glycine involvement in ddt��induced myoclonus

Movement Disorders

Q 1988 Movement Disorder Society Vol. 3, NO. 1. 1988, pp. 77-87

Glycine Involvement in DDT-Induced Myoclonus

Daniel Dung Truong, Justo Garcia De Yebenes, Gianni Pezzoli, Vernice Jackson-Lewis, and Stanley Fahn

Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.

Summary: The DDT syndrome in rats consists of tremor. myoclonus, running seizures, hyperthermia, episodic boxing, and excessive grooming. DDT did not change whole-brain glycine levels when the rats had stimulus-sensitive myoclonus, spontaneous myoclonus, or seizures. However, regional analysis showed a decrease in glycine levels in the pons and medulla initially, but they rose again despite worsening of the myoclonus. Glycine given intraventricularly and the glycine prodrug, milacemide, given intrapentoneally suppressed DDT-induced myoclonus. A dose of milacemide that prevented DDT-induced myoclonus caused a significant increase in glycine levels in cortex, septum accumbens, cerebellum, striatum, hypocampus. diencephalon, midbrain, pons, and medulla. The increase was most marked in the forebrain structures. There was no change in serine levels in these areas. These data suggest that the glycinergic system may be playing an important role in the manifestation of DDT-induced myoclonus. Key Words: Myoclonus-DDT-Glycine-Mila- cemide-Regional brain glycine levels.

Myoclonus refers to sudden, brief, shocklike involuntary movements caused by muscular contraction or inhibitions arising from the central nervous system (1). It accompanies a variety of neurological diseases. Some of them may be causally related to abnormalities of serotonin neurotransmission such as hypoxic intention myoclonus, in which biochemical and pharmacological data have indicated a depressed serotonin transmission in many patients (2,3).

The role of glycine, a putative inhibitory neurotransmitter at inhibitory synapses (4-7), particularly in the spinal cord and brainstem, is not clear in myoclonus. Unilateral stereotaxic infusion of strychnine, a glycine receptor antagonist, into rat medullary reticular formation has induced generalized stimulus-sensitive myoclonus (8). Valproic acid, an effective drug in some patients with myoclonus

~~

Presented in part at the American Neurological Association meeting in Boston 1986. Address correspondence and reprint requests to Dr. Stanley Fahn. Neurological Institute, 710 West

168th Street, New York, NY 10032, U.S.A.

77

78 D. D. TRUONG ETAL.

(9), applied iontophoretically, augments the inhibitory effects of glycine on retinal ganglion cells in vitro (10) and increases plasma and urinary glycine by inhibiting hepatic glycine cleavage enzymes (1 1). Benzodiazepines, also commonly used and effective in the treatment of myoclonus, are inhibitors of [3H]strychnine binding, and their clinical efficacy parallels the potency of antagonism of in vitro strychnine binding (12,13). On the other hand, hyperglycinemia has been asso- ciated with myoclonus (14).

The insecticide 1,1,l-trichloro-2,2-bis(-chlorophenyl)ethane (DDT) produces a neurotoxic syndrome consisting of tremor, myoclonus, respiratory depression, hyperthermia, and seizures, which often leads to death (15,16). The DDT-induced myoclonus has been a useful model in investigating myoclonus. Electrophysio- logical experiments have shown it to be more similar to human myoclonus (17) than the myoclonus in the serotonin syndrome which does not resemble its human counterpart (18). Previous investigations on DDT-induced myoclonus have concentrated on the role that serotonin may play in that syndrome (19). Treatment with 5-HTP, serotonin precursor, or serotonin agonists resulted in improvement; antagonists worsened it (19). We decided to investigate the possible role of glycine in DDT-induced myoclonus, and we report the results of these studies.

MATERIALS AND METHODS

Animals and drugs

Male Sprague Dawley rats weighing 200-230 g were used in all experiments. The animals had free access to food and water. They were housed under standard laboratory conditions and under 12-h light-dark cycles. Intraventricular cannulae (Plastic Products, Roanoke, VA) were implanted under pentobarbital anesthesia at least 7 days prior to experiments. The cannulae were kept in place with dental acrylic cement and secured by two jeweled screws, which were drilled to the scalp. The coordinates were anterior-posterior -0.08 cm, lateral - 0.13 cm, dorso ventral -0.40 cm from bregma. After implantation, cannulae were fitted with a stylet to keep them patent.

