Susceptibility to seizures produced by pilocarpine in rats after microinjection of isonnazid or γ-vinyl-GABA into the substantia nigra

Turski, Lechosław; Cavalheiro, Ésper A.; Schwarz, Michael; Turski, Waldemar A.; Mello, Luiz E.; Bortolotto, Z.A.; Klockgether, Thomas; Sontag, Karl‐Heinz

doi:10.1016/0006-8993(86)90484-1

Cited by 102 publications

(30 citation statements)

References 49 publications

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“…Recently, several investigators have shown that once the acute seizure episodes have been induced by a single convulsive dose of kainate, the animals maintain a long-lasting increase in their seizure susceptibility (43,44). Understanding the cellular and molecular mechanisms responsible for induction of this phenomenon may provide insight into potential therapeutic strategies for treating temporal lobe epilepsy.…”

Section: Discussionmentioning

confidence: 99%

A single dose of kainic acid elevates the levels of enkephalins and activator protein-1 transcription factors in the hippocampus for up to 1 year

Bing

Wilson

Hudson

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal plasticity plays a very important role in brain adaptations to environmental stimuli, disease, and aging processes. The kainic acid model of temporal lobe epilepsy was used to study the long-term anatomical and biochemical changes in the hippocampus after seizures. Using Northern blot analysis, immunocytochemistry, and Western blot analysis, we have found a long-term elevation of the proconvulsive opioid peptide, enkephalin, in the rat hippocampus. We have also demonstrated that an activator protein-1 transcription factor, the 35-kDa fos-related antigen, can be induced and elevated for at least 1 year after kainate treatment. This study demonstrated that a single systemic injection of kainate produces almost permanent increases in the enkephalin and an activator protein-1 transcription factor, the 35-kDa fos-related antigen, in the rat hippocampus, and it is likely that these two events are closely associated with the molecular mechanisms of induction of long-lasting enhanced seizure susceptibility in the kainate-induced seizure model. The long-term expression of the proenkephalin mRNA and its peptides in the kainate-treated rat hippocampus also suggests an important role in the recurrent seizures of temporal lobe epilepsy.Kainic acid is a rigid analog of the excitatory amino acid glutamate that binds to and activates ionotropic glutamate receptors. Kainate-induced epileptic seizures have been widely used as a model for studying human temporal lobe epilepsy (1-6). A single systemic injection of a convulsive dose of kainate results in both short-term and long-term effects on the rat central nervous system. Within 1 hr of its administration to rats, the neuronal circuitry of the hippocampus is activated and later the animal undergoes robust and recurrent seizures. Within 3-4 days after kainate injection, pyramidal cells in the CA1 and CA3 fields of the hippocampus begin to degenerate (4,5,7,8). One or 2 weeks later, spontaneous convulsions can be observed in kainate-treated rats. The neuronal excitation caused by kainate leads to increases in the expression of a variety of genes including immediate-early genes, growth factors, and opioid peptides. The short-term effects of kainate in the rat brain have been well characterized (9-14). However, the long-term effects of kainate, especially on the opioid peptides, have not been reported.The opioid peptides derived from the proenkephalin (PENK) and prodynorphin (PDYN) precursors occur at high levels in the central nervous system. Upon stimulation, opioid peptides and their precursors are released and can function as neuromodulators. Activation of opioid receptors by opioid peptides exerts a broad spectrum of effects on physiological and pathological processes (for reviews see refs. 15 and 16). Earlier studies by Sonnenberg et al. (17) suggested the involvement of the activator protein-1 (AP-1) transcription factors in the regulation of expression of PENK. Comb and coworkers (18) have defined important regulatory sequences in the human PENK promoter, w...

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Section: Discussionmentioning

confidence: 99%

A single dose of kainic acid elevates the levels of enkephalins and activator protein-1 transcription factors in the hippocampus for up to 1 year

Bing

Wilson

Hudson

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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“…Evidence also shows that the neuropharmacology of seizure propagation differs in the immature and the mature brain (123). In both immature and adult rats, the substantia nigra pars reticulata is a structure crucial in the spread of seizures (124)(125)(126). The substantial nigra pars reticulata contains high levels of GABA, the actions of which are mediated by at least two subtypes of GABA receptors, GABA, and GABA, (55).…”

