Experimental Pharmacology and Toxicology of Antituberculosis Drugs

Tettenborn, D

doi:10.1007/978-3-642-72873-0_5

Cited by 3 publications

(4 citation statements)

References 226 publications

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“…Although glycine ligands, such as D-CS, with higher intrinsic efficacy than ( +)-HA-966. have also been reported to cause seizures, corresponding doses in laboratory animals were extremely high (Tettenborn, 1988). This is also demonstrated by the present study in which D-CS doses up to 160 mgkg did not induce any paroxysmal activity.…”

Section: D-cysupporting

confidence: 89%

Low Doses of the Glycine/NMDA Receptor Antagonist R‐(+)‐HA‐966 but not d‐Cycloserine Induce Paroxysmal Activity in Limbic Brain Regions of Kindled Rats

Właź

Ebert

Löscher

1994

Eur J of Neuroscience

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(+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a functional antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex, was evaluated in amygdala-kindled rats, a model of epilepsy recently shown to exhibit enhanced susceptibility to the adverse effects of competitive and non-competitive NMDA receptor antagonists. Since (+)-HA-966 displays weak partial agonistic effects at the glycine site (approximately 10% efficacy of glycine), D-cycloserine, a glycine ligand with much higher intrinsic activity, was evaluated in kindled rats for comparison. Following drug administration, electrographic activity was recorded from the basolateral amygdala (i.e. the focal site) as well as the ipsilateral piriform cortex, ventral hippocampus and nucleus accumbens. In addition to the evaluation of original recordings, power spectrum analysis was used to delineate drug effects. (+)-HA-966 (20-40 mg/kg i.p.) induced marked alterations in electrographic recordings, including increases in amplitude and isolated spiking, i.e. signs of paroxysmal activity. The severity or duration of fully kindled seizures was not changed by (+)-HA-966, but the drug dramatically increased the duration of immobilization and limbic seizure activity following a kindled motor seizure. In contrast to (+)-HA-966, D-cycloserine did not induce any electrographic changes, even when administered in much higher doses than (+)-HA-966. The changes in electrographic recordings seen after administration of (+)-HA-966 in kindled rats were almost absent in non-kindled rats, indicating that kindling had increased the sensitivity to the paroxysmal effects of the glycine/NMDA receptor ligand. The data indicate that functional glycine/NMDA antagonists with low intrinsic efficacy may bear the risk of proconvulsant activity.

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Section: D-cysupporting

confidence: 89%

Low Doses of the Glycine/NMDA Receptor Antagonist R‐(+)‐HA‐966 but not d‐Cycloserine Induce Paroxysmal Activity in Limbic Brain Regions of Kindled Rats

Właź

Ebert

Löscher

1994

Eur J of Neuroscience

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“…As shown by experiments in rats, the anticonvulsant effect of DCS is antagonized by 7-chlorokynurenic acid (an antagonist at the glycine site, 20) and HA-966 (a low-efficacy partial agonist at the glycine site, 24), suggesting that this effect was not simply due to glycine antagonism. Furthermore, low doses of DCS are devoid of any signs of behavioral (1 8,19) or electrographic excitation (1 8,35), whereas very high doses of DCS may precipitate seizures (36). In addition, DCS given intracerebroventricularly at a dose of 1 pmol increased the afterdischarge threshold in kindled rats, but higher doses (5 and 10 pmol) produced dose-dependent convulsant effects (37).…”

Section: Discussionmentioning

confidence: 99%

Influence of D‐Cycloserine on the Anticonvulsant Activity of Phenytoin and Carbamazepine Against Electroconvulsions in Mice

WlazA¹,

RolinAski²,

Czuczwar

1996

Epilepsia

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“…In con-1990). Although the drug was found to be relatively nontoxic sin tissue inin experimental animals (Tettenborn, 1988), in clinical use the n ( Table 2). administration of high doses of D-cycloserine (1 g per day) to bly 0.13 after tuberculosis patients has been attended by symptoms of obtained after neurotoxicity, such as drowsiness, somnolence, hyperflexia, *sponding to mental confusion, psychotic states and tonic-clonic or absence seizures (Storey & McLean, 1957;Mandell & Sande, 1990).…”

