Glutamate is the main excitatory neurotransmitter in the brain and ionotropic glutamate receptors mediate the majority of excitatory neurotransmission (Dingeldine et al. 1999). The high level of glutamatergic excitation allows the neonatal brain (the 2(nd) postnatal week in rat) to develop quickly but it also makes it highly prone to age-specific seizures that can cause lifelong neurological and cognitive disability (Haut et al. 2004). There are three types of ionotropic glutamate receptors (ligand-gated ion channels) named according to their prototypic agonists: N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) and kainate (KA). During early stages of postnatal development glutamate receptors of NMDA and AMPA type undergo intensive functional changes owing to modifications in their subunit composition (Carter et al. 1988, Watanabe et al. 1992, Monyer et al. 1994, Wenzel et al. 1997, Sun et al. 1998, Lilliu et al. 2001, Kumar et al. 2002, Matsuda et al. 2002, Wee et al. 2008, Henson et al. 2010, Pachernegg et al. 2012, Paoletti et al. 2013). Participation and role of these receptors in mechanisms of seizures and epilepsy became one of the main targets of intensive investigation (De Sarro et al. 2005, Di Maio et al. 2012, Rektor 2013). LiCl/Pilocarpine (LiCl/Pilo) induced status epilepticus is a model of severe seizures resulting in development temporal lobe epilepsy (TLE). This review will consider developmental changes and contribution of NMDA and AMPA receptors in LiCl/Pilo model of status epilepticus in immature rats.

• MeSH
• AMPA receptory metabolismus   MeSH
• krysa rodu rattus MeSH
• mozek patofyziologie   MeSH
• nervový přenos * MeSH
• neurony metabolismus   MeSH
• novorozená zvířata MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• stárnutí * MeSH
• status epilepticus patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. METHODS: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). RESULTS: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). CONCLUSIONS: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

• MeSH
• autistická porucha * MeSH
• haploinsuficience MeSH
• krysa rodu rattus MeSH
• status epilepticus * MeSH
• TOR serin-threoninkinasy genetika   MeSH
• tuberin genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• elektroencefalografie MeSH
• krysa rodu rattus MeSH
• mozková kůra enzymologie   MeSH
• status epilepticus enzymologie   metabolismus   patologie   MeSH
• vývojová biologie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

AMPA receptors (AMPARs) are responsible for fast excitatory neurotransmission, and their prolonged activation can result in the generation and spread of epileptic seizures. At early stages of postnatal development, the majority of AMPARs are permeable to both Na(+) and Ca(2+) ions. This permeability, which increases neuronal excitability, is due to the lack of the GluA2 subunit, encoded by the GRIA2A gene, and/or the presence of an unedited GluA2 subunit Q/R site (glutamine instead of arginine). Lithium chloride- and pilocarpine-induced status epilepticus (LiCl/Pilo-SE) in rodents represents a model of severe seizures that result in development of temporal lobe epilepsy (TLE). The aim of this study was to determine how LiCl/Pilo-SE induced early in life (at postnatal day 12; P12) alters normal expression of the GRIA2A gene and GluA2 protein. SE was interrupted by an injection of paraldehyde (Para). Control groups were 1) naïve animals, and 2) siblings of SE rats receiving only LiCl and paraldehyde (LiCl/Para). The expression profile of GRIA2A mRNA was determined via qPCR, and GluA2 protein levels were measured by western blotting. The analysis was performed at 3h (protein levels), and then 3-, 6-, 13-, and 60days, following LiCl/Pilo-SE or LiCl/Para injection (i.e. at P12, P15, P18, P25, P72 respectively). Six different brain regions were analyzed: frontal (CXFR), parietal (CXPAR), and occipital (CXOC) cortex, dorsal (HD) and ventral (HV) hippocampus, and thalamus (TH). There was a significant increase in GRIA2A mRNA expression in the CXFR, CXPAR, and CXOC of P18 SE animals. In CXFR and HD, increased expression of GluA2 AMPAR subunit protein was detected, as well as a surge in GRIA2A mRNA and GluA2 protein expression especially at P18. In HD the surge was detected not only during development (P18), but also later in life (P72). Since high levels of GluA2 can be neuroprotective (by decreasing Ca(2+) permeability), our data suggest that the neocortex and dorsal hippocampus are able to activate endogenous antiepileptic mechanisms. A marked decrease in the overall expression of GluA2 protein in the HV in the LiCl/Pilo-SE and LiCl/Para rats, suggests that the HV is predisposed to excitotoxicity, not only during development, but even in adulthood. Interestingly, LiCl in combination with paraldehyde can also strongly alter the normal ontogeny of GRIA2A mRNA as well as GluA2 subunit protein expression.