Section: Age-related Changes In Propagation Of Seizuresmentioning

confidence: 99%

Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

1997

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Summary:Children with epilepsy present unique challenges to the clinician. In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome. It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. y-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats. There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures. These age-related Epilepsy is a common disorder, leading to staggering costs, both in regard to human suffering and to economics. Because epilepsy frequently begins during childhood and has a higher incidence during the first decade of life than at any other time (l), issues of morbidity and mortality represent a major concern in pediatrics.Clinicians caring for children with epilepsy and developmental neuroscientists have long been aware that the immature brain differs considerably from the mature brain in the development and propagation of seizures, the behavioral and EEG features of the seizures, and their consequences. It is becoming increasingly clear that lessons learned about the mature brain in regard to the pathophysiology and treatment of seizures can not always be applied to the developing brain. An understanding of the unique features of epileptogenesis during development is essential before progress can be made in improving treatment. Despite the significance of the health care problem, it is surprising that relatively little differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain. Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent. Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals. However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain. These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders. Key Words: Epilepsy-Developing brain-Electroencephalography-Epileptogenesis-Pathophysiology . attention has been directed toward developing treatment strategies that specifically address these age-related factors.In this article, features of epileptogenesis during brain development are reviewed and age-related differences in response to seizures and antiepileptic drugs (AEDs) are discussed. Table 1 shows some of the major p...

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“…Although PI and KA both cause similar epileptic seizures and pathological changes in the brain, they differ in their initial mode of action. PI is a selective agonist of muscarinic acetylcholine receptors (mAChR) that provokes seizures indirectly by overstimulation of glutamatergic neurons of the cortex [16]. Once triggered by the excessive cholinergic activity, seizures are propagated by the sustained cortical glutamatergic overactivity.…”

Section: Introductionmentioning

confidence: 99%

Differential Patterns of Synaptotagmin7 mRNA Expression in Rats with Kainate- and Pilocarpine-Induced Seizures

2012

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Previous studies in rat models of neurodegenerative disorders have shown disregulation of striatal synaptotagmin7 mRNA. Here we explored the expression of synaptotagmin7 mRNA in the brains of rats with seizures triggered by the glutamatergic agonist kainate (10 mg/kg) or by the muscarinic agonist pilocarpine (30 mg/kg) in LiCl (3 mEq/kg) pre-treated (24 h) rats, in a time-course experiment (30 min - 1 day). After kainate-induced seizures, synaptotagmin7 mRNA levels were transiently and uniformly increased throughout the dorsal and ventral striatum (accumbens) at 8 and 12 h, but not at 24 h, followed at 24 h by somewhat variable upregulation within different parts of the cerebral cortex, amigdala and thalamic nuclei, the hippocampus and the lateral septum. By contrast, after LiCl/pilocarpine-induced seizures, there was a more prolonged increase of striatal Synaptotagmin7 mRNA levels (at 8, 12 and 24 h), but only in the ventromedial striatum, while in some other of the aforementioned brain regions there was a decline to below the basal levels. After systemic post-treatment with muscarinic antagonist scopolamine in a dose of 2 mg/kg the seizures were either extinguished or attenuated. In scopolamine post-treated animals with extinguished seizures the striatal synaptotagmin7 mRNA levels (at 12 h after the onset of seizures) were not different from the levels in control animals without seizures, while in rats with attenuated seizures, the upregulation closely resembled kainate seizures-like pattern of striatal upregulation. In the dose of 1 mg/kg, scopolamine did not significantly affect the progression of pilocarpine-induced seizures or pilocarpine seizures-like pattern of striatal upregulation of synaptotagmin7 mRNA. In control experiments, equivalent doses of scopolamine per se did not affect the expression of synaptotagmin7 mRNA. We conclude that here described differential time course and pattern of synaptotagmin7 mRNA expression imply regional differences of pathophysiological brain activation and plasticity in these two models of seizures.

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Susceptibility to seizures produced by pilocarpine in rats after microinjection of isonnazid or γ-vinyl-GABA into the substantia nigra

Cited by 102 publications

References 49 publications

A single dose of kainic acid elevates the levels of enkephalins and activator protein-1 transcription factors in the hippocampus for up to 1 year

A single dose of kainic acid elevates the levels of enkephalins and activator protein-1 transcription factors in the hippocampus for up to 1 year

Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

Differential Patterns of Synaptotagmin7 mRNA Expression in Rats with Kainate- and Pilocarpine-Induced Seizures

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