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Hana Kubová - One of the best experts on this subject based on the ideXlab platform.
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Do stereoisomers of Homocysteic Acid exhibit different convulsant action in immature rats
Physiological Research, 2019Co-Authors: P. Mareš, Jaroslava Folbergrová, Renata Haugvicová, Hana KubováAbstract: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.
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Effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) on seizures induced in immature rats by Homocysteic Acid
Experimental Neurology, 2006Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Mareš, Rastislav Druga, Jakub Otáhal, Hana KubováAbstract:Abstract The present study has examined the effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl -Homocysteic Acid ( dl -HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl -HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures (∼ 45 – 50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl -HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl -HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by Homocysteic Acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.
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convulsant action of d l Homocysteic Acid and its stereoisomers in immature rats
Epilepsia, 1997Co-Authors: Pavel Mareš, Jaroslava Folbergrová, Renata Haugvicová, M Langmeier, Hana KubováAbstract:Summary: Purpose: We wished to characterize the convulsant effect of Homocysteic Acid (HCA) in developing rats. Methods: Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocor-ticograms (ECoG) were recorded after injection. Results: HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Conclusions: Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.
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Convulsant Action of D,L‐Homocysteic Acid and Its Stereoisomers in Immature Rats
Epilepsia, 1997Co-Authors: Pavel Mareš, Jaroslava Folbergrová, Renata Haugvicová, M Langmeier, Hana KubováAbstract:Summary: Purpose: We wished to characterize the convulsant effect of Homocysteic Acid (HCA) in developing rats. Methods: Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocor-ticograms (ECoG) were recorded after injection. Results: HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Conclusions: Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.
Tohru Hasegawa - One of the best experts on this subject based on the ideXlab platform.
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Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.
Journal of Alzheimer's Disease, 2020Co-Authors: Tohru Hasegawa, Kosoku Yoshinori, Yuka Sano, Yoshida Hiroshi, Chiaki Kudoh, Takeshi TabiraAbstract:Background In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD. Objective Homocysteic Acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. Methods We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. Results Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. Conclusion Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.
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Open Label Clinical Trial of Hydrogen Brain Food for 91 Alzheimer's Patients (Targeting Therapy for Homocysteic Acid in Blood is an Alzheimer's Cognitive Recovery)
Journal of Clinical Research, 2017Co-Authors: Tohru Hasegawa, Yasubumi UchidaAbstract:Introduction: Exercise and antioxidant nutrition based food are good prevention for Alzheimer’s Disease. But why are these preventions effective to prevent AD? Recent our findings that human AD patients could not excrete Homocysteic Acid (HA) into urine and their blood HA was a good marker for the cognitive decline in AD, which indicated that the treatment for HA in blood can be a good therapy for the recovery of cognitive decline of AD. Methods: We have developed new food supplement which can compete with HA and also reduce the sulfite group of HA. We named this supplement as HBF. We observed the effect of HBF on 91 AD patients as an open labeled clinical trial. Results: In fact we have developed the brain food which can decrease HA in blood. And we have observed that the open-labeled clinical trial of HBF (hydrogen brain food) for 91 AD patients was good positive results. Even the final stage of AD patients, their cognitive behavior was surprisingly recovered. Discussions: From our observations, it is suggested that targeting Homocysteic Acid in blood is a good therapy for the cognitive recovery of AD and also suggested that exercise and antioxidant nutrition food also can decrease HA in blood partially and these methods are good preventions for AD, because normal person’s HA level in blood is very low.
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Targeting therapy for Homocysteic Acid in the blood represents a potential recovery treatment for cognition in Alzheimer's disease patients.
Aging, 2016Co-Authors: Tohru Hasegawa, Wataru UkaiAbstract:At present, we have no reliable means of recovering cognitive impairment in Alzheimer's disease (AD) patients. We hypothesized that Homocysteic Acid (HA) in the blood might represent one such pathogen that could be excreted into the urine. Since DHA is known to reduce circulating levels of homocysteine, and since exercise attenuates this effect, it follows that supplementation of the diet with DHA, along with increased levels of physical activity, may help to reduce cognitive impairment in AD patients. Our hypothesis was proven to be correct because memory problems in 3xTg- AD mice (a model for AD in which animals develop amyloid pathology), and in a mouse model of familial AD, were recovered following treatment with an anti-HA antibody and not by amyloid treatment. Interestingly, 3xTg-AD mice with amyloid pathology showed increased levels of HA level. This could perhaps be explained by the fact that amyloid precursor protein and/or presenilin increases calcium influx, which could then increase levels of superoxide and consequently increase levels of HA from homocysteine or methionine. Our hypothesis is also partially supported by an open clinical trial of certain dietary supplements that has shown impressive results. Also there are other treatments hypothesis which would be possible for the effective therapies, such as ribonucleoprotein therapy, a β-secretase inhibitor treatment and the metabolic enhancement treatment.
