. 22: 403-413. BUCHWALD, J. S., AND C. M. HUANG. 1975. Far-field acoustic response: origins in the cat. Science 189: 382-384. ETO, Y., K. SUZUKI, AND K. SUZUKI. 1971. Lipid composition of rat brain myelin in triethyltin-induced edema. J. Lipid Res. 12: 570-579. GRAHAM, D. I., P. V. DE JESUS, D. E. PLEASURE, AND N. K. GONATAS. 1976. Triethyltin sulfate-induced neuropathy in rats: electrophysiologic, morphologic and biochemical studies. Arch. Neurol. 33: 40-48. JEWETT, D. L. 1970. Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Elecrroenceph. C/in. Neurophysiol. 28: 609-618.
1. ALEU,
2. 3. 4.
5.
F. P., R. KATZMAN,
AND
DEMYELINATION
AND EVOKED
POTENTIAL
LATENCIES
635
6. JOHNSON,R. C., C. M. MCKEAN, AND S. N. SHAH. 1977. Fatty acid composition oflipids in myelin and synaptosomes in phenylketonuria and Down’s Syndrome. Arch. Neural. 34: 288-294. 7. LEE, J. C., AND L. BAKAY. 1965. Ultrastructural changes in the edematous central nervous system: triethyltin edema. Arch. Neural. 13: 48-57. 8. MAGEE, P. N., M. B. STONER, AND J. M. BARNES. 1975. The experimental production of edema in the central nervous system of the rat by triethyltin compounds. J. Path. Butt. 63: 107- 123. 9. ROBINSON, K., AND P. RUDGE. 1977. Abnormalities of the auditory evoked potentials in patients with multiple sclerosis. Brain 11: 19-40. 10. SCHEINBERG, L. E., J. M. TAYLOR, I. HEIUOG, AND S. MANDELL. 1966. Optic and peripheral nerve response to triethyltin intoxication in rabbits. Biochemical and ultrastructural Studies. J. Neuropathol. Exp. Neural. 25: 202-213. 1 I. SHAH, S. N., V. K. BHARGAVA, R. C. JOHNSON, AND C. M. MCKEAN. 1978. Latency changes in brainstem auditory evoked potentials associated with impaired brain myelination. Exp. Neural. 58: 11 l- 118. 12. SHAH, S. N., V. K. BHARGAVA, AND C. M. MCKEAN. 1978. Maturationalchangesinearly auditory evoked potentials and myelination of the inferior colliculus in rats. Neuroscience 3: 561-563. 13. SMITH, M. E. 1973. Studies on the mechanism of demyelination: triethyltin-induced demyelination. J. Neurochem. 21: 357-372. 14. STARR. A., AND L. J. ACHOR. 1975. Auditory brainstem responses in neurological disease. Arch. Neural. 32: 761-766. 15. STOCKARD, J. J., AND V. S. ROSSITER. 1977. Clinical and pathological correlates of brainstem auditory response abnormalities. Neurology (Minneapolis) 27: 316-325.
NEUROLOGY
66, 629-635 (1979)
Brain Stem Auditory Evoked Potentials and Myelin Changes in Triethyltin-Induced Edema in Young Adult Rats A. AMOCHAEV, Brain-Behavior
R.C.
Research Center. Francisco at Sonoma
JOHNSON,
A. SALAMY,
Langley Porter State Hospital, Received
June
Institute, Eldridge,
AND S.N.SHAH~*~ University Cahyornia
of California-San 95431
6. 1979
The effect of white matter edema induced by triethyltin (TET) intoxication on the brain stem auditory evoked potentials was examined in young adult rats. Results show that animals which received TET had lower body weight, increased brain weight, and increased water content in brain tissue. The amount of myelin (normal flotation density) recovered was reduced in TET-treated rats by approximately 45%, however, the recovery of synaptosomes was normal. The decrease in myelin content in the central nervous system of the TET-treated rats was accompanied by a significant increase in the peak latencies of all brain stem auditory evoked potentials (waves I, II, III, IV) as well as the interpeak (IV - I) difference. The potential latencies and the amount of myelin recovered became normal within 2 weeks after discontinuing TET treatment. These results demonstrate the relationship between the amount of myelin in the central nervous system and the latencies of the brain stem auditory evoked potentials and suggest that they may serve as a noninvasive measure of myelin defect.
