Effects of levetiracetam on blood-brain barrier disturbances following hyperthermia-induced seizures in rats with cortical dysplasia

Department of Histology and Embryology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Life sciences (Impact Factor: 2.7). 09/2010; 87(19-22):609-19. DOI: 10.1016/j.lfs.2010.09.014
Source: PubMed


The mechanisms underlying the changes in blood-brain barrier (BBB) integrity and the generation of seizures in childhood associated with preexisting brain lesions like cortical dysplasia (CD) are poorly understood. We investigated the effects of levetiracetam (LEV) on BBB integrity and the survival during hyperthermic seizures in rats with CD.
Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. On postnatal day 28, hyperthermia-induced seizures were evoked in offspring with CD. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopy were performed.
Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P<0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P<0.01). While glial fibrillary acidic protein (GFAP) immunoreactivity slightly increased in brain sections of animals with CD during hyperthermia-induced seizures, LEV led to GFAP immunoreactivity comparable to that of controls. Decreased occludin immunoreactivity and expression in CD plus hyperthermia-induced seizures was increased by LEV. Opening of tight junctions and abundance of pinocytotic vesicles representing ultrastructural evidences of BBB impairment and severe perivascular edema were observed in animals with CD exposed to hyperthermia-induced seizures and LEV treatment led to the attenuation of these findings.
These results indicate that LEV may present a novel approach for the protection of the BBB besides its antiepileptic impact on hyperthermic seizures in the setting of CD.

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Available from: Candan Gürses, Apr 22, 2014
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    • "It has been known since the 1960s that seizures affect the BBB [18]. BBB disruption, as detected using the BBB tracers Evans Blue, Horse Radish Peroxidase or Fluorescein occurs within 5–30 min after acute seizures that are induced using pentylene tetrazole, bicuculline, pyridoxine or hyperthermia in several (limbic) brain regions of animals [19] [20] [21] [22]. These studies all suggest that seizure activity can lead to BBB opening, which may be caused by acute hypertension [23] [24] [25]. "
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    ABSTRACT: The blood–brain barrier (BBB) is a dynamic and complex system which separates the brain from the blood. It helps to maintain the homeostasis of the brain, which is essential for normal neuronal functioning. BBB function is impaired in several neurological diseases, including epilepsy in which it may lead to abnormal and excessive neuronal firing. In this review we will discuss how BBB dysfunction can affect neuronal function and how this can lead to seizures and epilepsy. We will also summarize new therapies that aim to preserve or restore BBB function in order to prevent or reduce epileptogenesis.
    Full-text · Article · Nov 2014 · Seminars in Cell and Developmental Biology
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    • "In CD studies, BBB integrity is underevaluated as a significant component . BBB integrity becomes more vulnerable or is impaired as a result of alterations in functional and structural BBB characteristics in the malformed brain tissues (Marchi et al., 2006; Kaya et al., 2008; Gürses et al., 2009; Ahishali et al., 2010). On the other hand, the overexpression of multidrug transporter proteins in the capillary endothelium of BBB, astrocytic end-feet, microglia, and neurons has been suggested as the major mechanism responsible for multidrug resistance in epilepsy (Golden & Pardridge, 2000; Sisodiya et al., 2002; Aronica et al., 2003; Lçscher et al., 2011). "

    Full-text · Dataset · Nov 2013
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    • "Marchi et al. [46] reported a disruption in BBB permeability after Li-PIL administration that is sufficient to elicit seizures, an effect that aids in the neutrophil infiltration. The reduction in MPO by LEV could be linked to its ability to maintain the BBB integrity [47], where LEV preserves the morphological and functional properties of the BBB together with the reduction of pinocytotic activity during epileptic seizures [48]. "
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    ABSTRACT: Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide.
    Full-text · Article · Oct 2013 · PLoS ONE
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