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Urinary Homocysteic Acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients.
Journal of Alzheimer's Disease, 2012Co-Authors: Tohru Hasegawa, Tatsuo Yamada, Masayoshi Ichiba, Shin-ei Matsumoto, Koji Kasanuki, Taku Hatano, Hiroshige Fujishiro, Eizo Iseki, Nobutaka Hattori, Takeshi TabiraAbstract:Homocysteic Acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-β increases HA toxicity and HA is an agonist of N-methyl-D-aspartic Acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD.
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Treatment of Alzheimer's disease with anti-Homocysteic Acid antibody in 3xTg-AD male mice.
PLoS ONE, 2010Co-Authors: Tohru Hasegawa, Nobuyuki Mikoda, Masashi Kitazawa, Frank M. LaferlaAbstract:Alzheimer's disease (AD) is an age-associated progressive neurodegenerative disorder with dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that Homocysteic Acid (HA) may be one of the pathological biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal amyloid-beta (Aβ) peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathological 3xTg-AD mice exhibited higher levels of HA in the hippocampus than did age-matched nontransgenic mice, suggesting that HA accumulation may precede both Aβ and tau pathologies. We then fed 3-month-old 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to increase the HA levels in the brain. Concomitantly, mice received either saline or anti-HA antibody intraventricularly via a guide cannula every 3 days during the course of the B6-deficient diet. We found that mice that received anti-HA antibody significantly resisted cognitive impairment induced by vitamin B6 deficiency and that AD-related pathological changes in their brains was attenuated compared with the saline-injected control group. A similar neuroprotective effect was observed in 12-month-old 3xTg-AD mice that received anti-HA antibody injections while receiving the regular diet. We conclude that increased brain HA triggers memory impairment and that this condition deteriorates with amyloid and leads to subsequent neurodegeneration in mouse models of AD.
Renata Haugvicová - One of the best experts on this subject based on the ideXlab platform.
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Do stereoisomers of Homocysteic Acid exhibit different convulsant action in immature rats
Physiological Research, 2019Co-Authors: P. Mareš, Jaroslava Folbergrová, Renata Haugvicová, Hana KubováAbstract: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.
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Mitochondrial complex I inhibition in cerebral cortex of immature rats following Homocysteic Acid-induced seizures.
Experimental Neurology, 2007Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Ješina, Zdeněk Drahota, Václav Lisý, Alena Vojtiskova, Josef HouštěkAbstract:Abstract The major finding of the present study concerns the marked decrease of respiratory chain complex I activity in the cerebral cortex of immature rats following seizures induced by bilateral intracerebroventricular infusion of dl -Homocysteic Acid (600 nmol/side). This decrease was already evident during the acute phase of seizures (60–90 min after infusion) and persisted for at least 20 h after the seizures. It was selective for complex I since activities of complex II and IV and citrate synthase remained unaffected. Inhibition of complex I activity was not associated with changes in complex I content. Based on enhanced lipoperoxidation and decreased aconitase activity, it can be postulated that oxidative modification is most likely responsible for the observed inhibition. Mitochondrial respiration, as well as cortical ATP levels remained in the control range, apparently due to excess capacity of the complex I documented by energy thresholds. On the other hand, the enhanced production of reactive oxygen species by inhibited complex I was observed in mitochondria from HCA-treated animals. The decrease of complex I activity was substantially attenuated when animals were treated with substances providing an anticonvulsant effect and also with selected free radical scavengers. We can assume that inhibition of complex I may elicit enhanced formation of reactive oxygen species and contribute thus to neuronal injury demonstrated in this model.
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Effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) on seizures induced in immature rats by Homocysteic Acid
Experimental Neurology, 2006Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Mareš, Rastislav Druga, Jakub Otáhal, Hana KubováAbstract:Abstract The present study has examined the effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl -Homocysteic Acid ( dl -HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl -HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures (∼ 45 – 50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl -HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl -HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by Homocysteic Acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.
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Neuroprotective effect of (R, S)-4-phosphonophenylglycine against neuronal damage associated with Homocysteic Acid-induced seizures in immature rats.