INTRODUCTION The brain stem evoked potential to acoustic stimulation represents activation of the pathways in the auditory system from the peripheral nerve (VIIIth) to the level of the inferior colliculi (2,5). At fixed intensity and rate of presentation, click stimuli produce short-latency evoked potentials that show, during brain development, a monotonic decrease in latency with increasing age (12). In normal matured animals, however, this response is remarkably stable. The developmental period during which the decline in Abbreviations: TET-triethyltin, BAEP-brain stem auditory evoked potential I This investigation was supported by National Institutes of Health Grant NS 14938. 2 To whom all correspondence should be addressed. 629 0014-4886/79/120629-07$02.00/O Copyright 0 1979 by Academic Press, Inc. All rights of reproductmn in any form reserved
630
AMOCHAEV
ET AL.
latency occurs coincides with the period of rapid myelination (12), thereby suggesting that age-dependent changes in the brain stem auditory evoked potential (BAEP) latency may be related to changes in myelin content. The aim of the present investigation was to establish in adult animals the correlation between BAEP latency and meylin content. The administration of triethyltin (TET) in drinking water is known to produce widespread edema in the white matter of the central nervous system due to splitting of myelin (1,7,8, 10). Histological examination of the edema revealed that (i) TET produced interstitial edema of the white matter without obvious damage to the neurons, (ii) the splitting of myelin occurred in white matter but not in gray matter, and (iii) no structural changes occurred in the synapses, mitochrondria, or clear glia cell process (7, 8). We therefore investigated the effect of triethyltin intoxication on the BAEP in young adult rats and related the changes to the myelin content of the central nervous system. MATERIALS
AND METHODS
Female Sprague-Dawley rats weighing approximately 250 g were divided into two groups and housed in individual cages. One group received triethyltin (TET) sulfate dissolved in tap water (20 mg/liter), and the other group drank regular tap water for 2 weeks. This dose schedule and time period were selected on the basis of studies by Graham et al. (4). After weakness and mild paralysis developed among TET-treated rats (within approximately 1 week), solid food was replaced with a paste of pulverized chow mixed with water containing TET. Auditory brain stem evoked potentials were recorded at the end of the 2-week (1Cday) period. To examine if the effects of TET were reversible, several rats which had received TET for 2 weeks drank normal tap water for another 2 weeks prior to testing. The animals were anesthetized with a-chloralose (65 mg/kg, i.p.). Recordings were obtained with platinum-needle electrodes (Grass E2) inserted subcutaneously at the vertex of the scalp (active lead) and at the anterior border of the pinna of the stimulated ear (reference lead). The stimulus consisted of 20-ps, 40-V positive pulses (60 dBHL above experimenter’s threshold) which activated a miniature hearing aid-type receiver (M-98 Radioear) connected to a plastic tube fitted snugly into the ear canal. Stimuli were delivered monaurally at a rate of 20 per s. Bioelectric activity was amplified by a Grass P511 preamplifier set to pass a lOO- to 3000-Hz signal (l/2 amplitude range) and led to a computer of average transients (Technical Measurements Corp. C400). Four hundred responses (sweep 32-ms duration) were summated to establish the brain
DEMYELINATION
AND
EVOKED
POTENTIAL
LATENCIES
631
