Comparison of seizures and brain lesions produced by intracerebroventricular kainic acid and bicuculline methiodide

doi:10.1016/0014-4886(86)90181-0

Experimental Neurology

Volume 93, Issue 3, September 1986, Pages 621-630

https://doi.org/10.1016/0014-4886(86)90181-0 Get rights and content

Abstract

Intracerebroventricular kainic acid produces in rats brain lesions similar to Ammon's horn sclerosis in humans. To test the hypothesis that these lesions result indirectly from prolonged seizure activity and not from a direct action of kainic acid on the neurons that are destroyed, the effects of intracerebroventricular kainic acid and bicuculline methiodide were compared. Although bicuculline methiodide seizures differed dramatically from kainic acid seizures, both electrographically and behaviorally, the resulting brain lesions were similar for a given total limbic seizure duration. These results, in combination with other data, support the view that lesions made by intracerebroventricular administration of convulsants are indeed caused by prolonged limbic seizures. The total duration of seizure activity appears to be one important variable.

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Chemically-induced TLE models: Topical application
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Accordingly, under this condition the model does not mimic MTLE-HS but rather lesion-associated TLE lacking gross morphological alterations in the hippocampus. However, at higher doses, bicuculline induces hippocampal damage similar to that observed after KA injection in rats, a finding that provides further evidence that seizures per se can induce degeneration of pyramidal neurons in the hippocampus (Turski et al., 1985; Gruenthal et al., 1986). Microperfusion of picrotoxin, a specific GABAA receptor antagonist, into the hippocampus dose dependently provokes partial or secondary generalized seizures (Sierra-Paredes and Sierra-Marcuno, 1996; Sierra-Paredes et al., 1998).
Epilepsy is a condition of the brain that occurs in many different forms. For obvious reasons, understanding the complex mechanisms underlying the process of epileptogenesis cannot be fully acquired in clinical studies or analyses of surgically resected human epileptic specimens. Accordingly, a variety of animal models have been developed that recapitulate different aspects of the various forms of epilepsies. In our review we mainly focus on those chemically induced models that recapitulate characteristics typically seen in human temporal lobe epilepsies. By comparing models based on topical application of different agents, advantages and disadvantages are discussed with respect to parameters including reliability and mortality, as well as the similarity with the human condition of functional and morphological alterations occurring in different brain regions in the course of epileptogenesis and in the chronic state.
Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy
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Inhibition of mTOR by rapamycin has been shown to suppress seizures in TSC/PTEN genetic models. Rapamycin, when applied immediately before or after a neurological insult, also prevents the development of spontaneous recurrent seizures (epileptogenesis) in an acquired model. In the present study, we examined the mTOR pathway in rats that had already developed chronic spontaneous seizures in a pilocarpine model. We found that mTOR is aberrantly activated in brain tissues from rats with chronic seizures. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduces seizure activity. Finally, mTOR inhibition also significantly suppresses mossy fiber sprouting. Our findings suggest the possibility for a much broader window for intervention for some acquired epilepsies by targeting the mTOR pathway.
Pyruvate protects against kainate-induced epileptic brain damage in rats
2007, Experimental Neurology
Although the majority of epileptic seizures can be effectively controlled with antiepileptic drugs and/or surgery, a significant number progress to status epilepticus of sufficient duration to cause permanent brain damage. Combined treatment with antiepileptic drugs and neuroprotective agents, however, may help protect these individuals from permanent brain damage. Since toxicity induced by endogenous zinc contributes to epileptic brain injury, and since pyruvate is effective in reducing zinc-triggered neuronal death in cortical culture as well as ischemic neuronal death in vivo, we examined whether systemic pyruvate administration reduces seizure-induced brain damage. Na pyruvate (500 mg/kg) or osmolarity-matched saline (265 mg/kg NaCl, i.p.) were given to adult SD rats 30 or 150 min after 10 mg/kg kainite injection (i.p.), and there was no significant difference in the time course or severity of seizures between these groups. Zinc accumulation in neuronal cell bodies in the hippocampus, however, was much lower in the pyruvate than in the saline group. There was a close correlation between zinc accumulation and cell death, as assessed by acid–fuchsin and TUNEL staining. Pyruvate treatment markedly reduced neuronal death in the hippocampus, neocortex and thalamus. Pyruvate increased HSP-70 expression in hippocampal neurons. These results suggest that pyruvate, a natural glucose metabolite, may be useful as adjunct treatment in status epilepticus to reduce permanent brain damage.
Modulation of cell death by mouse genotype: Differential vulnerability to excitatory amino acid-induced lesions
