The GABA-withdrawal syndrome: a new model of focal epileptogenesis

Brailowsky, Simón; Kunimoto, M; Ménini, C; Silva-Barrat, C.; Riché, D.; Naquet, R

doi:10.1016/0006-8993(88)91448-5

Cited by 65 publications

(19 citation statements)

References 12 publications

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“…In addition to concern over possibility of an acute overdose, there are concerns about long-term receptor and physiological changes that could lead to deleterious long-term effects, e.g., by downregulating the number of GABAbenzodiazepine complex receptors. A similar circumstance was demonstrated in the GABA withdrawal model of epilepsy in primates (20).…”

Section: Discussionmentioning

confidence: 66%

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

1997

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Summary: Purpose:We evaluated the efficacy of local perfusion of diazepam (DZP) in suppression of EEG spikes and behavioral seizures produced by bicuculline methiodide (BMI) applied to rat sensory motor cortex and hippocampus.Methods: Data were obtained from 37 rats implanted with EEG head plugs and perfusion cannulas. BMI 4 mM, 5 pl was infused on neocortex through the epidural space in 23 rats. BMI 0.1 mM, 2 p1 was infused into the left hippocampus in 14 rats.Results: DZP 0.75-1.0 mg markedly reduced the spiking to a level of 9.9 t 15.8% of baseline for DZP as compared with 90.2 t 57.9% of baseline for vehicle-treated rats. DZP reduced spiking in a hippocampal BMI focus to 1.9 k 2.4% of baseline spiking, as compared with 98.0 & 95.6% of that in vehicle-treated animals. The amount of spread of solution was estimated with methylene blue (MB) injections. Ictal events also were attenuated. In most of the animals, systemic levels of DZP were unmeasurable and injection on the contralateral side did not reduce spiking.Conclusions: These findings suggest that focal application of antiepileptic drugs (AEDs) in brain may be a useful new avenue for therapy of intractable partial seizures. Key Words: Seizures-Epilepsy-Electrophysiology-DiazePam-Bicuculline-Drug delivery systems.The mainstay of therapy for epilepsy remains systemic administration of antiepileptic drugs (AEDs). Approximately 25-30% of people with epilepsy are unresponsive to or intolerant of systemic medications (1). Some of these patients can be helped by surgical removal of the seizure focus (2), most commonly an anterior mesial temporal seizure lobe focus. Nevertheless, some individuals with intractable partial (focal) seizures in critical areas of the brain or in more than one location are not candidates for surgery. These patients experience ongoing partial or secondarily generalized seizures. New methods of treating such patients are required.We used white rats to study the local perfusion of diazepam (DZP) directly on brain tissue to stop focal seizures. These studies in an animal model system can serve as a first step toward examining the feasibility of a local perfusion system for epilepsy in humans. Preliminary reports of our findings were published in abstract form (3). METHODSRandomized, double-blinded data were obtained from 37 male Sprague-Dawley white rats weighing 250-500 g obtained from the Charles River breeding colony. In the first stage of the experiment, bone screws and cannulas were implanted in the rats. Each rat was anesthetized with ketamine 40 mg/kg, xylazine 5.5 mg/kg, and acepromazine maleate 0.8 mg/kg by intramuscular injection in -0.2-ml vol.While under anesthesia, rats were placed in a head holder with atraumatic ear bars, and the cranium was exposed through a longitudinal incision. Bone screws (Small Parts, Coral Gables, FL, U.S.A.) were implanted in the left and right frontal bones and the middle and posterior left and right parietal bones and overlying the midline sinus as a reference. A wire was inserted in neck muscle as...

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Section: Discussionmentioning

confidence: 66%

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

1997

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“…Homeostatic plasticity may contribute to epileptogenesis in other conditions with prolonged periods of reduced activity, such as in the GABA withdrawal syndrome (GWS) (Brailowsky et al, 1988). In GWS, chronic perfusion of GABA in the sensorimotor cortex results upon cessation in the appearance of continuous focal epileptic discharges.…”

Section: Discussionmentioning

confidence: 99%

Homeostatic Synaptic Plasticity Can Explain Post-traumatic Epileptogenesis in Chronically Isolated Neocortex

Houweling¹,

Bazhenov²,

Timofeev³

et al. 2004

Cerebral Cortex

153

150

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Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1-3 cm/s and consisted of large (10-15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.

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“…The histologic changes observed at the GABAinfused site as well in homolateral thalamic structures for the I-mol dose were reported previously (Brailowsky et al, 1988) and consisted mainly of local gliosis and neuronal depopulation. For the 100-mmol dose, the gliotic changes due to the intracortical penetration by the cannulas were comparable to those described in our first study , although less intense.…”

Section: Histologymentioning

confidence: 57%

“…In both cases, cessation of chronic (7 days) GABA application gave rise to an epileptogenic process localized to the infused area. This "GABAwithdrawal syndrome" (GWS) has also been observed in nonepileptic rats after cortical (Brailowsky et al, 1988) or limbic GABA infusions (Le Gal La Salle et al, 1988) and in nonepileptic baboons (Brailowsky et al, 1989(Brailowsky et al, , 1990) . We describe in detail the qualitative EEG features of the GWS: discharge patterns, spatial and temporal evolution, and sleep effects. We also report pilot studies that show the differential reactivity of the cortex to local infusion of either another inhibitory amino acid (taurine) or another GABA agonist specific to the GABA, receptor (baclofen).…”

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confidence: 87%

Electroencephalographic Study of the GAB A‐Withdrawal Syndrome in Rats

et al. 1990

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The spatial and temporal EEG features of the epileptogenic syndrome induced by cessation of chronic intracortical GABA infusion in normal rats are described. In the initial stages, the paroxysmal discharges (PDs) induced by withdrawal from unilateral GABA application may appear either unilaterally or bilaterally, although with greater amplitude on the infused side. PDs are transitorily accompanied by behavioral signs of distal myoclonus of the body territory corresponding to the infused area (contralateral hindlimb). Later, the paroxysmal activity becomes more localized, circumscribed to the cannula-infused site and with ipsilateral propagation to anterior cortical areas. The amplitude of PDs decreases progressively while their frequency increases, reaching its maximal value at about 4 h after the first PDs have appeared. In the final stages of the syndrome, which may last several days, clinical manifestations are absent and PDs are activated by slow-wave sleep and reduced during REM sleep and waking. Chronic intracortical applications of taurine failed to induce any electroclinical changes on withdrawal and were unable to inhibit the focus elicited by GABA withdrawal, whereas reinstatement of GABA infusion into the epileptogenic area was effective in blocking the paroxysmal activity. Intracortical infusion of baclofen induced the appearance of an epileptogenic focus that waned on withdrawal. The GABA-withdrawal syndrome appears to be a new model of focal status epilepticus; it may be useful as an experimental model of human partial epilepsy to investigate the role of GABAergic neurotransmission.

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The GABA-withdrawal syndrome: a new model of focal epileptogenesis

Cited by 65 publications

References 12 publications

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

Local Perfusion of Diazepam Attenuates Interictal and Ictal Events in the Bicuculline Model of Epilepsy in Rats

Homeostatic Synaptic Plasticity Can Explain Post-traumatic Epileptogenesis in Chronically Isolated Neocortex

Electroencephalographic Study of the GAB A‐Withdrawal Syndrome in Rats

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