Prague medical report, 2006Co-Authors: M Langmeier, Renata Haugvicová, J. Folbergrová J., V RiljakAbstract:Incidence of human epilepsy in infants and children is high and prolonged seizures in the early developmental period can cause brain damage and lead to serious consequences later in the life. The present study was aimed to investigate potential protective effect of (R, S)-4-phosphonophenylglycine ((R, S)-PPG), a potent and selective group III mGluR agonist, on brain damage associated with Homocysteic Acid-induced seizures in immature 12-day-old rats. This compound does not exhibit any proconvulsive effect. Moreover, (R, S)-PPG was shown to protect NMDA and quinolinic Acid-induced lesions in rats. Seizures were induced by bilateral intracerebroventricular (i.c.v.) infusion of Homocysteic Acid (DL-HCA, 600 nmol/side). (R, S)-PPG was given by bilateral i.c.v. infusions (5 nmol/side) at 15- to 20-min time intervals prior to administration of DL-HCA. After 1 or 6 days of survival, animals in all experimental groups (13-day-old and 18-day-old) were perfused transcardially under deep ether anaesthesia with heparinized normal saline and subsequently with the fixation solution (4% paraformaldehyde in the phosphate buffer, pH 7.4, both solutions at room temperature). Two histological methods were used in our study. Fluoro-Jade B dye is an anionic fluorescein derivative useful for the histological staining of neurons undergoing degeneration and staining with bis-benzimide (Hoechst 33342) was used to detect apoptotic cells according nuclei with condensed and/or fragmented DNA. Animals perfused 1 day after the treatment (13-day-old): After only (R, S)-PPG application, no obvious pathological changes were found. After only DL-HCA application, distinct destruction of the hippocampal region both in the dorsal and ventral hippocampus was observed. Particularly affected were cells in the CA1 and CA3 regions. In addition, neurons with segmented or fragmented nuclei were found in the granule cell layer of the dentate gyrus. (R, S)-PPG + DL-HCA administration resulted in a lower number of Fluoro-Jade B positive cells. All areas of the hippocampus were protected by (R, S)-PPG pre-treatment. Animals perfused 6 days after the treatment (18-day-old): In the group where only (R, S)-PPG has been applied, no obvious pathological changes were found in the hippocampal area. After only DL-HCA administration almost complete destruction of the hippocampal region both in the dorsal and ventral hippocampus was observed. Particularly affected were the cells in the CA1 and CA3 regions, granule cells of the dentate gyrus and many interneurons in all hippocampal areas. (R, S)-PPG + DL-HCA administration resulted in lower number of Fluoro-Jade B positive cells. All areas of the hippocampus have been protected by (R, S)-PPG pre-treatment. In conclusion, the present data support the hypothesis that (R, S)-PPG can have a beneficial effect in those disorders where excitotoxicity is one of the dominant pathogenetic mechanisms.
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Neuronal cell death in hippocampus induced by Homocysteic Acid in immature rats.
Epilepsia, 2003Co-Authors: Miloš Langmeier, Jaroslava Folbergrová, Renata Haugvicová, Jaroslav Pokorný, Pavel MarešAbstract:Summary: Purpose: To examine the morphologic alterations in the cerebral cortex and hippocampus of immature rats 6 days after the generalized clonic‐tonic seizures induced by Homocysteic Acid (HCA). Methods: Seizures were induced by bilateral intracerebroventricular infusion of HCA (600 nmol per each side) in 12day-old rats. After 6 days, rat pups were transcardially perfused under deep ether anesthesia with heparinized normal saline and subsequently with the fixation solution (4% paraformaldehyde in phosphate buffer, pH 7.4, for light microscopy) or with Karnovsky’s solution (4% paraformaldehyde and 2% glutaraldehyde in phosphate buffer, pH 7.4, for electron microscopic analysis). Nissl stain and the DNA-specific dye bis-benzimide (Hoechst 33342) were used. Results: No pathologic changes were found in the cerebral cortex, whereas serious alterations occurred in the hippocampus. A total loss of CA3 pyramidal cells was observed, with marked changes in the CA1 region and dentate gyrus. A prominent glial reaction was seen in many regions of the hippocampal formation. A slight dilatation of the cerebral ventricles was noticed in some experimental as well as control animals. In the granule cell layer of the dentate gyrus, neurons with segmented or fragmented nuclei in various stages of degeneration were detected, displaying the features of apoptotic death. Conclusions: These findings demonstrate the vulnerability of the immature rat brain, which most likely reflects both the direct neurotoxic effect of HCA and prolonged seizure activity. The relative contribution of these two factors still remains to be assessed. Key Words: Homocysteic Acid—Immature rats— Seizures—Cell degeneration—Nuclear fragmentation.
