Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam

Itoh, Kouichi; Inamine, Moriyoshi; Oshima, Wataru; Kotani, Masaharu; Chiba, Yoichi; Ueno, Masaki; Ishihara, Yasuhiro

doi:10.1016/j.brainres.2015.03.005

Cited by 37 publications

(27 citation statements)

References 41 publications

(45 reference statements)

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“…32 Increases in FA in gray matter areas have been attributed to inflammation and gliosis where the infiltrating glial cells create a more directional water diffusion. 33 These changethat is, blood-brain barrier disruption, 34 cytotoxic edema, 35 extracellular space contraction, 36 cytoskeletal changes, 37 inflammation, 38 and gliosis 39 may occur in gray matter areas during epileptogenesis and therefore could be the underlying cause of the DTI changes observed in our model.…”

Section: Discussionmentioning

confidence: 90%

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Network evolution in mesial temporal lobe epilepsy revealed by diffusion tensor imaging

et al. 2017

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OBJECTIVE The objective of the present study is to identify novel, time-indexed imaging biomarkers of epileptogenesis in mesial temporal lobe epilepsy (MTLE). METHODS We used high-resolution brain diffusion tensor imaging (DTI) of the translationally relevant methionine sulfoximine (MSO) brain infusion model of MTLE. MSO inhibits astroglial glutamine synthetase, which is deficient in the epileptogenic hippocampal formation of patients with MTLE. MSO-infused (epileptogenic) rats were compared with phosphate buffered saline (PBS)-infused (nonepileptogenic) rats at early (3–4 days) and late (6–9 weeks) time points during epileptogenesis. RESULTS The epileptogenic rats exhibited significant changes in DTI-measured fractional anisotropy (FA) in numerous brain regions versus nonepileptogenic rats. Changes included decreases and increases in FA in regions such as the entorhinal-hippocampal area, amygdala, corpus callosum, thalamus, striatum, accumbens and neocortex. The FA changes evolved over time as animals transitioned from early to late epileptogenesis. For example, some areas with significant decreases in FA early in epileptogenesis changed to significant increases late in epileptogenesis. Finally, the FA changes significantly correlated with the seizure load. SIGNIFICANCE Our results suggest (a) that high resolution DTI can be used for early identification and tracking of the epileptogenic process in MTLE, and (b) that the process identified by DTI is present in multiple brain areas, even though infusion of MSO is restricted to the unilateral entorhinal-hippocampal region.

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Section: Discussionmentioning

confidence: 90%

“…These changes – i.e. blood-brain barrier disruption 34 , cytotoxic edema 35 , extracellular space contraction 36 , cytoskeletal changes 37 , inflammation 38 and gliosis 39 – may occur in gray matter areas during epileptogenesis and therefore could be the underlying cause of the DTI changes observed in our model.…”

Section: Discussionmentioning

confidence: 96%

Network evolution in mesial temporal lobe epilepsy revealed by diffusion tensor imaging

et al. 2017

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“…17 In the mouse pilo-SE model, a single LEV dose of 500 mg/kg administered 30 minutes after SE cessation reduced frequency and severity of seizures 4 weeks later. This was associated with block of both cytotoxic and vasogenic edema, reduced blood-brain barrier (BBB) leakage at 3 hours-2 days after SE, 18 and inhibition of increase in the expression of angiogenic factors, neovascularization, activation of microglia, and upregulation of proinflammatory cytokines. 19 Chronic treatment (21 days after pilo-SE in rats) with LEV at clinically relevant exposures counteracted the increased amplitude of population spikes recorded in vivo in the dentate gyrus and reduced paired-pulse inhibition in the CA1, when compared to vehicle-treated rats.…”

Section: Key Pointsmentioning

confidence: 97%

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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“…Increasing evidence has suggested that 33 intravenous VPA and LEV may be acceptable 34 alternatives to the recommended first-line treatments for 35 status epilepticus (SE) (Trinka, 2009(Trinka, , 2011Meierkord 36 et al, 2010;Shorvon and Trinka, 2013). Because of their 37 relatively favorable pharmacokinetic profiles, good tolera-38 bility and few side effects (Trinka, 2009(Trinka, , 2011Meierkord 39 et al, 2010) (Turnbull et al, 1986;Jacob and Chand, 1998;Berning 45 et al, 2009;Belcastro et al, 2010) (Simister et al, 2007;Garcia et al, 2009;Li et al, 2010;66 Evans et al, 2011;Bakker et al, 2012;Liguori et al, 67 2012; Ziyeh et al, 2002;Itoh et al, 2015;68 Wandschneider et al, 2014); however, the VBM method 69 has not been conducted for this purpose. Moreover, the 70 rapid effects of single-dose intravenous VPA or LEV 71 administration have not yet been explored via neuroimag- 72 ing.…”

mentioning

confidence: 99%

Single-dose intravenous administration of antiepileptic drugs induces rapid and reversible remodeling in the brain: Evidence from a voxel-based morphometry evaluation of valproate and levetiracetam in rhesus monkeys

Tang

Zhang

et al. 2015

Neuroscience

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Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam

Cited by 37 publications

References 41 publications

Network evolution in mesial temporal lobe epilepsy revealed by diffusion tensor imaging

Network evolution in mesial temporal lobe epilepsy revealed by diffusion tensor imaging

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

Single-dose intravenous administration of antiepileptic drugs induces rapid and reversible remodeling in the brain: Evidence from a voxel-based morphometry evaluation of valproate and levetiracetam in rhesus monkeys

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