Neuroprotection and anti-seizure effects of levetiracetam in a rat model of penetrating ballistic-like brain injury

Caudle, Krista L.; Lu, Xi‐Chun M.; Mountney, Andrea; Shear, Deborah A.; Tortella, Frank C.

doi:10.3233/rnn-150580

Cited by 7 publications

(7 citation statements)

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“…In addition, an early post-TBI seizure promotes epileptogenesis and also profoundly suppresses synaptic plasticity: The early onset of post-TBI seizures affected the severity and duration of those seizures, which may contribute to epileptogenesis [ 13 ]. However, the infusion of prophylactic levetiracetam could provide significant neuroprotection, a finding which was also previously documented [ 13 , 51 ]. Such infusions may protect the cellular structure of CA1 Schaffer collateral synapses and preserve not only short-term but also long-term synaptic plasticity [ 52 , 53 ].…”

Section: Discussionsupporting

confidence: 69%

“…The antiepileptic effects of LEV may involve several mechanisms [ 51 , 52 ]: (1) interaction with SV2A which is one isoform of synaptic vesicle protein 2 (SV2) (2) removal of the Zn++-induced suppression of GABA-mediated presynaptic inhibition. (3) the combination of inhibitory effects on depolarization-induced and Ca2+ release-associated neurotransmitter releases.…”

Section: Discussionmentioning

confidence: 99%

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Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam

et al. 2018

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AimTo determine the precise effects of post-traumatic seizure activity on hippocampal processes, we induced seizures at various intervals after traumatic brain injury (TBI) and analyzed plasticity at CA1 Schaffer collateral synapses.Material and MethodsRats were initially separated into two groups; one exposed solely to fluid percussion injury (FPI) at 2 Psi and the other only receiving kainic acid (KA)-induced seizures without FPI. Electrophysiological (ePhys) studies including paired-pulse stimulation for short-term presynaptic plasticity and long-term potentiation (LTP) of CA1 Schaffer collateral synapses of the hippocampus for post-synaptic function survey were followed at post-event 1 hour, 3 and 7 days respectively. Additional rats were exposed to three seizures at weekly intervals starting 1 week or 2 weeks after TBI and compared with seizures without TBI, TBI without seizures, and uninjured animals. An additional group placed under the same control variables were treated with levetiracetam prior to seizure induction. The ePhys studies related to post-TBI induced seizures were also followed in these additional groups.ResultsSeizures affected the short- and long-term synaptic plasticity of the hippocampal CA3-CA1 pathway. FPI itself suppressed LTP and field excitatory post synaptic potentials (fEPSP) in the CA1 Schaffer collateral synapses; KA-induced seizures that followed FPI further suppressed synaptic plasticity. The impairments in both short-term presynaptic and long-term plasticity were worse in the rats in which early post-TBI seizures were induced than those in which later post-TBI seizures were induced. Finally, prophylactic infusion of levetiracetam for one week after FPI reduced the synaptic plasticity deficits in early post-TBI seizure animals.ConclusionOur data indicates that synaptic plasticity (i.e., both presynaptic and postsynaptic) suppression occurs in TBI followed by a seizure and that the interval between the TBI and seizure is an important factor in the severity of the resulting deficits. Furthermore, the infusion of prophylactic levetiracetam could partially reverse the suppression of synaptic plasticity.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam

et al. 2018

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“…In an Operation Brain Trauma Therapy (OBTT) project, a single intravenous LEV dose of 54 or 170 mg/kg 15 minutes after TBI in FPI and CCI models improved histological neuroprotection and cognitive function in both models, and motor function in the CCI model . The authors of the OBTT project described LEV as “the most promising drug tested thus far by OBTT, and the only drug to improve cognitive outcome in any model.” Similar improvement in motor and spatial learning occurred with LEV 50 mg/kg/d treatment for 10 days after penetrating ballistic brain injury …”

Section: Levetiracetammentioning

confidence: 53%

“…Similar improvement in motor and spatial learning occurred with LEV 50 mg/kg/d treatment for 10 days after penetrating ballistic brain injury. 27 Thus, there is broad evidence of LEV's antiepileptogenic and disease-modifying effects and some neuroprotective effect. The effects occur in the majority of the models with clinically relevant doses, and, in some models, with associated clinically applicable blood levels.…”

Section: Key Pointsmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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“…16 Hayvan deneylerinde nöroprotektif etkileri gösterilen ve son yıllarda kullanımı gittikçe artan levetiresetamın yapılan çalışmalarda antiepileptik etkisinin fenitoin ile benzer, yan etkilerinin fenitoinden daha az olduğu bulunmuştur. [16][17][18][19][20] Yazarlar sundukları olguda 1 posttravmatik epilepsi profilaksisi amacı ile fenitoin kullandıklarını belirtmişlerdir. Yukarıda bahsedilen nedenlerden dolayı epilepsi profilaksisinde levetiresetamın fenitoin ve diğer antiepileptik ilaçlara tercih edilmesi gerektiğini düşünmekteyim.…”

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Current Medical Treatment of Severe Traumatic Brain Injury

Yeşilbaş¹

2018

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Neuroprotection and anti-seizure effects of levetiracetam in a rat model of penetrating ballistic-like brain injury

Abstract: These findings support the dual anti- seizure and neuroprotective role of LEV, but more importantly identify the importance of an extended dosing protocol which was specific to the therapeutic targets studied.

Cited by 7 publications

References 50 publications

Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam

Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Current Medical Treatment of Severe Traumatic Brain Injury

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