Progress 01/01/90 to 12/31/91
Outputs
Studies on the neurotoxicity of a new class of antimicrobial drugs, the fluoroquinolones, were undertaken. Clinical data in humans and animals indicate that these drugs may aggravate seizures, particularly in seizure-prone individuals such as patients with idiopathic epilepsy. Using an animal model of epilepsy, amygdala kindling in rats, we found that fluoroquinolones such as ciprofloxacin, norfloxacin and enrofloxacin did not aggravate behavioral and electrographic parameters of seizure activity; indeed, high doses of enrofloxacin appeared to have an antiseizure effect. As reported clinically in people, when fluoroquinolones were co-administered with theophylline, the neurostimulatory effects of the latter drug were enhanced to the point that seizures were induced in the kindled rats. Pharmacokinetic studies indicated that this enhancement was not due to fluoroquinolone-induced alterations in theophylline elimination. Attenuation of fluoroquinolone-theophylline
aggravation of kindled seizures with 2-chloroadenosine and diazepam, drugs which act, respectively, at central adenosine and GABA/benzodiazepine receptor sites, suggests that central receptor-mediated mechanisms may be involved in the enhanced seizure activity induced by this drug combination.
Impacts
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Publications
- VANCUTSEM, P. M., BABISH, J.G. and SCHWARK, W.S. 1990. The fluoroquinolone antimicrobials: structure, antimicrobial activity, pharmacokinetics, clinical use in domestic animals and toxicity. Cornell Vet 80: 173-186.
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Progress 01/01/89 to 12/30/89
Outputs
Studies on the neurotoxicity of a new class of antimicrobial drugs, the fluoroquinolones, were initiated. Mechanisms involved in the seizure-inducing effects of these drugs, particularly those relating to alteration of GABA-mediated events, will be studied using the amygdala kindling seizure model.
Impacts
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Progress 01/01/88 to 12/30/88
Outputs
Studies on the role of brain gamma-aminobutyric acid (GABA) mediated mechanisms in the kindling model of epilepsy were continued. In particular, the regulatory influence of GABAergic systems in the substantia nigra on the initiation and propagation of kindled seizures was studied. Using chronically implanted cannulae, a GABA uptake inhibitor (SKF100330A) could be introduced bilaterally into the nigral region of the brain in fully kindled rats. Administration of the drug in this manner raised the threshold for induction of kindled seizures. In contrast, control vehicle (saline) administration into the nigral region was without effect on seizure threshold, as was introduction of the GABA uptake inhibitor into brain regions other than the substantia nigria (e.g., cerebral cortex). The data lend further support to the hypothesis that nigral GABAergic mechanisms play a key role in the kindled seizure state.
Impacts
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Progress 01/01/87 to 12/30/87
Outputs
A new method to measure the time course of antiepileptic drugs was developed andvalidated. Using the amygdala kindling seizure model in rats, studies with the benzodiazepine, diazepam, and the GABA uptake inhibitor, SKF89976-A (N-(4,4-diphenyl-3-butenyl)-nipecotic acid), indicated that multiple stimulation episodes can be used to determine the time course of drug action following a single administration of antiseizure compounds. This will allow more efficient investigation of this important pharmacological parameter, particularly when minimal amounts of novel antiepileptic drugs are available. Studies were initiated on the pharmacological control of experimental status epilepticus. A consistentt model of status epilepticus in rats was produced by combined administration of lithium and pilocarpine; behavioral, electroencephalographic and neuropathological features of the model were consistent with clinical status epilepticus in humans and animals. Preliminary data
with SKF100330-A (N-(4,4-diphenyl-3-buntenyl)-guvacine) indicate that this experimental antiepileptic drug may be able to prevent drug induced status epilepticus.