Animals were fasted overnight before being treated with DDT 600 mg/kg mixed in warmed corn oil and administered per 0 s in a volume of 2 mykg. Due to uncer- tainty about the penetration of glycine and other amino acids across the blood- brain barrier (20), we gave glycine, serine, aminobutyric acid (GABA), and p- alanine intraventricularly (i.c.v.), dissolved in saline and infused via an infusion pump over 10 min. Milacemide, a glycine pro-drug, which has been shown to penetrate the blood-brain barrier and increase the brain glycine level (20), was given intraperitoneally (i.p.). DDT was obtained from Aldrich Pharmaceuticals (Milwaukee, WI), glycine, serine, and tetrahydrofuran from Sigma Chemical Co. (St. Louis, MO), milacemide from Continental Pharma (Belgium), and fluoralde- hyde from Pierce Chemical (Rockfort, IL). Glycine, serine, GABA, p-alanine, and milacemide were dissolved in 0.9% saline before use.

Movement Disorders, Vol. 3, No. I . 1988

GLYCINE IN DDT-INDUCED MYOCLONUS 79

Behavioral assessment

Animals were housed in individual Plexiglas cages and their behaviors were rated according to a myoclonus rating scale (Table 1). External acoustic stimulation was done by a General Electric tape recorder (Model 3-5151B) which gave a sound taped from a metronome at intervals of 1 ticus at a-preset volume. Each observation lasted 2 min, the first one without acoustic stimulation, the second with acoustic stimulation prior to intragastric treatment with DDT, and then at 30-min intervals over 5-6 h afterwards, depending on the experiments.

Biochemical determinations

Rats given 600 mg/kg of DDT in warmed corn oil p.0. were killed at different time intervals; the control group received corn oil only. After decapitation, the brains were removed immediately, dissected rapidly, and frozen on dry ice. Brain regions were immediately weighed and homogenized in ice-cold 0.2 M perchloric acid (Polytron). They were centrifuged for 10 min at 15,000 rpm. The superna- tants were stored at -80°C until used. Glycine levels were measured using high performance liquid chromatography with fluorometric detection modified from the method previously described (21) using a 3km Ultrasphere column 4.5 mm x 7.5 cm. Due to the decay of the fluorescence amino acid o-phthaldialdehyde (OPA) compound, especially glycine (22), an automatic time-fixed Gilson 23 1 sample injector and Gilson Model 407 Dilutor were used (Gilson, Middleton, WI). Other equipment included a DuPont Instrument 850 gradient pump and a Kratos FS 950 fluorescence detector. The mobile phase was pure methanol. The buffer solution consisted of 0. I M sodium acetate, methanol, and tetrahydrofuran (900:95:5) at pH 7.2. We used commercial OPA solution. After 100 pI of OPA was allowed to react with 100 pl of sample for exactly I min, the pH of the mixed solution was then lowered with 100 11.1 0.1 M sodium monophosphate buffer, pH 4, to protect the column before injection. Norvaline was used as internal standard. Good separation of glycine and threonine peaks was obtained by isocratic run of the mobile phase concentration at 13% until the glycine peak had eluted before switching to gradient phase with increasing methanol concentration. The entire run lasted 24 min. Calculations were done by a Spectra Physic SP 4100 computing integrator.

TABLE 1. Myoclonus rating scale

Rating Behavior

0 Normal 1 2 3 Marked stimulus-sensitive axial myoclonus 4 5 6

Myoclonus of isolated body parts such as forepaws; ear twitches and wetdog shakes Stimulus-sensitive axial myoclonus but irregularly following external stimulation

Intermittent myoclonus without external stimulation Continuous myoclonus without external stimulation Intermittent convulsions or death during the evaluation period

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80 D. D . TRUONG ET AL.

