2Research reportLevetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice
Introduction
Levetiracetam (LEV) is an established second-generation anti-epileptic drug (AED) that exerts broad-spectrum anti-epileptic effects and is widely used to treat partial onset and generalized seizures (Lyseng-Williamson, 2011). In addition, LEV is a candidate second-line AED for status epilepticus (SE) (Manno, 2011, Glauser et al., 2016) and a candidate anti-epileptogenic drug (Pearl et al., 2013, Klein et al., 2012). One of the pharmacological mechanism unique to LEV is its ability to bind to SV2A, a protein of the synaptic vesicle complex, to inhibit neurotransmitter release (Lynch et al., 2004, Meehan et al., 2012). In addition, several other mechanisms of LEV have been reported concerning the control of neurotransmitter release (Cataldi et al., 2005; Nagarkatti et al., 2008, Rigo et al., 2002; Lukyanetz et al., 2002).
Animal studies have shown that LEV exerts anti-epileptogenic and neuroprotective effects for the treatment of a pilocarpine (PILO)-SE model (Mazarati et al., 2004, Zheng et al., 2010, Itoh et al., 2015). However, the findings from previous reports in other post-SE animal models have been conflicting regarding whether LEV can prevent or modify epileptogenesis (Löscher et al., 1998, Glien et al., 2002, Klitgaard and Pitkanen, 2003, Stratton et al., 2003, Gibbs et al., 2006). Furthermore, the mechanisms responsible for the anti-epileptogenic and neuroprotective effects of LEV are still unknown.
Post-brain insult epilepsy (post-traumatic, PTE; post-stroke, PSE; and post-SE, PSEE; etc.) accounts for approximately 20% of symptomatic seizures and 5% of all epileptic seizures (Herman, 2002, Brodie et al., 2009). Given such prevalence, the prevention of these post-brain insult epilepsies is one of important issue. However, although 47 clinical studies have examined the efficacy of conventional AEDs (e.g. phenobarbital, valproate, carbamazepine, phenytoin, lamotrigine, topiramate), none of these drugs was able to prevent the development of epilepsy (Temkin, 2001, Temkin, 2003, Temkin, 2009, Krumholz et al., 2015). Therefore, several non-AEDs, such as anti-inflammatory drugs and mTOR inhibitors, were recently examined in basic and clinical studies to prevent these acquired epilepsies (Galanopoulou et al., 2012, Jiang et al., 2012). While LEV is an AED for managing post-brain insult epilepsies, several recent clinical studies for LEV in PTE, PSE, and PSEE have suggested that it may decrease the risk of acquired epilepsy or prevent the development of epilepsy, where conventional AEDs failed (Belcastro et al., 2008, Klein et al., 2012, Pearl et al., 2013). LEV has promising pharmacokinetic properties, including excellent bioavailability (>90%), linear kinetics, low plasma albumin binding (<10%), and a rapid rate of reaching steady state concentrations. In addition, LEV does not have any drug-drug interactions with AEDs or other agents that operate via the hepatic CYP-dependent metabolic pathway (Cloyd and Remmel, 2000, Patsalos, 2000, Panayiotopoulos, 2010).
We focused our attention on preventing the development of post-SE epilepsy. SE causes 3–5% of cases of symptomatic epilepsy; as such, SE patients are at a high risk of developing acquired epilepsy (Hesdorffer et al., 1998, Temkin, 2003, Jacobs et al., 2009). Various clinical trials have indicated that conventional AEDs suppressed acute seizures, but so far, none have been able to prevent the development of post-SE epilepsy ( Temkin, 2001, Temkin, 2003, Temkin, 2009). Although the mechanisms underlying the relationship between SE and the development of epilepsy as part of the epileptogenic process are not well understood, the lack of efficacy of the conventional AEDs suggests that the biological mechanisms of the epileptogenic process may be differ markedly from that of the established epileptic brain models (Pitkanen et al., 2009).
Therefore, in the present study, we used a mouse model of PILO-induced SE as a model of epileptogenesis and investigated whether or not LEV treatment could protect against the SE-induced BBB failure associated with angiogenesis and brain inflammation in the latent period after SE.
Section snippets
PILO-induced SE developed brain edema in MR images
In the MRI study, the SI of T2WI and DWI was measured in epileptogenic brains during the latent period after SE termination by DZP (Fig. 1A). At 2 days but not at 3 h post-SE, T2WI signal hyperintense areas were identified in the limbic regions (dorsal hippocampus, amygdala and piriform cortex) (Fig. 1A, b and c). In contrast, increased SI of DWI compared to the findings in pre-SE animals (Fig. 1A, e) was observed in the dorsal hippocampus and amygdala and piriform cortex at both 3 h and 2 days
Discussion
The ZP prevented BBB failure associated with angiogenesis and neurodegeneration induced by inflammatory responses in PILO-SE model mice.
LEV, one of the newer AEDs, has a unique mechanism of action, wide therapeutic spectrum, and a favorable pharmacokinetic profile (Panayiotopoulos, 2010). In addition, this drug may also prevent or modify the development of acquired epilepsy in basic and clinical studies (Löscher et al., 1998, Klitgaard and Pitkanen, 2003, Belcastro et al., 2008, Klein et al.,
Experimental animals
The protocols for all animal experiments were approved by the Tokushima Bunri University Animal Care Committees and were performed in accordance with the National Institutes of Health (USA) Animal Care and Use Protocol. All efforts were made to minimize the number of animals used and their suffering. Male, eight-week-old ICR mice were purchased from Japan SLC (Shizuoka, Japan). All mice were maintained with laboratory chow and water ad libitum on a 12-h light/dark cycle. The utilized animals
Conflicts of interest
The authors declare that there are no potential conflicts of interest related to the present manuscript.
Acknowledgements
This work was supported by JSPS KAKENHI Grant number JP16K10216 (to K.I.), JP15K18947 (to R.K.) JP15K08122 (to H.N.) and JP26740024 (to Y. I.) and was financially supported in part by Tokushima Bunri University. This manuscript has been checked by a professional language editing service (Japan Medical Communication, Inc).
References (64)
- et al.
Levetiracetamin newly diagnosed late-onset post-stroke seizures: a prospective observational study
Epilepsy Res.
(2008) - et al.
Prophylactic treatment with levetiracetam after status epilepticus: lack of effect on epileptogenesis, neuronal damage, and behavioral alterations in rats
Neuropharmacology
(2007) - et al.
Epilepsy in later life
Lancet Neurol.
(2009) - et al.
Pentylentetrazole-induced loss of blood-brain barrier integrity involves excess nitric oxide generation by neuronal nitric oxide synthase
Brain Res.
(2013) - et al.
Blood-arachnid barrier disruption in experimental rat meningitis detected using gadolinium-enhancement ratio imaging
Brain Res.
(2011) - et al.
Dual Role of Superoxide Dismutase 2 induced in activated microglia: oxidative stress tolerance and convergence of inflammatory responses
J. Biol. Chem.
(2015) - et al.
Prevention of status epilepticus-induced brain edema and neuronal cell loss by repeated treatment with high-dose levetiracetam
Brain Res.
(2015) - et al.
Inflammation induced at different developmental stages affects differently the range of microglial reactivity and the course of seizures evoked in the adult rat
Epilepsy Behav.
(2015) - et al.
The anti-ictogenic effects of levetiracetam are mirrored by interictal spiking and high-frequency oscillation changes in a model of temporal lobe epilepsy
Seizure
(2015) - et al.
Inflammatory pathways of seizure disorders
Trends Neurosci.
(2014)
Anticonvulsant effects of levetiracetam and levetiracetam diazepam combinations in experimental status epilepticus
Epilepsy Res.
Increased angiopoietin2 expression is associated with endothelial apoptosis and blood–brain barrier breakdown
Lab. Invest.
Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture
Neurosci. Lett.
Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis
FEBS Lett.
Pharmacokinetic profile of levetiracetam: toward ideal characteristics
Pharmacol. Ther.
Antiepileptogenic like effects of lamotrigine in a rat amygdala kindling model
Epilepsy Res.
Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation steps
Blood
Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: behavioral, physiological and histological studies
Neuropharmacology
Inflammatory neurodegeneration and mechanisms of microglial killing of neurons
Mol. Neurobiol.
The antiepileptic drug levetiracetam decreases the inositol 1,4,5-trisphosphatedependent [Ca2+]i increase induced by ATP and bradykinin in PC12 cells
J. Pharmacol. Exp. Ther.
The pilocarpine model of epilepsy in mice
Epilepsia
Antiepileptic drug pharmacokinetics and interactions: impact on treatment of epilepsy
Pharmacotherapy
Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments
Curr. Opin. Neurol.
Antiepileptogenesis therapy with levetiracetam: data from kindling versus status epilepticus models
Epilepsy Curr.
Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target
Epilepsia
Levetiracetam: antiepileptic properties and protective effects on mitochondrial dysfunction in experimental status epilepticus
Epilepsia
Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy
Epilepsia
Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society
Epilepsy Curr.
Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus
Ann. Neurol.
Epilepsy after brain insult: targeting epileptogenesis
Neurology
Curing epilepsy: progress and future directions
Epilepsy Behav.
Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2
Proc. Natl. Acad. Sci. USA
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These authors contributed equally to this work.