Effects of Pentylenetetrazol-Induced Status Epilepticus on Local Cerebral Blood Flow in the Developing Rat

Vasconcelos, Anne Pereira de; Boyet, Sylvette; Koziel, Violette; Nehlig, Astrid

doi:10.1038/jcbfm.1995.33

Cited by 19 publications

(16 citation statements)

References 45 publications

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“…Our inulin data demonstrated that BBB integrity was not altered, 16 suggesting that the increase in diazepam uptake is more likely due to enhanced cerebral blood flow. This is consistent with the fact that diazepam is often used as a marker of cerebral blood flow 16 and that this parameter increases following convulsive seizures 15 . Interestingly, the brain uptake of diazepam was not enhanced in the mouse model of absence epilepsy, which may be attributed, in part, to the fact that cerebral blood flow does not increase in absence epilepsy but, rather, decreases 17,18 …”

Section: Discussionsupporting

confidence: 81%

“…The brain uptake of diazepam, an AED that permeates the BBB via passive diffusion, was significantly enhanced following PTZ administration. This enhanced exposure of diazepam after acute seizure may be due to a disruption in the BBB architecture or an enhancement in cerebral blood flow, two phenomena that have been observed in rodents after PTZ‐induced seizures 1,15 . Our inulin data demonstrated that BBB integrity was not altered, 16 suggesting that the increase in diazepam uptake is more likely due to enhanced cerebral blood flow.…”

Section: Discussionsupporting

confidence: 49%

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Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

Nicolazzo

Steuten

Charman

et al. 2010

Clin Exp Pharma Physio

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1. Although many studies have assessed changes to brain uptake of anti-epileptic drugs (AEDs) in chemically and electrically induced seizure models, there are limited data available on changes to brain uptake of AEDs in spontaneous seizure animal models, such as genetic absence epilepsy. 2. In the present study, the brain uptake of diazepam and phenytoin was assessed in a genetic mouse model of absence seizures harbouring a human GABA(A) receptor gamma2-subunit gene GABRG2 mutation (R43Q) and results were compared with those obtained during acute seizures induced by subcutaneous administration of pentylenetetrazole (PTZ; 90 mg/kg). Diazepam and phenytoin were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations were determined 60 min after administration using liquid chromatography-mass spectrometry. 3. Although the brain uptake of phenytoin was significantly reduced following PTZ administration, no changes were observed in phenytoin disposition in the genetic absence epilepsy model. Similarly, the brain uptake of diazepam was significantly enhanced following PTZ administration, but it was not affected in absence epilepsy. 4. The cerebrovascular plasma volume (assessed by administration of the non-absorbable marker [(14)C]-inulin) was not significantly different in saline-treated compared with PTZ-treated mice and in wild-type compared with mutant R43Q mice. 5. These results demonstrate that although the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the non-convulsive genetic absence epileptic model.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 49%

Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

Nicolazzo

Steuten

Charman

et al. 2010

Clin Exp Pharma Physio

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“…1992; Pereira de Vasconcelos et al . 1992, 1995). It consisted of an injection of the first dose of 40 mg/kg PTZ, followed by 20 mg/kg 10 min later and then, every 10 min, additional i.p.…”

Section: Methodsmentioning

confidence: 99%

“…We showed previously that PTZ‐induced SE leads to acute and long‐term age‐specific changes in cerebral metabolism and blood flow (Pereira de Vasconcelos et al . 1992, 1995; Hussenet et al . 1995; Nehlig & Pereira de Vasconcelos 1996).…”

Section: Introductionmentioning

confidence: 99%

Mapping of neuronal networks underlying generalized seizures induced by increasing doses of pentylenetetrazol in the immature and adult rat: a c-Fos immunohistochemical study

André

Pineau

Motté

et al. 1998

European Journal of Neuroscience

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114

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Previous studies from our group have shown that pentylenetetrazol (PTZ)-induced status epilepticus (SE) leads to age-dependent acute and long-term metabolic and circulatory changes in immature rats. In order to define the neural substrates involved in PTZ seizures according to age, the purpose of the present study was to map the areas of cellular activation during seizures of increasing severity in 10-day-old (P10), 21-day-old (P21) and adult rats. Seizures were induced by repetitive injections of subconvulsive doses of PTZ. The total dose received by the animals ranged from 4 to 125 mg/kg. These doses induced a variety of seizure profiles including absence-like, clonic seizures and SE. The cellular activation was measured as the density of c-Fos immunoreactive cells in animals at 2 h after the onset of the seizures. In P10 rats receiving a behaviourally non-active dose of PTZ, c-Fos immunoreactivity appeared only in the amygdala. The dose of 40 mg/kg that induced absence-like seizures led to a weak c-Fos expression in the medial thalamus, some cortical areas and globus pallidus. Clonic seizures reinforced labelling in the previous areas and induced a spread of c-Fos immunoreactivity to other cortical areas, thalamus, hypothalamus and some brainstem nuclei. At that age, only SE led to a widespread and stronger expression of c-Fos which was, however, totally lacking in the midbrain, and remained incomplete in the brainstem and forebrain limbic system, including the hippocampus. In P21 and adult rats, the inactive dose of PTZ induced c-Fos immunoreactivity in thalamus and hypothalamus. With absence-like seizures, c-Fos labelling spread to the cerebral cortex, amygdala, septum and some brainstem regions. With clonic seizures, immunoreactivity was reinforced in all areas already activated by absence-like seizures, and appeared in the striatum, accumbens, brainstem and hippocampus, except in CA1. After SE, c-Fos was strongly expressed in all brain areas. The intensity of c-Fos labelling was higher in most regions of P21 compared to adult rats. These data are in agreement with the immaturity of cellular and synaptic connectivity in P10 rats, the known greater sensitivity of rats to various kinds of seizures during the third week of life and the nature of the neural substrates involved in PTZ seizures.

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“…In other models of SE (e.g., pentylenetetrazol), no neuronal damage occurs even in P21 rats after approximately 80 minutes of seizure activity. In that model, the lack of neuronal damage may arise from relatively moderate metabolic increases compared with those recorded in the lithium-pilocarpine model and the maintenance of coupling between LCMR glc and LCBF rates (Pereira de Vasconcelos et al, 1992Vasconcelos et al, , 1995.…”

Section: A Pereira De Vasconcelos Et Al 202mentioning

confidence: 99%

Local Cerebral Blood Flow during Lithium–Pilocarpine Seizures in the Developing and Adult Rat: Role of Coupling between Blood Flow and Metabolism in the Genesis of Neuronal Damage

Vasconcelos

Ferrandon

Nehlig

2002

J Cereb Blood Flow Metab

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Summary:Coupling between local cerebral blood flow and local cerebral metabolic rate for glucose is involved in the pathogenesis of epilepsy-related neuronal damage in the adult brain; however, its role in the immature brain is unknown. Lithium-pilocarpine-induced status epilepticus is associated with extended damage in adult rats, mostly in the forebrain limbic areas and thalamus, whereas damage was moderate in 21-day-old rats (P21) or absent in P10 rats. The quantitative autoradiographic [14 C]iodoantipyrine technique was applied to measure the consequences of lithium-pilocarpine status epilepticus on local cerebral blood flow. In adult and P21 rats, local cerebral blood flow rates increased by 50% to 400%; the highest increases were recorded in regions showing damage in adults. At P10, local cerebral blood flow rates decreased by 40% to 60% in most areas, except in some forebrain regions showing no change during status epilepticus. In areas injured when status epilepticus was induced in adults, a strong hypermetabolism (Fernandes et al., 1999) not matched by comparable local cerebral blood flow increases was present in rats of all ages, whereas in damage-resistant areas, local cerebral metabolic rate for glucose and local cerebral blood flow remained coupled in the three age groups. Thus, the level of coupling between blood flow supply and metabolism is not involved in seizure-related brain damage in the developing brain, which appears to be resistant to the consequences of such a mismatch. Key Words: Cerebral blood flow-Coupling between flow and metabolism-Seizures-Lithium-pilocarpine-Postnatal development-Neuronal damage.Changes in cerebral blood flow and metabolism in epilepsy have been of interest because of their involvement in the pathogenesis of neurologic damage. Indeed, during severe and prolonged seizures or status epilepticus (SE), large and sustained metabolic increases were recorded that are correlated with neuronal damage in various experimental models of severe seizures or SE (Meldrum, 1983;Ingvar, 1986;Handforth and Treiman, 1995). Nevander et al. (1985) showed that in vulnerable areas, after an initial marked metabolic increase, local cerebral metabolic rates for glucose (LCMR glc 's) return to normal levels and eventually decrease below the level recorded in the control situation as seizures continue; these low levels of LCMR glc 's coincide with the occurrence of neuronal damage. In addition, changes in cerebral blood flow are characterized by large increases up to 500% to 900% within seconds of the onset of seizure activity, and during this initial phase these large increases in rates of local cerebral blood flow (LCBF) are similar in amplitude to those of LCMR glc 's. However, as seizures continue, LCBF values decrease to 150% to 300% of control values after 1 or 2 hours of continuous seizure activity or SE, inducing a progressively established relative hypoperfusion, while the metabolic demand remains high. This situation may reach a critical level in terms of supplying adequate amounts ...

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Effects of Pentylenetetrazol-Induced Status Epilepticus on Local Cerebral Blood Flow in the Developing Rat

Cited by 19 publications

References 45 publications

Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

Mapping of neuronal networks underlying generalized seizures induced by increasing doses of pentylenetetrazol in the immature and adult rat: a c-Fos immunohistochemical study

Local Cerebral Blood Flow during Lithium–Pilocarpine Seizures in the Developing and Adult Rat: Role of Coupling between Blood Flow and Metabolism in the Genesis of Neuronal Damage

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