Statistical analysis Statistical analysis was performed using the CLINFO software program, ver-

sion 4.3, on a Digital Computer VAXNMS at the General Clinical Research Center, Columbia University College of Physicians and Surgeons. The effects of glycine, serine, GABA, beta-alanine, and milacemide on DDT-induced myoclonus were analyzed using the analysis of variance. When the null hypothesis was rejected, the Student-Newman-Keuls test was used to analyze the differ- ences between groups. Comparisons at particular glycine levels were made using the unpaired Student’s c test.

RESULTS Behaviors

Rats treated with DDT (600 mg/kg) developed a progressive neurological syndrome. Excessive grooming was present after 1 h. Forepaw myoclonus, ear- twitches, and wet-dog shakes were observed at 1.5 h. Acoustical sensitive myoclonus was present at 2 h and its frequency increased with time. Interestingly, at this time point, actions such as walking suppressed the myoclonus. The rats often had hunchback and a sphinx-like posture. Spontaneous myoclonus was present at 3 h after the treatment. Its severity increased with time and was potentiated by sensory stimuli such as sounds, blowed air, and touching. A dystonic feature of axial body twisting and recurrent episodes of boxing, especially in the presence of other rats, were observed. Ataxia developed at around 4.5 h and when severe the animals were unable to walk or stand; they lay flat on the floor. At 5 h 20% of the rats had running seizures, with short-burst episodes of running. The seizures evolved later into clonic, then tonic fits in the upper extremities and clonic fits in the lower extremities prior to expiration. Death was nearly uniform-between 5 and 7 hours.

Intracerebroventricular injection of glycine to normal rats produced sedation, mastication, piloerection, and hypothermia. Glycine, when given at the same time as DDT, reduced the severity and delayed the onset of DDT-induced myoclonus in a dose-dependent pattern (Table 2 and Fig. I). At a glycine dose of 26 pmol per rat only acoustic-induced rnyoclonus was seen. When glycine was given at 2.5 h after DDT (after the onset of myoclonus), no significant difference in the myoclonus scores between 3 and 6 h was found between the control and glycine- treated groups. Serine and p-alanine in equimolar concentration to glycine did not modify the latency nor the severity of the myoclonus (Table 2). GABA slightly decreased the myoclonus scores and was considered statistically significant by Student’s t test; analysis of variance (ANOVA), however, did not reject the null hypothesis.

Milacemide dose and frequency were chosen from preliminary experiments in which the drug caused hypothermic effects similar to glycine given i.c.v. (unpub- lished observations). Milacemide given at 200 mg/kg or 400 mg/kg i.p. every 2 h reduced DDT-induced myoclonus in a dose-dependent pattern (Table 3 and Fig. 2A). At a dose of 400 m a g every 2 h the myoclonus was fully suppressed, ataxia was not noticed, and the rats moved freely. Milacemide was also shown to de-

Movement Disorders, Vol. 3. No. I , 1988


TABLE 2. Effect of intracerebroventricular administered inhibitory amino acids on DDT-induced myoclonus

Time after Dose DDT

Mean myoclonus Score + SEM

Saline 10 pi Glycine 6.5 pmoV10 pl

13 pmol/lO pl 19.5 pmoVlO pl 26 pmol/lO pl

Serine 26 pmol/lO pi GABA 26 pmoVlO p1 P- Alanine 26 pmoV10 pi Saline 10 pl Glycine 26 p,mol/lO pI

0 0 0 0 0 0 0 0 2S/h 2.5lh

3.76 + 0.24 2.82 + 0.67 2.96 + 0.59 1.43 + 0.24" 0.76 + 0.25" 2.82 + 0.16 1.98 + 0.29 2.40 + 0.40 4.56 + 0.28 4.11 + 0.28

~

Drugs were given intracerebroventricularly at the same time as DDT (600 mg/kg) p.0. The mean myoclonus score for each treatment group was calculated by averaging the scores recorded at 0.5 h intervals over a 2-5 h period following administration of DDT. Glycine suppressed myoclonus in a dose-dependent pattern but serine, GABA, and beta-alanine at 26 pnol/lO pl were not effective. When glycine or saline control were given at 2.5 h, the mean myoclonus scores were averaged for the interval between 3 and 6 h. Glycine was not effective when given after the appearance of myoclonus.

a p < 0.05.

crease myoclonus scores when given after the onset of the myoclonus in the DDT model. However, it was less effective than when given before the onset of the myoclonus and required more frequent dosage (Table 4 and Fig. 2B).