• MeSH
• AMPA receptory genetika   metabolismus   MeSH
• chlorid lithný toxicita   MeSH
• fluoresceiny farmakokinetika   MeSH
• konvulziva toxicita   MeSH
• krysa rodu rattus MeSH
• messenger RNA metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   růst a vývoj   metabolismus   MeSH
• novorozená zvířata MeSH
• pilokarpin toxicita   MeSH
• potkani Wistar MeSH
• status epilepticus chemicky indukované   metabolismus   patologie   MeSH
• věkové faktory MeSH
• vývojová regulace genové exprese účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

• MeSH
• bílá hmota * diagnostické zobrazování   patologie   MeSH
• dospělí MeSH
• epilepsie temporálního laloku * patologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myelinová pochva patologie   MeSH
• předškolní dítě MeSH
• status epilepticus * chemicky indukované   patologie   MeSH
• zobrazování difuzních tenzorů MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• předškolní dítě MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• časové faktory MeSH
• degenerace nervu patologie   MeSH
• finanční podpora výzkumu jako téma MeSH
• krysa rodu rattus MeSH
• neurony patologie   MeSH
• novorozená zvířata růst a vývoj   MeSH
• status epilepticus patologie   MeSH
• thalamus patofyziologie   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

• MeSH
• elektroencefalografie metody   MeSH
• finanční podpora výzkumu jako téma MeSH
• krysa rodu rattus MeSH
• mozková kůra patofyziologie   růst a vývoj   MeSH
• neurony fyziologie   MeSH
• novorozená zvířata MeSH
• status epilepticus patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• MeSH
• degenerace nervu etiologie   patologie   MeSH
• finanční podpora výzkumu jako téma MeSH
• jádra thalamu anatomie a histologie   patologie   MeSH
• krysa rodu rattus MeSH
• lithium škodlivé účinky   MeSH
• modely nemocí na zvířatech MeSH
• pilokarpin škodlivé účinky   MeSH
• status epilepticus patologie   MeSH
• vývojová biologie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH

Status epilepticus (SE) poškozuje mozek. Následky u nezralých a dospělých jedinců jsou rozdílné: k zániku neuronů se v nezralém mozku přidává ještě ovlivnění vývoje statem, ale i použitou terapií. Důležitý je i stupeň vývoje, na kterém status proběhne. Budeme studovat dlouhodobé funkční a morfologické změny po lithium-pilokarpinovém statu u dvou věkových skupin mláďat laboratorních potkanů. Pozornost bude věnována i rozvoji mozkové léze v závislosti na době přežití po statu. K prevenci následků použijeme látky, u kterých byl nalezen pozitivní efekt na mozkové poškození u dospělých jedinců, tj. antagonisty excitačních aminokyselin (NMDA i AMPA receptorů), nootropika a dále blokátory apoptózy. paralelně budeme sledovat vliv testovaných látek na morfologický a funkční vývoj intaktních jedinců. Výsledky umožní posoudit, zda je terapeutický a neuroprotektivní přínos významnější než možný negativní dopad agresivní terapie na další vývoj mozku.; Status epilepticus has detrimental effects on brain. Its consequences in developing brain differ from those in mature brain; in addition to neuronal death subsequent development may be compromised not only by status but also by drugs used for therapy. Long-term functional and morphological consequences of experimental status epilepticus will be studied in two age groups of immature laboratory rats. Relationship between extension and character of brain damage and period after SE will be also examined. Toprevent consequences of status epilepticus antagonists of excitatory aminoacids, nootropics and apoptosis blockers will be used. The effects of these drugs on normal development of intact animals will be examined. Data from these experiments allow to decide if therapeutic and neuroprotective actions overweight possible negative influence of aggressive therapy on development.

• MeSH
• chronické poškození mozku MeSH
• dítě MeSH
• excitační aminokyseliny MeSH
• neuroprotektivní látky MeSH
• psychomotorické poruchy MeSH
• status epilepticus MeSH
• vývojová biologie MeSH
• Check Tag
• dítě MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurologie
• neurochirurgie
• farmacie a farmakologie
• pediatrie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Lithium-pilocarpine status epilepticus (SE) resulted in delayed changes of single cortical interhemisperic (transcallosal) responses in immature rats. Low-frequency stimulation inducing depression and/or potentiation was studied to analyze possible dynamic changes in cortical responses. Status was elicited in 12-day-old (SE12) or 25-day-old (SE25) rats. Control siblings received saline instead of pilocarpine. Interhemispheric responses were elicited by stimulation of the sensorimotor region of the cerebral cortex 3, 6, 9, 13, or 26 days after status. A series of 5 biphasic pulses with intensity equal to twofold threshold were used for stimulation. The interval between pulses was 100, 125, 160, 200 or 300 ms, eight responses were always averaged. Peak amplitude of the first positive, first negative and second positive waves was measured and responses to the second, third, fourth and fifth pulse were compared with the first one. Animals after status epilepticus as well as lithium-paraldehyde controls exhibit a frequency depression at nearly all the intervals studied. An outlined increase of responses in SE rats in comparison with the controls three days after SE stayed just below the level of statistical significance. In addition, animals in the SE12 group exhibited potentiation of responses at this interval after SE. With longer intervals after SE, the relation between SE and control animals changed twice resulting in a tendency to lower amplitude of responses in SE than in control rats 26 days after SE. Rats in the SE25 group exhibited higher responses than controls 13 days after status, but this difference was not present at the longest interval after SE. Low-frequency stimulation did not reveal increased cortical excitability as a long-lasting consequence of status epilepticus induced in immature rats. In addition, the outlined differences between SE and control rats changed with the time after SE.

• MeSH
• deprese etiologie   patofyziologie   MeSH
• epilepsie enzymologie   etiologie   patofyziologie   MeSH
• evokované potenciály účinky léků   MeSH
• financování organizované MeSH
• implantované elektrody virologie   MeSH
• interpretace statistických dat MeSH
• pilokarpin škodlivé účinky   MeSH
• potkani Wistar MeSH
• vývojová biologie metody   MeSH