Vliv vybraných farmak na předčasné degenerativní poškození mozku v experimentu. XXX XXX XXX

• MeSH
• degenerace nervu etiologie   farmakoterapie   MeSH
• modely nemocí na zvířatech MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• farmacie a farmakologie
• neurologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

The present study aimed to elucidate the effect of sulforaphane (a natural isothiocyanate) on oxidative stress and mitochondrial dysfunction during and at selected periods following status epilepticus (SE) induced in immature 12-day-old rats by Li-pilocarpine. Dihydroethidium was employed for the detection of superoxide anions, immunoblot analyses for 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) levels and respiratory chain complex I activity for evaluation of mitochondrial function. Sulforaphane was given i.p. in two doses (5 mg/kg each), at PD 10 and PD 11, respectively. The findings of the present study indicate that both the acute phase of SE and the early period of epileptogenesis (1 week and 3 weeks following SE induction) are associated with oxidative stress (documented by the enhanced superoxide anion production and the increased levels of 3-NT and 4-HNE) and the persisting deficiency of complex I activity. Pretreatment with sulforaphane either completely prevented or significantly reduced markers of both oxidative stress and mitochondrial dysfunction. Since sulforaphane had no direct anti-seizure effect, the findings suggest that the ability of sulforaphane to activate Nrf2 is most likely responsible for the observed protective effect. Nrf2-ARE signaling pathway can be considered a promising target for novel therapies of epilepsy, particularly when new compounds, possessing inhibitory activity against protein-protein interaction between Nrf2 and its repressor protein Keap1, with less "off-target" effects and, importantly, with an optimal permeability and bioavailability properties, become available commercially.

• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• isothiokyanatany farmakologie   MeSH
• KEAP-1 metabolismus   MeSH
• krysa rodu rattus MeSH
• mitochondrie metabolismus   MeSH
• oxidační stres MeSH
• status epilepticus * metabolismus   MeSH
• sulfoxidy metabolismus   farmakologie   MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Perinatal hypoxic-ischemic insult (HII) is one of the main devastating causes of morbidity and mortality in newborns. HII induces brain injury which evolves to neurological sequelae later in life. Hypothermia is the only therapeutic approach available capable of diminishing brain impairment after HII. Finding a novel therapeutic method to reduce the severity of brain injury and its consequences is critical in neonatology. The present paper aimed to evaluate the effect of sulforaphane (SFN) pre-treatment on glucose metabolism, neurodegeneration, and functional outcome at the acute, sub-acute, and sub-chronic time intervals in the experimental model of perinatal hypoxic-ischemic insult in rats. To estimate the effect of SFN on brain glucose uptake we have performed 18F-deoxyglucose (FDG) microCT/PET. The activity of FDG was determined in the hippocampus and sensorimotor cortex. Neurodegeneration was assessed by histological analysis of Nissl-stained brain sections. To investigate functional outcomes a battery of behavioral tests was employed. We have shown that although SFN possesses a protective effect on glucose uptake in the ischemic hippocampus 24 h and 1 week after HII, no effect has been observed in the motor cortex. We have further shown that the ischemic hippocampal formation tends to be thinner in HIE and SFN treatment tends to reverse this pattern. We have observed subtle chronic movement deficit after HII detected by ladder rung walking test with no protective effect of SFN. SFN should be thus considered as a potent neuroprotective drug with the capability to interfere with pathophysiological processes triggered by perinatal hypoxic-ischemic insult.

• MeSH
• fluorodeoxyglukosa F18 terapeutické užití   MeSH
• glukosa MeSH
• hypoxie komplikace   MeSH
• isothiokyanatany MeSH
• krysa rodu rattus MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• mozková hypoxie a ischemie * diagnostické zobrazování   farmakoterapie   MeSH
• novorozená zvířata MeSH
• poranění mozku * MeSH
• sulfoxidy MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mechanism of ictogenesis of D- and L-stereroisomers of homocysteic acid was studied in 12-day-old rats by means of antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. There was no qualitative difference between the two stereoisomers in generation of emprosthotonic (flexion) as well as generalized tonic-clonic seizures. Moderate differences were observed in the first, nonconvulsive effects of the two isomers. As generation of the two types of seizures is concerned, NMDA and AMPA participate in generalized tonic-clonic seizures whereas NMDA receptors play a dominant role in generation of flexion seizures.

• MeSH
• 2-amino-5-fosfonovalerát analogy a deriváty   MeSH
• AMPA receptory antagonisté a inhibitory   MeSH
• benzodiazepiny MeSH
• chinoxaliny MeSH
• dizocilpinmaleát MeSH
• homocystein analogy a deriváty   chemie   toxicita   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   MeSH
• stereoizomerie MeSH
• záchvaty chemicky indukované   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Epilepsy is one of the most common neurologic disorders affecting a substantial part of the population worldwide. Epileptic seizures represent the situation of increased neuronal activity associated with the enhanced demands for sufficient energy supply. For that purpose, very efficient regulatory mechanisms have to operate to ensure that cerebral blood flow, delivery of oxygen, and nutrients are continuously adapted to the local metabolic needs. The sophisticated regulation has to function in concert at several levels (systemic, tissue, cellular, and subcellular). Particularly, mitochondria play a key role not only in the energy production, but they are also central to many other processes including those leading to neuronal death. Impairment of any of the involved pathways can result in serious functional alterations, neurodegeneration, and potentially in epileptogenesis. The present review will address some of the important issues concerning vascular and metabolic changes in pathophysiology of epilepsy.

• MeSH
• epilepsie komplikace   genetika   MeSH
• lidé MeSH
• metabolické nemoci etiologie   genetika   MeSH
• mitochondriální DNA genetika   MeSH
• mozek metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The existing data indicate that status epilepticus (SE) induced in immature animals is associated with oxidative stress and mitochondrial dysfunction. This has been demonstrated using two models of SE, induced by substances with a different mechanism of action (DL-homocysteic acid and 4-aminopyridine) which suggests that the findings are not model-dependent but they reflect more general phenomenon. Oxidative stress occurring in immature brain during and following seizures is apparently due to both the increased free radicals production and the limited antioxidant defense. Pronounced inhibition of mitochondrial complex I in immature brain was demonstrated not only during the acute phase of SE, but it persisted during long periods of survival, corresponding to the development of spontaneous seizures (epileptogenesis). The findings suggest that oxidative modification is most likely responsible for the sustained deficiency of complex I activity. It can be assumed that the substances with antioxidant properties combined with conventional therapies might provide a beneficial effect in treatment of epilepsy.

• MeSH
• krysa rodu rattus MeSH
• kyslík metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• mozek patofyziologie   MeSH
• oxidační stres * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• záchvaty patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Mitochondrial dysfunction has been identified as one potential cause of epileptic seizures. Impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca(2+) homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.

• MeSH
• energetický metabolismus MeSH
• epilepsie patofyziologie   MeSH
• homeostáza MeSH
• lidé MeSH
• mitochondrie fyziologie   MeSH
• modely nemocí na zvířatech MeSH
• neurony fyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The widely-held assumption was that oxidative stress does not occur during seizures in the immature brain. The major finding of the present study concerns evidence of oxidative stress in the brain of immature rats during seizures induced by DL-homocysteic acid. Seizures were induced in 12-day-old rats by bilateral intracerebroventricular infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side) and oxidative stress was evaluated by in situ detection of superoxide anion (O(2)·(-)). Using hydroethidine (Het) method, the fluorescent signal of the oxidized products of Het (reflecting O(2)·(-) production) significantly increased (by 50%-60%) following 60 min lasting seizures in all the studied structures, namely CA1, CA3 and dentate gyrus of the hippocampus, cerebral cortex and thalamus. The enhanced O(2)·(-) production was substantially attenuated or completely prevented by substances providing an anticonvulsant effect, namely by a competitive NMDA receptor antagonist AP7, a highly selective and potent group II metabotropic glutamate receptor (mGluR) agonist 2R,4R-APDC and highly selective group III mGluR, subtype 8 agonist (S)-3,4-DCPG. Complete protection was achieved by two SOD mimetics Tempol and MnTMPYP which strongly suggest that the increased fluorescent signal reflects O(2)·(-) formation. In addition, both scavengers provided a partial protection against brain damage associated with the present model of seizures. Signs of neuronal degeneration, as evaluated by Fluoro-Jade B staining, were detected at 4h following the onset of seizures. The present findings thus suggest that the increased superoxide generation precedes neuronal degeneration and may thus play a causative role in neuronal injury. Occurrence of oxidative stress in brain of immature rats during seizures, as demonstrated in the present study, can have a clinical relevance for a novel approach to the treatment of epilepsy in children, suggesting that substances with antioxidant properties combined with the conventional therapies might provide a beneficial effect.

