Profile of anticonvulsant action of levetiracetam, tiagabine and phenobarbital against seizures evoked by DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in neonatal rats

Kulick, Catherine V.; Gutherz, Samuel B.; Beck, Veronica C.; Medvedeva, N. A.; Soper, C.J.; Forcelli, Patrick A.

doi:10.1016/j.ejphar.2014.09.016

Cited by 12 publications

(7 citation statements)

References 30 publications

(49 reference statements)

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“…We selected a high dose to best test the hypothesis would induce behavioral alterations. The dose of phenobarbital was selected on the basis of prior reports from our group [36,37] and others [38] showing the efficacy of phenobarbital in P7 rats. This dose provides almost complete suppression of pentylenetetrazole-induced seizures in neonatal rats and falls above the range for complete blockade of forebrain seizures induced by methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate in P7 rats [37,38].…”

Section: Methodsmentioning

confidence: 99%

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Frankel

Medvedeva

Gutherz

et al. 2016

Epilepsy & Behavior

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Anticonvulsant drugs, when given during vulnerable periods of brain development, can have long-lasting consequences on nervous system function. In rats, the second postnatal week approximately corresponds to the late third trimester of gestation/early infancy in humans. Exposure to phenobarbital during this period has been associated with deficits in learning and memory, anxiety-like behavior, and social behavior, among other domains. Phenobarbital is the most common anticonvulsant drug used in neonatology. Several other drugs, such as lamotrigine, phenytoin, and clonazepam have also been reported to trigger behavioral changes. A new generation anticonvulsant drug, retigabine, has not previously been evaluated for long-term effects on behavior. Retigabine acts as an activator of KCNQ channels, a mechanism that is unique among anticonvulsants. Here, we examined the effects retigabine exposure from postnatal day (P)7 to P14 on behavior in adult rats. We compared these effects to those produced by phenobarbital (as a positive control) and saline (as a negative control). Motor behavior was assessed using the open field and rotarod, anxiety-like behavior by the open field, elevated plus maze, and light-dark transition task, and learning/memory by the passive avoidance task; social interactions were assessed in same-treatment pairs and nociceptive sensitivity was assessed via the tail-flick assay. Motor behavior was unaltered by exposure to either drug. We found that retigabine and phenobarbital exposure both induced increased anxiety-like behavior in adult animals. Phenobarbital, but not retigabine exposure impaired learning and memory. These drugs also differed in their effects on social behavior, with retigabine-exposed animals displaying greater social interaction than phenobarbital-exposed animals. These results indicate that neonatal retigabine induces a subset of behavioral alterations previously described for other anticonvulsant drugs, and extend our knowledge of drug-induced behavioral teratogenesis to a new mechanism of anticonvulsant action.

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Section: Methodsmentioning

confidence: 99%

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Frankel

Medvedeva

Gutherz

et al. 2016

Epilepsy & Behavior

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“… Retigabine : We have previously reported that the minimal effective dose in P7 rats for retigabine is 5 mg/kg, whereas anticonvulsant effects plateau at 15–30 mg/kg . Thus, the doses selected (5, 15, and 30 mg/kg) fall at the low, middle, and upper end of the anticonvulsant range. Phenobarbital (positive control) : The dose of phenobarbital is based on prior reports from our group and others showing the efficacy of phenobarbital in P7 rats. The dose selected (75 mg/kg) is just below the dose that provides complete suppression against pentylenetetrazole (PTZ)–induced seizures (both minimal and maximal) in P7 rat pups .…”

Section: Methodsmentioning

confidence: 99%

“…26 This dose of lamotrigine does not induce apoptosis in the developing brain. 5 Levetiracetam (negative control): The dose of levetiracetam selected (250 mg/kg) is well above the therapeutic range we have reported previously in rats, 23 which plateaus between 50 and 100 mg/kg when tested against seizures evoked by methyl-6,7-dimethoxy-4-ethyl-bcarboline-3-carboxylate. This dose has been reported previously to be devoid of pro-apoptotic effects.…”

Section: Selection Of Drug Dosesmentioning

confidence: 98%

“…Phenobarbital (positive control): The dose of phenobarbital is based on prior reports from our group 22,23 and others 24 showing the efficacy of phenobarbital in P7 rats. The dose selected (75 mg/kg) is just below the dose that provides complete suppression against pentylenetetrazole (PTZ)-induced seizures (both minimal and maximal) in P7 rat pups.…”

Section: Selection Of Drug Dosesmentioning

confidence: 99%

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Profile of retigabine‐induced neuronal apoptosis in the developing rat brain

et al. 2016

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Summary Objective Acute neonatal exposure to some, but not all, anticonvulsant drugs induces a profound increase in neuronal apoptosis in rats. Phenobarbital, and phenytoin induce apoptosis at therapeutically-relevant dose range, lamotrigine and carbamazepine do so only at supratherapeutic doses or in polytherapy, and valproate does so even at subtherapeutic doses. Levetiracetam is devoid of pro-apoptotic effects. Retigabine, a new generation drug, acts uniquely by enhancing the M-type potassium current. Because its safety profile in developing animals is unstudied, we sought to determine if retigabine would induce apoptosis. Methods Postnatal day (P) 7 rat pups were treated with retigabine (5–30 mg/kg), vehicle (saline), or comparator drugs (phenobarbital, lamotrigine, levetiracetam, or carbamazepine). Cell death was assessed using AminoCupricSilver staining. A separate group of animals was treated repeatedly (3x) with retigabine (15 mg/kg) or vehicle over 24. To establish a pharmacokinetic profile for retigabine, we measured plasma and brain levels after drug treatment. Results Consistent with prior studies from us and others, we found phenobarbital induced cell death throughout thalamus, nucleus accumbens and several neocortical areas. By contrast, levetiracetam, lamotrigine, and carbamazepine were found to have no appreciable apoptotic effect on the aforementioned structures. Acute (single) exposure to retigabine, even at doses of 30 mg/kg was also without effect on apoptosis. However, repeated (3x) exposure to retigabine triggered apoptosis in a subset of brain areas. The half-life of retigabine in plasma was 2.5 h, with appreciable concentrations reached in the brain within 1 h of administration. Significance These data demonstrate that retigabine, like many other anticonvulsant drugs, is capable of triggering neuronal apoptosis in the developing rat brain. Unlike other drugs, repeated dosing of retigabine was necessary to induce this effect. This may be due to its shorter half-life as compared to other drugs, such as phenobarbital.

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“…The doses of phenobarbital, phenytoin, lamotrigine, carbamazepine, and levetiracetam fell within the anticonvul-sant dose range in neonatal rats. [22][23][24][25] Moreover, the doses selected for phenobarbital, MK-801, and phenytoin trigger neuronal apoptosis in the developing rat brain. 4,5,7,26 By contrast, the doses selected of lamotrigine, carbamazepine, and levetiracetam do not.…”

Section: Selection Of Drug Dosesmentioning

confidence: 99%

Anticonvulsant drug–induced cell death in the developing white matter of the rodent brain

et al. 2016

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Summary Objective During critical periods of brain development, both seizures and anticonvulsant medications can affect neurodevelopmental outcomes. In rodent models, many anticonvulsants trigger neuronal apoptosis. However, white matter apoptosis (WMA) has not been examined after anticonvulsant drug treatment. Here, we sought to determine if anticonvulsant drugs induced apoptosis in the developing white matter (WM) in rodent model. Methods Postnatal day (P)7 rats were treated with phenobarbital (PB-75), MK-801 (0.5), lamotrigine (LTG-20), carbamazepine (CBZ-100), phenytoin (PHT-50), levetiracetam (LEV-250) or saline; all doses are mg/kg. Brain tissue collected 24 h after treatment was stained using the TUNEL method. The number of degenerating cells within WM i.e. Anterior Commissure (AC), Corpus Callosum, Cingulum and Hippocampus-associated WM tracts was quantified. Results Saline-treated rats showed low baseline level of apoptosis in developing WM on P8 in all the areas examined. PB, PHT, and MK-801 significantly increased apoptosis in all 4 brain areas examined. Exposure to CBZ, LTG or LEV failed to increase apoptosis in all regions. Significance Commonly used anticonvulsants (PB, PHT) cause apoptosis in the developing WM in a rat model, the NMDA receptor antagonist MK-801 has a similar effect. These results are consistent with reports of anesthesia-induced WMA during brain development. Consistent with the lack of neuronal apoptosis caused by LTG, LEV and CBZ, these drugs did not not cause WMA. Many infants treated with anticonvulsant drugs have underlying neurological injury, including white matter damage (e.g., following intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE)). The degree to which anticonvulsant drug treatment will alter outcomes in the presence of underlying injury remains to be examined, but avoiding drugs (when possible) that induce WMA may be beneficial.

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Profile of anticonvulsant action of levetiracetam, tiagabine and phenobarbital against seizures evoked by DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in neonatal rats

Cited by 12 publications

References 30 publications

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Comparison of the long-term behavioral effects of neonatal exposure to retigabine or phenobarbital in rats

Profile of retigabine‐induced neuronal apoptosis in the developing rat brain

Anticonvulsant drug–induced cell death in the developing white matter of the rodent brain

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