Jaroslava Folbergrová - One of the best experts on this subject based on the ideXlab platform.
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Do stereoisomers of Homocysteic Acid exhibit different convulsant action in immature rats
Physiological Research, 2019Co-Authors: P. Mareš, Jaroslava Folbergrová, Renata Haugvicová, Hana KubováAbstract: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.
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Mitochondrial complex I inhibition in cerebral cortex of immature rats following Homocysteic Acid-induced seizures.
Experimental Neurology, 2007Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Ješina, Zdeněk Drahota, Václav Lisý, Alena Vojtiskova, Josef HouštěkAbstract:Abstract The major finding of the present study concerns the marked decrease of respiratory chain complex I activity in the cerebral cortex of immature rats following seizures induced by bilateral intracerebroventricular infusion of dl -Homocysteic Acid (600 nmol/side). This decrease was already evident during the acute phase of seizures (60–90 min after infusion) and persisted for at least 20 h after the seizures. It was selective for complex I since activities of complex II and IV and citrate synthase remained unaffected. Inhibition of complex I activity was not associated with changes in complex I content. Based on enhanced lipoperoxidation and decreased aconitase activity, it can be postulated that oxidative modification is most likely responsible for the observed inhibition. Mitochondrial respiration, as well as cortical ATP levels remained in the control range, apparently due to excess capacity of the complex I documented by energy thresholds. On the other hand, the enhanced production of reactive oxygen species by inhibited complex I was observed in mitochondria from HCA-treated animals. The decrease of complex I activity was substantially attenuated when animals were treated with substances providing an anticonvulsant effect and also with selected free radical scavengers. We can assume that inhibition of complex I may elicit enhanced formation of reactive oxygen species and contribute thus to neuronal injury demonstrated in this model.
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Effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) on seizures induced in immature rats by Homocysteic Acid
Experimental Neurology, 2006Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Mareš, Rastislav Druga, Jakub Otáhal, Hana KubováAbstract:Abstract The present study has examined the effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl -Homocysteic Acid ( dl -HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl -HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures (∼ 45 – 50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl -HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl -HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by Homocysteic Acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.
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Neuronal cell death in hippocampus induced by Homocysteic Acid in immature rats.
Epilepsia, 2003Co-Authors: Miloš Langmeier, Jaroslava Folbergrová, Renata Haugvicová, Jaroslav Pokorný, Pavel MarešAbstract:Summary: Purpose: To examine the morphologic alterations in the cerebral cortex and hippocampus of immature rats 6 days after the generalized clonic‐tonic seizures induced by Homocysteic Acid (HCA). Methods: Seizures were induced by bilateral intracerebroventricular infusion of HCA (600 nmol per each side) in 12day-old rats. After 6 days, rat pups were transcardially perfused under deep ether anesthesia with heparinized normal saline and subsequently with the fixation solution (4% paraformaldehyde in phosphate buffer, pH 7.4, for light microscopy) or with Karnovsky’s solution (4% paraformaldehyde and 2% glutaraldehyde in phosphate buffer, pH 7.4, for electron microscopic analysis). Nissl stain and the DNA-specific dye bis-benzimide (Hoechst 33342) were used. Results: No pathologic changes were found in the cerebral cortex, whereas serious alterations occurred in the hippocampus. A total loss of CA3 pyramidal cells was observed, with marked changes in the CA1 region and dentate gyrus. A prominent glial reaction was seen in many regions of the hippocampal formation. A slight dilatation of the cerebral ventricles was noticed in some experimental as well as control animals. In the granule cell layer of the dentate gyrus, neurons with segmented or fragmented nuclei in various stages of degeneration were detected, displaying the features of apoptotic death. Conclusions: These findings demonstrate the vulnerability of the immature rat brain, which most likely reflects both the direct neurotoxic effect of HCA and prolonged seizure activity. The relative contribution of these two factors still remains to be assessed. Key Words: Homocysteic Acid—Immature rats— Seizures—Cell degeneration—Nuclear fragmentation.
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convulsant action of d l Homocysteic Acid and its stereoisomers in immature rats
Epilepsia, 1997Co-Authors: Pavel Mareš, Jaroslava Folbergrová, Renata Haugvicová, M Langmeier, Hana KubováAbstract:Summary: Purpose: We wished to characterize the convulsant effect of Homocysteic Acid (HCA) in developing rats. Methods: Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocor-ticograms (ECoG) were recorded after injection. Results: HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Conclusions: Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.