stem auditory evoked potential. Three averages were obtained from each rat and written out on an X-Y plotter (Hewlett Packard 7004b). The latencies and amplitudes of the first four positive-going peaks were measured and averaged to represent each rat’s evoked potential. In addition, the latency difference between peaks IV and I was computed. This measure provides an index of central conduction from the VIIIth nerve (peak I) to the level of the inferior colliculi (peak IV). A two-way, repeated measures analysis of variance was carried out separately for latency and amplitude. After stimulation, body weights were noted, the animals in each group were killed, and their brains were removed and weighed. Brains from several rats in each group were dissected to separate the brain stem. Half cortices from the remaining rats in each group were used for the preparation of myelin and synaptosomes by sucrose density gradient centrifugation (6). The other half of the cortices and the brain stems were weighed, frozen, and lyophilized for determination of moisture content. RESULTS Typical recordings from four representative rats of the control (A) and TET-treated (B) groups are shown in Fig. 1. TET produced an increase in response latency of all peaks and a decrease in amplitude of peaks I, II, and III. The means and standard deviations for peak latencies and amplitudes are presented in Table 1. The results of the two-way analysis of variance on the peak latencies showed a significant difference between groups (F[l/25] = 698, P < 0.001) as well as a significant group x peak interaction (F[3/75] = 27.5, P < 0.001). An analysis of specific contrasts (Newman-Keul’s) showed a significant difference between all four peaks as well as the peak IV - I latency difference (P < 0.01). Similar results were observed for peak amplitudes (F[l/25] = 12.8, P < 0.001). Again a significant group x peak interaction (F[3/75] = 3.28, P < 0.02) emerged. Specific contrasts revealed that the amplitude of the first three peaks (P < O.Ol), but not peak IV, differed among groups. When TET-treated rats were recovered, the peak latencies returned to normal within the 2-week period. Although the amplitude of peak III was normal, the amplitude of peaks I and II remained lower. The results presented in Table 2 indicate that rats receiving TET had reduced body weights and brain weights were higher as a result of increased moisture content (Student’s t = 2.46, P < 0.05) with respect to the controls. The increase in moisture was most evident in the brain stem (t = 7.82, P < 0.01). The yield of myelin was reduced approximately 45% as a result of TET administration, whereas synaptosomal yield was un-
632
AMOCHAEV
ET AL.
A
FIG. 1. Effect of triethyltin administration on brain stem auditory evoked potentials. Each trace represents an average of 400 potentials obtained from a different rat. A-four control animals, B-four TET-treated animals. Upward deflection indicates positivity at the active electrode (vertex).
affected. Body and brain weights and water and myelin content of the central nervous system became normal within 2 weeks after discontinuing TET treatment. DISCUSSION It is well established that triethyltin produces an increase in the water content of the brain. This effect is apparent only in the white matter. Electron microscopic examination of triethyltin-induced edema also revealed that the water is intramyelinic and causes splitting of myelin at the intraperiod line (1). Eto et al. (3) and Smith (13) measured, by careful chemical analysis, the extent of myelin loss and the compositional changes
DEMYELINATION
AND EVOKED TABLE
Effect of Triethyltin
(TET) Intoxication
POTENTIAL
633
LATENCIES
1 on Brain Stem Auditory Potentials
Peak latencies (ms) Treatment
I
II
III
IV
IV - 1”
Control (14)” TET (13) Post-TET (4) 2 weeks
1.10 2 0.12’ 1.36* ? 0.21
1.98 + 0.08 2.37* r 0.13
2.62 k 0.13 3.15* 2 0.10
3.70 + 0.23 4.56* 2 0.20
2.61 + 0.24 3.21* + 0.27
1.10 + 0.21
1.98 it 0.23
2.60 + 0.22
3.60 ? 0.24
2.55 -t 0.17
Peak amplitudes (standardized Control (14) TET (13) Post-TET (4) 2 weeks
units)
14.5 2 3.6 5.6* r+ 2.3
16.8 ? 4.1 11.4 + 3.9*
13.9 r 4.6 7.2* 2 3.4
6.1 ? 2.3 5.0 i- 1.3
-
8.5 + 3.3
12.0 + 4.5
11.5 i- 6.4
5.1 t 1.0
-
D Difference in latencies of peaks IV and I is taken as a measure of central conduction. DNumbers in parentheses represent the number of rats tested. c Mean + S.D. * Significantly different from control: P < 0.01.