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Previously we have demonstrated that mature inbred strains of mice differ significantly in their response to kainate-induced cell death. While both C57BL/6 and FVB/N mice exhibit similar seizure activity in response to kainate, only C57BL/6 mice can be characterized as resistant to kainate-induced cell death. To examine further the molecular pharmacological basis for this strain difference in hippocampal sensitivity, we assessed the ability of the ionotropic glutamate receptor agonists, kainic acid (KA), N-methyl-d-aspartate (NMDA), ibotenic acid (IBO), and quinolinic acid (QUIN), to promote excitotoxic damage. We examined seizure-related behavior and subsequent neurotoxicity in C57BL/6 and FVB/N mice following intrahippocampal administration of the kainate receptor agonist, KA, the NMDA receptor agonists NMDA or QUIN, or the NMDA and metabotropic glutamate receptor agonist, IBO. The time course and extent of cell death in mice were evaluated using Nissl and selective silver stains, and Fluoro-Jade, a fluorescent marker for dying neurons. In the present study, FVB/N mice were exquisitely sensitive to injection of KA at all doses, while susceptibility in C57BL/6 mice was dose dependent. In contrast, while hippocampal damage was present in both strains at all doses of QUIN, the extent of cell damage was significantly less in C57BL/6 mice at low doses (30 and 60 mM). Similarly, IBO administration resulted in differences in the extent of cell death when administered at the highest dose (126 mM). No strain-dependent differences in cell loss were observed following NMDA lesions. These results provide further evidence that susceptibility to excitotoxin-induced cell death is highly strain dependent and is kainate and NMDA receptor dependent.
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Complex partial seizures most often originate from the temporal lobe. The temporal lobe comprises rhinencephalic (limbic) structures, such as the hippocampus and amygdala located in the mesial surface of the lobe and neocortical structures located laterally. The syndrome of mesial temporal lobe epilepsy is the most common cause of complex partial seizures. This syndrome has specific historical features and characteristic pathology termed mesial temporal sclerosis. The characteristic pathological changes associated with intractable mesial temporal lobe epilepsy often occur within the hippocampus and are referred to as hippocampus sclerosis. Hippocampal sclerosis is found in 50 to 70% of the cases of intractable temporal lobe epilepsy who undergo temporal lobectomy. The hippocampal neuronal loss is often accompanied by reorganization of the mossy fiber system into the inner molecular layer of the dentate gyrus, leading to the formation of new synaptic contacts. The functional significance of this synaptic reorganization remains unclear; however, its existence may indicate that there is a lesion in the hippocampus and its interconnecting structures, which may not be apparent with conventional anatomical techniques. The immature brain also has a greater susceptibility to the development of prolonged provoked seizures in response to environmental stimuli, such as fever, infection, and head trauma. Consequently, it is quite likely that the initial precipitating injury may be associated with a seizure and, particularly a febrile seizure. Thus, it is assumed that these early seizures may lead to the development of mesial temporal sclerosis and subsequent temporal lobe epilepsy.
Electroencephalographic and histological characteristics of a model of limbic status epilepticus permitting direct control over seizure duration
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Status epilepticus is a neurological emergency associated with substantial morbidity and mortality. Experimental and clinical investigations suggest that prolonged seizure activity is associated with injury to vulnerable neurons. Compounds with neuroprotective properties may minimize such injury. Existing methods of inducing experimental status epilepticus result in seizure activity of variable duration and neuronal injury of variable degree. To minimize such variability, status epilepticus may be stopped with anticonvulsants, but this limits the ability to screen for independent neuroprotective properties. We have developed a simple and reliable non-pharmacological model of limbic status epilepticus in which the duration of status epilepticus is under direct experimental control. Status epilepticus is induced by continuous, unilateral hippocampal stimulation. Using this model, the degree of hippocampal pyramidal cell injury varies in direct proportion to status epilepticus duration across a range of 15–140 min. A progressive sequence of EEG changes unfolds with increasing status epilepticus duration, resembling that seen in other models. This model may serve as a reference against which the effects of potential neuroprotective compounds can be studied.

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¹: This study was supported by National Institutes of Health grant NS 17771 and a postdoctoral fellowship (NS 07018 to M.G.).

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Comparison of seizures and brain lesions produced by intracerebroventricular kainic acid and bicuculline methiodide

Abstract

Neuroscience

Brain Res.

Neuroscience

Neurosci. Lett.

Life Sci.

Neuroscience

Brain Res.

Brain Res.

Electroenceph. Clin. Neurophysiol.

Brain Res.

Efficacy of baclofen and phenobarbital against the kainic acid limbic seizure-brain damage syndrome

J. Pharmacol. Exp. Ther.