Biochemistry

Whole brain glycine and serine levels in animals treated with DDT (600 mg/kg) and killed at 2.5 h (the time of stimulus-induced rnyoclonus), 3.5 h (time of spontaneous myoclonus), and at 5 h (time of seizure activity) did not change significantly statistically (results not shown). Regional brain dissections were performed on rats killed at 2.5 h and 5 h. Glycine levels decreased significantly statistically only in midbrain. pons, and medulla but not in cortex, cerebellum, striatum, diencephalon, or cervical cord (Table 5 ) . A time-course study of glycine levels of the pons and medulla showed a decrease of glycine concentration for up

6 - *---* Glycim 26 r m O l / I01 &....A Glycine 19.5 pmoV rot m--a Glycinr 6.5 pmol/ rat

5- - Solinr

4-

0 I 2 3 4 5

HOURS AFTER DOT

FIG. 1. Effect of i.c.v. glycine on DDT-induced myoclonus. Glycine i.c.v. suppressed rnyoclonus in a dose-dependent manner and also prolonged the latency until onset of myoclonus.

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82 D. D. TRUONG ET AL.

TABLE 3. Effect of milacemide on DDT-induced myoclonus

Dose in mg/kg Number of Mean myoclonus score Drug every 2 h rats between 2 and 5 h + SEM

Normal saline (controls) - 14 Milacemide 200 mg 6 Milacemide 400 mg 8

3.90 + 0.46 2.09 + 0.37" 0.43 + 0.03"

~~~ ~

Milacemide 200 mg/kg or 400 mg/kg, i.p., was given every 2 h because of its short half-life. Control rats received normal saline every 2 h. Milacemide suppressed DDT-induced myoclonus in a dose-dependent manner. The null hypothesis of equality was rejected among all three groups.

a p < 0.05.

to 4 h and then an increase afterwards, despite continuous worsening of the myoclonus evolving into seizures (Fig. 3).

Milacemide (400 mg/kg) increased brain glycine levels 1 h after i.p. injection in all eight brain regions dissected. The increase was, however, low in the brainstem compared with the marked increase in other brain areas (Table 6). Serine levels did not change significantly. Milacemide given at 0 and 2 h increased glycine levels in pons and medulla in DDT (600 mg/kg)-treated rats killed 3 h after DDT exposure (Fig. 4). Glycine i.c.v. also increased glycine levels in DDT-treated rats (Fig. 4).

DISCUSSION

Our results confirm and extend a previous report that milacemide increases brain glycine levels (20). Interestingly, the increases were more marked in the

B o D D T t SALINE

DDT t MlLA 400mg/kg 6 - o DDTtSALINE v) A D DT t MlLA 200 mg/ kg

A

v)

4 - 2 3 -

2 2 - V

0 I I I I I I

0 1 2 3 4 5 6 0 1 2 3 4 5 6 HOURS AFTER DOT HOURS AFTER DDT

FIG. 2. A Effect of milacemide on DDT-induced myoclonus. Rats were given DDT 600 mg/kg p.0. and treated with milacemide 200 mg/kg or 400 mg/kg i.p., each dose being given at 0, 2. and 4h. Milacemide suppressed myoclonus in a dose-dependent manner. Axial myoclonus failed to develop. B: Effect of milacemide on DDT-induced myoclonus when given after the onset of myoclonus. Rats were treated with DDT 600 mg/kg p.0. at time 0 and were given milacemide 400 mdkg at 2.5 and 4 h. Arrows show time of milacemide injections. *p < 0.05.

Movement Disorders, Vol. 3, No. 1 , 1988


TABLE 4. Effect of milacemide on DDT-induced rnyoclonus when given after the onset of rnyoclonus

Time of drug Number of Mean myoclonus scores Drug and dose administration animals between 3 and 6 h -c SEM

Saline 2.5 and 4 h 6 Milacemide 400 mgkg i.p. 2.5 and 4 h 6

4.95 + 0.25 1.20 + 0.16"