Impacts
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Progress 01/01/86 to 12/30/86
Outputs
Neuropharmacological studies of an experimental model of epilepsy, amygdala kindling in the rat, were conducted using a novel series of antiepileptic drugs which inhibit synaptic GABA uptake. Dose response and time course studies indicated that these drugs are capable of inhibiting full kindled seizures in dosages which cause no depressant side effects. Antiepileptic effects are exerted following either oral or parenteral administration and the duration of antiseizure action exceeds 2 hours with either route of administration. Stereospecificity for this effect was observed since the d-isomer of one of these drugs (N-(4,4-diphenyl-3-butenyl)-nipecotic acid) was much more potent than the l-isomer in seizure inhibition. In addition to inhibition of full kindled seizures, administration of the GABA uptake inhibitor from the initiation of kindling prevented the development of the epileptic state, indicating that these drugs may be useful in the prophylaxis of seizure
disorders.
Impacts
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Progress 01/01/85 to 12/30/85
Outputs
The neurochemical and neuropharmacological basis of an experimental seizure model, amygdala kindling in the rat, was studied. Mechanisms relating to GABA involvement in the seizure state were studied using drugs which interact with different components of central GABA function. In animals with full kindled seizures, GABA receptor agonists had either minimal antiseizure activity (progabide) or no antiepileptic action at all (muscimol, gaboxadol). In contrast, novel inhibitors of synaptic GABA uptake (SKF 100330A; SKF89976A) had potent antiseizure effects at dosages which produced no depressant side effects. Chronic administration of the latter compound also prevented the development of kindling, indicating that these drugs may have a prophylactic effect on epileptic states. This latter effect was also observed with diazepam, but only in dosages which produces marked sedation and ataxia. Preliminary studies on the role of central opiate mechanisms in seizures were
also undertaken. Of the opiates studied, fentanyl (100 mu/kg) had a pronounced inhibitory effect on kindled seizures whereas other opiates (pentazocine, meperidine, morphine) had little effect. Paradoxically, while fentanyl resulted in an inhibition of the intensity of behavioral and electrographic seizures, it lowered the seizure threshold, indicating an increased sensitivity to seizure induction.
Impacts
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Progress 01/01/84 to 12/30/84
Outputs
Studies on the involvement of GABA-ergic mechanisms in the amygdaloid kindling model of epilepsy were undertaken. Neurochemical investigations in 12 brain regions, including the olfactory bulb, frontal cortex, corpus striatum, hippocampus, amygdala, thalamus, hypothalamus, tectum, substantia nigra, pons, medulla oblongata, and cerebellum demonstrated a marked and specific alteration of GABA-ergic mechanisms in the substantia nigra, corpus striatum, and amygdala. The levels of GABA and the GABA-synthesizing enzyme, GAD, were significantly inhibited by 20-50% in these brain regions of epileptic rats when compared to sham-operated controls. Binding of ((3)H)GABA to postsynaptic receptors was significantly decreased in the amygdala and substantia nigra and significantly increased in the corpus striatum. Further evidence for impaired GABA-ergic mechanisms in these seizure-prone rats was provided by our studies with two novel inhibitors of GABA uptake, SKF 100330A and SKF
89976A; both of these drugs had a profound inhibitory effect on full kindled seizures while producing absolutely no CNS depressant side effects. Our data support the concept that impaired GABA-ergic mechanisms are involved in the pathogenesis of the epileptic state and are in agreement with recent data (Eur. J. Pharmacol. 88:485, 1983) which indicate that the substantia nigra is an important relay station in the propagation of seizure phenomnena.
Impacts
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Progress 01/01/83 to 12/30/83
Outputs
We have continued our studies on the neurochemical basis of an experimental model of epilepsy, amygdaloid kindling in the rat. In particular, alterations in the benzodiazepine-GABA receptor-chloride ionophore complex have been studied. In vitro binding studies with [DTH]-diazepam in brain membranes obtained from normal rats indicated that two populations of benzodiazepine receptors exist in brain regions such as the frontal cortex, i.e., a high affinity population (KD = 6.3 +/- 1.2 nM; Bmax = 0.79 +/- 0.19 pmol/mg protein) and a low affinity population (KD = 28.2 +/- 4.9 nM; Bmax 1.71 +/- 0.27 pmol/mg protein). In contrast, a single benzodiazepine receptor type was found in the cerebellum (KD = 6.8 +/- 0.8 nM; Bmax = 0.85 +/- 0.08 pmol/mg protein). [DTH]-Diazepam binding properties were not altered in the cerebellum or frontal cortex of kindled rats which had not experienced a seizure within 1 week prior to the time of sacrifice. However, significant increases in
cerebellar KD and Bmax values were observed in kindled rats which experienced a seizure just prior to death. In addition, inosine-induced increases in KD of [DTH]-diazepam binding were markedly impaired in cerebellar tissues obtained from kindled rats. Our data support the idea that alterations in endogenous mechanisms mediated by the benzodiazepine receptor complex may be instrumental in the epileptogenesis produced by amygdaloid kindling.