in the myelin membrane. In animals exposed to TET (5 to 10 mg/liter) for periods of 1 and 2 months, myelin loss approximated 39 and 46%, respectively (3). Smith (13), however, observed only 16% loss of myelin in male and 25% loss in the brains of female rats exposed to TET (10 mg/l) for 4 TABLE
2
Effect of Triethyltin (TET) Intoxication on Body Weight, Brain Weight, Moisture Content, and Myelin and Synaptosomal Yield Control Body weight (g) Brain weight (g) Moisture content (%) Cortex Brain stem Myelin yield (mg/g brain) Synaptosomal yield (mg/g brain)
TET
2 weeks post-TET
237.5 c 5.24 (14)” 156.6* k 6.05 (13) 1.8700 ? 0.193 (14) 2.0804* t 0.0832 (13)
223.0 2 6.7 (5) 2.033 ? 0.09 (5)
80.00 + 0.46 (8) 76.35 + 1.25 (6) 19.6 + 0.60 (8)
82.70** 2 0.64 81.15* k 0.82 10.38* 2 0.90
(7) (6) (7)
78.6 k 0.28 (5) 77.4 k 1.41 (5) 17.25 + 1.88 (5)
14.19 + 1.11 (8)
14.39* + 1.02
(7)
16.14 2 1.11 (5)
U Numbers in parentheses represent the number of rats or tissue samples analysed. Mean 2 SD. * Significantly different: P < 0.005. ** Significantly different: P < 0.025.
634
AMOCHAEV
ET AL.
weeks. Although the amount of TET in drinking water (20 mg/liter) used in the present study was relatively high, the animals received TET administration for the substantially shorter period of 2 weeks. Despite these methodologic differences, similar results in terms of myelin loss were obtained by us and by Eto et pl. (3). Further, under our experimental conditions, the recovery of synaptosomes (nerve ending particles) was not affected. This appears to be consistent with the electron microscopic studies (7,8) in which no structural changes were observed in the synapses. Triethyltin intoxication produced significant alterations in selected parameters of the surface-recorded brain stem auditory evoked potential. The effect of TET on response latencies was evident from the periphery to the level of the inferior colliculi (i.e., peaks I-IV). The increase in peak latency and its reversal within 2 weeks resemble the finding of Graham et al. (4) on the effect of TET on motor nerve conduction velocity. Because the reduction in myelin yield parallels the increase in potential latency, this change must be attributed to the disruption of myelin sheaths. This view is supported by the fact that when the recovery of myelin attains normality (after 2-week discontinuation of TET), peak latencies also approach their normal values. This association between experimentally induced myelin loss and latency prolongation in adult rats is consistent with the finding of our earlier studies in developing rats (11, 12). Support for the high correlation between latency changes and myelin abnormalities can also be derived from human studies of brain stem auditory evoked potentials in multiple sclerosis (9) and other demyelinating diseases. (14, 15). Patients with brain stem lesions showed increased latencies and interpeak differences. Triethyltin-treated rats may therefore be considered as a model for edema-associated demyelination or for diseases where spongy degeneration of white matter occurs such as in Canavan’s disease. The brain stem auditory evoked potential may hold diagnostic value for these and other types of demyelinating diseases. REFERENCES R. D. TERRY. 1%3. Fine structure and electrolyte analysis of cerebral edema induced by alkyl tin intoxication. J. Neuropathoi. Exp. Neurol. 22: 403-413. BUCHWALD, J. S., AND C. M. HUANG. 1975. Far-field acoustic response: origins in the cat. Science 189: 382-384. ETO, Y., K. SUZUKI, AND K. SUZUKI. 1971. Lipid composition of rat brain myelin in triethyltin-induced edema. J. Lipid Res. 12: 570-579. GRAHAM, D. I., P. V. DE JESUS, D. E. PLEASURE, AND N. K. GONATAS. 1976. Triethyltin sulfate-induced neuropathy in rats: electrophysiologic, morphologic and biochemical studies. Arch. Neurol. 33: 40-48. JEWETT, D. L. 1970. Volume-conducted potentials in response to auditory stimuli as detected by averaging in the cat. Elecrroenceph. C/in. Neurophysiol. 28: 609-618.
1. ALEU,
2. 3. 4.
5.
F. P., R. KATZMAN,
AND
DEMYELINATION
AND EVOKED
POTENTIAL
LATENCIES
635
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