- ~~~ ~~

Rats were given DDT 600 mgkg p.0. At 2.5 h, when most of the rats had stimulus-induced myoclonus as well as mild spontaneous axial myoclonus, they were treated with milacemide 400 mg/kg i.p. The milacemide effect on myoclonus was statistically significant. A second dose at the 4th h gave further improvements.

p < 0.05 by ANOVA.

forebrain than in the brainstem. The smaller increment in the brainstem may be due to the higher baseline levels of glycine in those areas. There were no statistically significant increases in serine levels, although glycine can be converted to serine. This could be due to the fact that conversion to serine is in only one of the several metabolic pathways of glycine (7). Our data also showed that drugs that increase brain glycine levels, such as

glycine i.c.v. or the glycine pro-drug milacemide, attenuate the severity of myoclonus and prolong the latency of the onset of myoclonus and seizures after DDT treatment. These findings are in agreement with previous reports that glycine provided protection against seizures and amplified the anticonvulsant effects of other drugs (23-26). Glycine, as an inhibitory neurotransmitter, is known to hy- perpolarize the membrane and decrease the firing of cells in the spinal neurons and other areas of the CNS (27-29).

The mechanism of DDT toxicity is not known, but experiments on the giant axon of the cockroach have shown an increase in the negative after-potential, which has been thought to be responsible for repetitive discharges (30). It has been proposed that these discharges induced by DDT increase neurotransmitter release from the nerve terminals (31). It is not clear how the increased repetitive discharges relate to the decrease in brain inhibitory neurotransmitter levels, in- cluding glycine, in the whole brain of both acutely and chronically treated mice with DDT (32,33). Glycine's role in myoclonus has also been implicated by other

TABLE 5 . Regional brain glycine levels afer DDT administration

Brain areas Controls 2.5 h after DDT 5 h after DDT

Cortex 0.62 + 0.02 0.52 + 0.05 0.53 + 0.03 Cerebellum 0.63 + 0.02 0.55 + 0.10 0.60 + 0.04 Striatum 0.90 + 0.07 0.89 + 0.05 1.12 + 0.10 Diencephalon 0.97 + 0.07 1.08 + 0.08 1.10 + 0.10

1.12 + 0.03" Midbrain 1.57 + 0.08 Pons and medulla 3.24 + 0.17 2.52 + 0.14O 2.63 + 0.07" Cervical cord 3.78 + 0.10 3.63 + 0.31 3.91 + 0.06

1.09 + 0.06"

Rats were fed DDT 600 mgkg 2.5 or 5 h prior to sacrifice. Glycine levels did not change except in

0 p < 0.05 by unpaired Student's f test. the medulla, pons, and midbrain. Amounts are expressed in nmolkng of wet tissue.

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3.0 G c Y C I N E 2.5

L E V E L S 2.0

D . D . TRUONG ET AL.

3.03+0.04 3.06+0.07 2.82+0.12 2.55*0.11 2.46*0.13 2.51 +0.25 2.85+0.23

171 151 151 161 151 151 151 T T

0 HR 1 HR 2HR 3HR 4 HR 5 HR 6 HR HOURS AFTER DDT INTAKE

FIG. 3. Time course study of glycine levels in the pons and medulla after DDT. Rats were fed DDT 600 mg/kg and sacrificed at the indicated time points. Glycine levels in the pons and medulla decreased at first but then rose again despite worsening of the myoclonus. The decrease was significantly statistically different between 3 and 5 h compared with a control group. Amounts were expressed in nanomoles per milligram of wet tissue -C SEM. *p < 0.05 by unpaired Student's f test. Numbers in brackets indicate numbers of animals.

studies. Infusion of DDT and the glycine antagonist strychnine into the medullary formation also induced myoclonus similar to the systemic administration of these compounds (8). In urea-induced myoclonus, urea has been found to displace glycine at its receptor site in the medullary reticular formation (34). Thus, glycine deficiency or antagonism could play a role in animal and possibly human myoclonus.