Impacts
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Progress 01/01/82 to 12/30/82
Outputs
This project has continued to explore the neurochemical basis of an experimentalmodel of epilepsy, amygdaloid kindling in the rat. Various benzodiazepine (Valium-like) drugs were found to have a potent ability to inhibit these seizures. In agreement with their order of potency in controlling seizures and other CNS disorders in humans, the rank order of the different benzodiazepines in abolishing amygdaloid kindled seizures was clonazepam greater than nitrazepam greater than diazepam greater than medazepam. Preliminary In Vitro studies using receptor binding and gel electrophoretic techniques indicate that benzodiazepine receptors may be qualitatively and quantitatively altered in the brain of kindled rats. The putative endogenous benzodiazepine receptor ligand inosine, when administered intraventricularly, partially suppressed seizure activity, raising the possibility that this seizure state may be related to alterations in this seizure suppressant
neurotransmitter. We have also initiated studies on the influence of lead on the kindled seizure state in adult rats. While chronic intoxication with this heavy metal did not appear to appreciably alter behavioral seizures, the electrographic aspect of the seizures was accentuated. Studies are planned to investigate this phenomenon in neonatal rats where lead is known to have a more profound effect on neurological function.
Impacts
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Progress 01/01/81 to 12/30/81
Outputs
Studies have been initiated to determine the role of the benzodiazepine-GABA receptor complex in the amygdaloid kindling model of epilepsy. Previous studies in our laboratory indicated that the levels of the inhibitory neurotransmitter GABA are unaltered in the brain of animals with this seizure state. In contrast, benzodiazepine drugs, such as diazepam (Valium), which are believed to be intimately involved with the GABA system in the brain, have a potent inhibitory effect on amygdaloid kindled seizures. Preliminary evidence indicates that intracerebral administration of inosine, a putative benzodiazepine receptor ligand, attenuates amygdaloid kindled seizures. Methods are being developed to determine possible benzodiazepine receptor alternations in the brain of animals with this model of epilepsy.
Impacts
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Progress 01/01/80 to 12/30/80
Outputs
The role of neurotransmitter amino acids in the amygdaloid kindling model of epilepsy in the rat was studied. Analysis of amino acid levels in the frontal lobes, cerebellum and brain stem of amygdaloid kindled (Amy-Kin) and control rats was performed with cation exchange column chromatography. Alanine was found to be significantly reduced in the brain stem of Amy-Kin animals along with a trend for reduction of most other amino acids except taurine and gamma-amino butyric acid. The synaptosomal uptake of taurine was found to be increased in the cerebellum of Amy-Kin rats compared to controls. The alterations in the levels and uptake of these putative neurotransmitters may play a role in the seizure state which characterizes amygdaloid kindling.
Impacts
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Progress 01/01/79 to 12/30/79
Outputs
The kindling model of epilepsy is based on a permanent alteration of brain function induced by chronic stimulation of brain sites with low intensity electrical stimuli. Since these alterations may be neurochemical in nature, the role of serotonin (5-HT) in the development of kindled seizures was studied. Amygdaloid kindling led to significant decreases in 5-HT and the 5-HT metabolite, 5-hydroxyindoleacetic acid in the midbrain but no alterations in brain regions such as the hypothalamus, amygdala and brain stem. Administration of 5-hydroxytryptophan, a 5-HT precursor, retarded the kindling process whereas p-chlorophenylalanine, a depletor of brain 5-HT, facilitated evolution of amygdaloid kindled seizures. These data suggest that 5-HT plays a suppressive role in amygdaloid kindled seizures.
Impacts
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