Pavel Mareš - One of the best experts on this subject based on the ideXlab platform.
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Effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) on seizures induced in immature rats by Homocysteic Acid
Experimental Neurology, 2006Co-Authors: Jaroslava Folbergrová, Renata Haugvicová, Pavel Mareš, Rastislav Druga, Jakub Otáhal, Hana KubováAbstract:Abstract The present study has examined the effect of free radical spin trap N-tert-butyl-α-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl -Homocysteic Acid ( dl -HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl -HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures (∼ 45 – 50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl -HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl -HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by Homocysteic Acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.
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Neuronal cell death in hippocampus induced by Homocysteic Acid in immature rats.
Epilepsia, 2003Co-Authors: Miloš Langmeier, Jaroslava Folbergrová, Renata Haugvicová, Jaroslav Pokorný, Pavel MarešAbstract:Summary: Purpose: To examine the morphologic alterations in the cerebral cortex and hippocampus of immature rats 6 days after the generalized clonic‐tonic seizures induced by Homocysteic Acid (HCA). Methods: Seizures were induced by bilateral intracerebroventricular infusion of HCA (600 nmol per each side) in 12day-old rats. After 6 days, rat pups were transcardially perfused under deep ether anesthesia with heparinized normal saline and subsequently with the fixation solution (4% paraformaldehyde in phosphate buffer, pH 7.4, for light microscopy) or with Karnovsky’s solution (4% paraformaldehyde and 2% glutaraldehyde in phosphate buffer, pH 7.4, for electron microscopic analysis). Nissl stain and the DNA-specific dye bis-benzimide (Hoechst 33342) were used. Results: No pathologic changes were found in the cerebral cortex, whereas serious alterations occurred in the hippocampus. A total loss of CA3 pyramidal cells was observed, with marked changes in the CA1 region and dentate gyrus. A prominent glial reaction was seen in many regions of the hippocampal formation. A slight dilatation of the cerebral ventricles was noticed in some experimental as well as control animals. In the granule cell layer of the dentate gyrus, neurons with segmented or fragmented nuclei in various stages of degeneration were detected, displaying the features of apoptotic death. Conclusions: These findings demonstrate the vulnerability of the immature rat brain, which most likely reflects both the direct neurotoxic effect of HCA and prolonged seizure activity. The relative contribution of these two factors still remains to be assessed. Key Words: Homocysteic Acid—Immature rats— Seizures—Cell degeneration—Nuclear fragmentation.
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convulsant action of d l Homocysteic Acid and its stereoisomers in immature rats
Epilepsia, 1997Co-Authors: Pavel Mareš, Jaroslava Folbergrová, Renata Haugvicová, M Langmeier, Hana KubováAbstract:Summary: Purpose: We wished to characterize the convulsant effect of Homocysteic Acid (HCA) in developing rats. Methods: Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocor-ticograms (ECoG) were recorded after injection. Results: HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Conclusions: Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.
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Convulsant Action of D,L‐Homocysteic Acid and Its Stereoisomers in Immature Rats
Epilepsia, 1997Co-Authors: Pavel Mareš, Jaroslava Folbergrová, Renata Haugvicová, M Langmeier, Hana KubováAbstract:Summary: Purpose: We wished to characterize the convulsant effect of Homocysteic Acid (HCA) in developing rats. Methods: Seizures were induced in 7-, 12-, 18-, and 25-day-old rats by intraperitoneal (i.p.) administration of D,L-HCA and in 12-day-old rats by i.p. injection of L- and D-stereoisomers of HCA. The animals were observed for 30 min after injection. The incidence, latencies, pattern of motor seizures, and all behavioral phenomena were noted. Fifty percent convulsant dose (CD50) values were calculated by probit analysis. Electrocor-ticograms (ECoG) were recorded after injection. Results: HCA did not elicit minimal clonic seizures whereas generalized tonic-clonic seizures (GTCS) occurred in all the age groups studied. Flexion (emprosthotonic) convulsions occurred to postnatal day 18. ECoG recordings exhibited delta activity in younger pups and sharp graphoelements in older pups, but electroclinical correlation was poor. Young animals were more sensitive to the convulsant effect of D,L-HCA. In addition, D-HCA was significantly more effective than L-HCA in inducing both flexion and generalized seizures. Conclusions: Our data clearly indicate that seizures induced by HCA differ from those evoked by homocysteine. There are no qualitative differences in the motor pattern of seizures induced by the two stereoisomers of HCA, but marked differences were apparent in the very first signs of their action. These differences might be due to interaction with different glutamate receptor subtypes.