We could not confirm findings by others (32,33) that whole-brain glycine levels decrease in DDT-treated animals. Our results showed no change in whole-brain glycine levels at the time when rats had stimulus-induced or spontaneous myoclonus, or seizures. The regional dissection studies, however, revealed a decrease in glycine levels in the brainstem areas. Although glycine levels decreased initially, they rose again despite worsening of myoclonus and evolution into seizures. This suggests that a deficiency of glycine, therefore, may not be the patho- genesis of DDT-induced myoclonus. On the other hand, decreased glycinergic transmission may have triggered the myoclonus, and other subsequent changes

Movement Disorders. Vol. 3, No. I , 1988


TABLE 6. Effect of milacemide on regional glycine levels of normal rats

Glycine levels Serine levels in nmollmg Percent (nmol/mg) in

Brain region tissue change tissue

Cortex

Hippocampus

Septum acc.

Striatum

Cerebellum

Diencephalon

Midbrain

Pons and medulla

Control Milacemide Controls Milacemide Controls Milacemide Controls Milacemide Controls Milacemide Controls Milacemide Controls Milacemide Controls Milacemide

0.562 + 0.019 0.806 + 0.049 0.683 + 0.032 0.908 + 0.036" 0.602 + 0.017 0.842 + 0.037" 0.753 + 0.034 0.895 + 0.021" 0.606 + 0.035 0.814 + 0.038" 0.915 + 0.032 1.183 + 0.083b 2.011 + 0.07 2.259 + 0.084b 2.910 + 0.091 3.428 + 0.2156

+ 43

+ 33

+ 40

+ 19

+ 34

+ 29

+ 12

+ I7

1.051 + c.049 1.067 + 0.020 I . 198 + 0.023 1.13 + 0.022

0.884 + 0.018 0.91 + 0.044

1.271 + 0.04 1.230 + 0.061 0.709 + 0.036 0.69 + 0.033

0.624 + 0.022 0.5% + 0.018 0.56 + 0.039

0.545 + 0.043 0.391 + 0.021 0.439 + 0.044

Rats were given either milacemide 400 mg/kg i.p. or saline I h prior to sacrifice. Glycine levels in forebrain structures increased markedly compared with midbrain. pons. and medulla. The change in serine did not reach statistical significance. Amounts were in nmol/mg of wet tissue.

a p < 0.001; bp < 0.05.

induced by rnyoclonus may have rendered the myoclonus and ultimate seizures irreversible. Certainly, from our findings, it appears that increased brain glycine levels attenuate the severity and onset of rnyoclonus.

The effect of DDT on glycine levels may not be specific as interaction of different pathways involving a-noradrenergic inhibitory synapses (33, serotonin (19,35), prostaglandin (36), acetylcholine (37,38), and norepinephrine (39) have been reported in the DDT toxic syndrome.

Glycine given after the appearance of myoclonus was not effective, and the effect of rnilacernide was also weaker and required more frequent dosings. This was in accord with a previous report that the effect of DDT was irreversible (30).

T

FIG. 4. Effect of glycine ICV and milacemide i.p. on glycine levels in the pons and medulla of DDT-treated rats. Rats were treated with DDT (600 mgkg p.0.) and sacrificed at 3 h. Glycine i.c.v. given at 0 h or milacemide 400 mdkg i.p. at 0 and 2 h increased glycine levels in the pons and medulla. Amounts were expressed in nmoU mg of wet tissue -C SEM. *p < 0.05.

OWT

I WT+MWEMIDE

DDT+GLYCINEI,C,V,

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D. D . TRUONG ETAL.

Similarly, the effect of 5-HTP was more marked when given prior to the appearance of myoclonus (17).

In summary, increasing brain glycine levels had an antimyoclonic effect. Since the glycine levels were augmented by either i.c.v. glycine or parented milacemide, both of which also prevented myoclonus, a glycine mechanism for this type of myoclonus is suggested by our studies. Our findings also suggest that milacemide may be a promising drug for various myoclonic syndromes in humans. The short half-life of this drug will need to be taken into account when treating patients who suffer from myoclonus.

Acknowledgment: This study was supported by a grant from the Myoclonus Research Fund. We are grateful to David Balch for his dedicated assistance.

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Movement Disorders. Vol. 3, No. 1. 1988

glycine involvement in ddt���induced myoclonus

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glycine involvement in ddt��induced myoclonus