• MeSH
• 2-amino-5-fosfonovalerát analogy a deriváty   terapeutické užití   MeSH
• antikonvulziva terapeutické užití   MeSH
• časové faktory MeSH
• homocystein analogy a deriváty   toxicita   MeSH
• intraventrikulární infuze MeSH
• krysa rodu rattus MeSH
• metaloporfyriny metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   metabolismus   MeSH
• neparametrická statistika MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• prolin analogy a deriváty   terapeutické užití   MeSH
• superoxidy metabolismus   MeSH
• záchvaty chemicky indukované   patologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.

• MeSH
• agonisté excitačních aminokyselin farmakologie   MeSH
• aldehydy metabolismus   MeSH
• časové faktory MeSH
• down regulace účinky léků   fyziologie   MeSH
• energetický metabolismus účinky léků   fyziologie   MeSH
• epilepsie metabolismus   patofyziologie   MeSH
• homocystein analogy a deriváty   toxicita   MeSH
• konvulziva toxicita   MeSH
• krysa rodu rattus MeSH
• metabolické sítě a dráhy fyziologie   MeSH
• míra přežití MeSH
• mitochondriální nemoci chemicky indukované   metabolismus   patofyziologie   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   patologie   patofyziologie   MeSH
• novorozená zvířata MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• potkani Wistar MeSH
• respirační komplex I účinky léků   metabolismus   MeSH
• scavengery volných radikálů farmakologie   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• záchvaty chemicky indukované   metabolismus   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The present study has examined the anticonvulsant and neuroprotective effect of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective agonist for group II metabotropic glutamate receptors (mGluRs) when given 10-15 min after the onset of seizures induced in 12-day-old rats by bilateral icv infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion of DL-HCA. Comparable time intervals were used for sacrificing the animals which received 2R,4R-APDC (0.05 nmol/side) or saline. The severity of seizures was influenced only slightly when the agonist was given after the onset of seizures, as evaluated both from the behavioral symptoms and from EEG recordings. A tendency to lower number and a shorter duration of seizures was outlined in animals posttreated with 2R,4R-APDC, but the differences did not reach the level of statistical significance. Cortical energy metabolite changes which normally accompany seizures in immature rats (large decrease of glucose and glycogen and a marked rise of lactate) were ameliorated only partially. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration in many brain regions, mainly in the hippocampus and thalamus, following infusion of DL-HCA alone was only partially attenuated after 2R,4R-APDC posttreatment. The present findings clearly indicate that both anticonvulsant and neuroprotective effect of 2R,4R-APDC against DL-HCA-induced seizures is substantially diminished when the agonist is given after the onset of seizures as compared with its efficacy after the pretreatment (Exp. Neurol.192, 420-436, 2005).

• MeSH
• agonisté excitačních aminokyselin terapeutické užití   MeSH
• cytoprotekce fyziologie   účinky léků   MeSH
• degenerace nervu chemicky indukované   patofyziologie   prevence a kontrola   MeSH
• epilepsie farmakoterapie   metabolismus   patofyziologie   MeSH
• hipokampus metabolismus   růst a vývoj   účinky léků   MeSH
• homocystein analogy a deriváty   farmakologie   MeSH
• konvulziva farmakologie   MeSH
• krysa rodu rattus MeSH
• lékové interakce fyziologie   MeSH
• mozek metabolismus   růst a vývoj   účinky léků   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• potkani Wistar MeSH
• prolin analogy a deriváty   terapeutické užití   MeSH
• receptory metabotropního glutamátu agonisté   metabolismus   MeSH
• rozvrh dávkování léků MeSH
• stárnutí metabolismus   MeSH
• thalamus metabolismus   růst a vývoj   účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH