We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.

• MeSH
• endotelin-1 toxicita   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• ischemie mozku chemicky indukované   metabolismus   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• receptor endotelinu A metabolismus   MeSH
• receptor endotelinu B metabolismus   MeSH
• záchvaty chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Status epilepticus (SE), especially in immature animals, is known to produce recurrent spontaneous seizures and behavioral comorbidities later in life. The cause of these adverse long-term outcomes is unknown, but it has been hypothesized that free radicals produced by SE may play a role. We tested this hypothesis by treating immature (P25) rats with the free radical scavenger N-tert-butyl-α-phenylnitrone (PBN) at the time of lithium chloride (LiCl)/pilocarpine (PILO)-induced SE. Later, long-term outcomes were assessed. Cognitive impairment (spatial memory) was tested in the Morris water maze (MWM). Emotional disturbances were assessed by the capture test (aggressiveness) and elevated plus maze's (EPM) test (anxiety). Next, the presence and severity of spontaneous seizures were assessed by continuous video/EEG monitoring for 5 days. Finally, immunochemistry, stereology and morphology were used to assess the effects of PBN on hippocampal neuropathology and neurogenesis. PBN treatment modified the long-term effects of SE in varying ways, some beneficial and some detrimental. Beneficially, PBN protected against severe anatomical damage in the hippocampus and associated spatial memory impairment. Detrimentally, PBN treated animals had more severe seizures later in life. PBN also made animals more aggressive and more anxious. Correlating with these detrimental long-term outcomes, PBN significantly modified post-natal neurogenesis. Treated animals had significantly increased numbers of mature granule cells (GCs) ectopically located in the dentate hilus (DH). These results raise the possibility that abnormal neurogenesis may significantly contribute to the development of post-SE epilepsy and behavioral comorbidities.

• Publikační typ
• časopisecké články MeSH

The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes - does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40pmol/μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70nmol/μl) or ETB receptors (BQ788; 70nmol/1μl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40pmol/1μl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10mM PBS or 0.01% DMSO-PBS solution; pH7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~25% and pO2 to ~10% for about 1.5h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them.

• MeSH
• elektroencefalografie * účinky léků   MeSH
• endotelin-1 aplikace a dávkování   toxicita   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• injekce intraventrikulární MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• receptor endotelinu A agonisté   metabolismus   MeSH
• receptor endotelinu B agonisté   metabolismus   MeSH
• záchvaty chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH