Michael W. Kalichman

Neurochemical correlates of the kindling model of epilepsy.

Repeated electrical stimulation of the brain can produce many epileptogenic effects including those which characterize the kindling model. Kindling stimulation, by definition, changes the brain is such a way that formerly subconvulsive stimuli can elicit electrographic and convulsive seizure activity. In addition, the kindled animal becomes more susceptible to many, but not all, other types of seizures. These facts suggest that kindling produces brain changes which may selectively model some types of epileptiform excitability. In order to understand the basis for such changes numerous neurochemical studies have been attempted in the last few years. Although many changes have been demonstrated to be produced by kindling, few studies have been designed to specifically examine the long-lasting (permanent) neurochemical correlates of kindling stimulation. In this review, neurochemical data relevant to kindling are presented and discussed in terms of their possible significance to the seizure susceptibility changes produced by kindling.

Histomorphometric analysis of optic nerve changes in experimental glaucoma.

PURPOSE To assess relative changes in different tissue components of optic nerve and their relationship to nerve fiber loss in the experimental monkey model of glaucoma. METHODS Chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the right eye of eight monkeys (Macaca fascicularis). Both experimental right optic nerves and control left optic nerves were studied. Histomorphometric analysis was performed on optic nerve cross-sections using bright field microscopy with camera lucida. Cross-sectional areas of optic nerve tissue components were estimated by point counting. Nerve fiber density was estimated by unbiased random sampling. Nerve fiber number was calculated by multiplying nerve fiber density with neuroglial area. RESULTS Varying degrees of nerve fiber loss were seen in eight optic nerves with chronic IOP elevation. More than 50% nerve fiber loss was noted in four of eight experimental optic nerves. In these severely affected optic nerves, total optic nerve area was significantly decreased compared with control optic nerves. Among the optic nerve tissue components, only the ratio of myelinated fiber area to total optic nerve area was significantly decreased. The ratio of extraaxonal area to total optic nerve area was significantly increased, whereas the ratio of interfascicular septal area to total optic nerve area did not change significantly. For all optic nerves, differences in nerve fiber count between control and experimental optic nerves showed the strongest correlation with differences in myelinated fiber area, followed by differences in extraaxonal area and total optic nerve area. CONCLUSION This histomorphometric study suggests the validity of the experimental monkey model of glaucoma in studying changes occurring in the nonaxonal optic nerve tissue components in human glaucomatous optic neuropathy. Glial scar tissue area was significantly increased in optic nerves with severe glaucomatous damage. Although a decrease in total optic nerve area was observed, among the optic nerve tissue components only myelinated nerve fiber area decreased significantly. Myelinated nerve fiber area also showed the strongest association with nerve fiber loss in experimental glaucoma.

Pharmacological investigation of γ-aminobutyric acid (GABA) and the development of amygdala-kindled seizures in the rat

Abstract The effect of GABA agonists and antagonists on the rate of kindled seizure development was studied in rats. Drugs and drug doses were selected to modify GABA function by a variety of mechanisms. In the drug treatment groups, drugs were administered daily before kindling stimulation, and matched control groups received only drug vehicle before stimulation. Kindling development was (i) accelerated by the GABA-synthesis inhibitor 3-mercaptopropionic acid (20 mg/kg) and the GABA antagonist bicuculline (2.5 mg/kg); (ii) retarded by pentobarbital (5 mg/kg); and (iii) not altered by the GABA-response antagonist picrotoxin (2 mg/kg), the GABA agonist imidazole acetic acid (100 mg/kg), or the GABA metabolism inhibitor γ-vinyl GABA (100 mg/kg). These results are interpreted as evidence that endogenous GABA may play a role in opposing kindled seizure development, but that the mechanism of that development does not primarily involve failure of the GABA system.

Pharmacological Investigation of Convulsant γ‐Aminobutyric Acid (GABA) Antagonists in Amygdala‐Kindled Rats

Summary: The convulsant potencies of several drugs that antagonize GABAergic neurotransmission were assessed in amygdala‐kindled and control rats. The potencies of picrotoxin, pentylenetetrazol, and a convulsant barbiturate were increased by amygdala kindling. No significant potentiation, however, was observed with isoniazid, 3‐mercaptopropionic acid, bicuculline, or the glycine antagonist strychnine. Destruction, by electrolytic lesion, of the amygdala focus did not reverse the kindling‐induced potentiation of picrotoxin convulsions. The potentiation of picrotoxin convulsions was correlated with the pattern of kindling development but not with the number of stimulations or seizures. The present results are consistent with the hypotheses that (1) kindling potentiates only some convulsant agents, (2) kindling‐induced convulsant potentiation takes place outside of the kindled focus, and (3) kindling is not produced by a failure of the GABA system.

Locomotor and convulsive responses to picrotoxin in amygdala-kindled rats

Abstract Amygdala-kindled rats and handled controls were tested for differences in locomotion and convulsive activity produced by picrotoxin, a specific synaptic antagonist of the putative neurotransmitter GABA. Compared with controls, the gross activity of kindled rats decreased more rapidly with dose (0.5 to 2.0 mg/kg, i.p.) and kindled rats were more likely to convulse with the higher doses (1.0 to 2.0 mg/kg). These results suggest a functional deficit in the GABA system of kindled rats as measured by locomotion and convulsive activity.

Anticonvulsant and convulsant properties of flurazepam

The anticonvulsant efficacy of the benzodiazepine flurazepam was tested in rats treated with a convulsant dose of either picrotoxin or 3-mercaptopropionic acid. Against picrotoxin, a significant anticonvulsant effect was observed in the range of 30-60 mg/kg, i.p. Epileptogenicity increased as doses of flurazepam were increased from 60 to 200 mg/kg, and at a dose of 400 mg/kg all subjects died. In similar tests, the benzodiazepines clonazepam and triazolam produced only dose-dependent increases in anticonvulsant efficacy. Flurazepam also proved to be an effective anticonvulsant in tests against 3-mercaptopropionic acid. The results of this study provide further evidence that benzodiazepines have varying degrees of epileptogenicity.