Section: Imentioning

confidence: 99%

“…Consistent with the present data, peak 0.36 brain levels were determined after 60 min, and brain levels with two rapidly declined thereafter with a half-life of about 2.2 h ;tered at a (Crema & Berte, 1960). In view of the limited penetration of D-cycloserine from blood to brain in intact animals, the higher neurotoxicity of D-cycloserine in tuberculosis patients compared to laboratory animals (Tettenborn, 1988) may thus be a consequence of disturbed blood-brain-barrier function.…”

Section: Imentioning

confidence: 99%

Anticonvulsant effects of the glycine/NMDA receptor ligands d‐cycloserine and d‐serine but not R‐(+)‐HA‐966 in amygdala‐kindled rats

Löscher¹,

Właź²,

Rundfeldt³

et al. 1994

British J Pharmacology

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1. The effects of the glycine/NMDA receptor partial agonists, D-cycloserine and (+)-HA-966 and the full agonist, D-serine, on focal seizure threshold and behaviour have been determined in amygdala-kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA receptor antagonist, MK-801, was used for comparison. 2. The high efficacy glycine partial agonist, D-cycloserine, did not alter the threshold for induction of amygdaloid afterdischarges (ADT) at doses of 20-80 mg kg-1 i.p., but significant ADT increases were determined after application of higher doses (160 and 320 mg kg-1). The ADT increases after these high doses were long-lasting; significant elevations were still observed 2 days after drug injection. Determination of D-cycloserine in plasma and brain tissue showed that it was rapidly eliminated from plasma. Compared to peak levels in plasma, only relatively low concentrations of D-cycloserine were measured in brain tissue. 3. The low efficacy glycine partial agonist, (+)-HA-966, 10-40 mg kg-1 i.p., did not alter the ADT or seizure recordings (seizure severity, seizure duration, afterdischarge duration) at ADT currents. However, the drug dose-dependently increased the duration of postictal behavioural and electroencephalographic depression in kindled rats. At the higher dose tested, postictal immobilization was dramatically increased from 3 min to about 120 min. This might indicate that glutamatergic activity is decreased postictally, which is potentiated or prolonged by (+)-HA-966. 4. Like D-cycloserine, the glycine receptor full agonist, D-serine, injected bilaterally into the lateral ventricles at a dose of 5 mumol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 mumol). 5. The anticonvulsant effects observed with D-cycloserine were completely antagonized by combined treatment with (+)-HA-966, indicating that the effects of D-cycloserine were mediated by the glycine/NMDA receptor complex. 6. MK-801, 0.1 mg kg-1, did not alter the focal seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)-like behavioural alterations, such as hyperlocomotion, stereotypies and motor impairment. No PCP-like behaviours were observed after D-cycloserine, D-serine or (+)-HA-966. High doses of (+)-HA-966 induced moderate motor impairment in kindled rats. 7. The long lasting increases in seizure threshold observed after the high efficacy glycine partial agonist,D-cycloserine but not the low efficacy partial agonist, (+)-HA-966, may suggest that the effects of D-cycloserine are mediated by adaptive changes in the NMDA receptor complex in response to glycine receptor stimulation.8. Pharmacological intervention at the strychnine-insensitive glycine receptor by high-efficacy partial agonists with systemic bioavailability may be an effective means of increasing seizure-threshold without concomitantly inducing PCP-like adverse effects.

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Experimental Pharmacology and Toxicology of Antituberculosis Drugs

Cited by 3 publications

References 226 publications

Low Doses of the Glycine/NMDA Receptor Antagonist R‐(+)‐HA‐966 but not d‐Cycloserine Induce Paroxysmal Activity in Limbic Brain Regions of Kindled Rats

Low Doses of the Glycine/NMDA Receptor Antagonist R‐(+)‐HA‐966 but not d‐Cycloserine Induce Paroxysmal Activity in Limbic Brain Regions of Kindled Rats

Influence of D‐Cycloserine on the Anticonvulsant Activity of Phenytoin and Carbamazepine Against Electroconvulsions in Mice

Anticonvulsant effects of the glycine/NMDA receptor ligands d‐cycloserine and d‐serine but not R‐(+)‐HA‐966 in amygdala‐kindled rats

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