Biomedical subjects

J Velísková

Publications and source records attributed to J Velísková.

At least 19 recordsLinked to original sources

PubMed2005

The role of estrogens in seizures and epilepsy: the bad guys or the good guys?

Estrogens influence neuronal activity and are important for normal brain functions. Effects of estrogens on seizures are contradictory. It is commonly accepted that estrogens may increase neuronal excitability and thus mediate proconvulsant effects. However, clinical and animal data show that estrogen may also have no effect or anticonvulsant effects. The action of estrogens on seizures depends on various factors, such as treatment duration and latency prior to the seizure testing, estrogen dose, hormonal status (naïve vs gonadectomized animals), estrogenic substance, the region/neurotransmitter system involved, the seizure type/model used, and sex. Besides the effects on seizure susceptibility, estrogens may also play an important role in seizure-induced damage. Pretreatment with beta-estradiol in ovariectomized female rats has neuroprotective effects on status epilepticus-induced hippocampal damage and prevents the loss of inhibition in the dentate gyrus during the early post-status epilepticus period determined by the in vitro paired pulse paradigm. Several signaling pathways may be involved in the neuroprotective effects of beta-estradiol on status epilepticus-induced hippocampal damage but at least one of these pathways involves interactions with neuropeptide Y.

Animals↗

PubMed2005

Cognitive performance in people with Parkinson's disease and mild or moderate depression: effects of dopamine agonists in an add-on to L-dopa therapy.

In a randomized prospective multi-centre study, we evaluated the cognitive performances of a group of 41 non-demented patients, all with advanced Parkinson's disease (PD) and a current depressive episode, in whom the effects of pramipexole (PPX) and pergolide (PRG) in an add-on to l-dopa therapy were also studied and published with regard to motor symptoms of PD, motor complications and depression. The Trail Making Test, the Stroop test and four subtests (arithmetic, picture completion, digit symbols and similarities) of the Wechsler Adult Intelligence Scale-Revised were performed prior to and 8 months after the administration of either PPX or PRG. We found no statistically significant difference between the two tested drugs or between the first and the last visit in any of the above-listed neuropsychological tests. All patients' motor outcomes significantly improved and we conclusively demonstrated the anti-depressive effect of PPX. The dissociation of dopaminomimetic effects on the different tested domains indicates that there are different pathological mechanisms of cognitive, motor and affective disturbances in advanced PD patients. In our non-demented group of fluctuating depressed PD subjects, both PPX and PRG administration in combination with l-dopa were safe in terms of the effect on cognitive performance.

Aged↗

PubMed2004

[Effects of sex hormones in the CNS].

Sex steroid hormones influence the mammalian brain and modulate its activity during the lifespan. They are involved in regulation of gene transcription, neuronal excitability and neuronal survival. During development, sex hormones produce organizing effects in discrete brain regions. These regions include not only structures regulating sexual behavior but also other brain regions such as substantia nigra, hippocampus, cortex or amygdala. In mature brain, sex hormones have activational effects and modulate brain activity through excitatory or inhibitory mechanisms. Effects of sex hormones on seizure susceptibility and neuroprotective effects of beta-estradiol on status epilepticus-induced hippocampal damage will be discussed.

Animals↗

PubMed2003

Testosterone regulates androgen and estrogen receptor immunoreactivity in rat substantia nigra pars reticulata.

At postnatal day (PN)1, there are sex differences in gonadal receptor expression in the rat substantia nigra pars reticulata (SNR). Male pups have lower levels of androgen receptor (AR) and estrogen receptor (ER)beta immunoreactivity (IR) compared to female pups, while ERalpha IR is equally expressed in the two sexes. To test whether these differences are due to sex differences in testosterone exposure, we injected female pups with testosterone propionate (TP) on the day of birth and analyzed the levels of AR and ER IR at PN1. TP-treated females have lower levels of AR and ERbeta IR than control, while there are no differences in the levels of ERalpha IR. TP treatment did not affect the number of AR and ER expressing cells. The regulation of SNR AR and ERbeta IR by testosterone may be important for the development of sex-specific functional systems involved in motor control.

Animals↗

PubMed2003

Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.

An 8-month multicentre prospective randomized study aimed at comparing the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin) and pergolide (PRG; Permax) as add-on to L-dopa therapy on depression [Montgomery and Asberg Depression Rating Scale (MADRS)] in 41 non-demented patients (25 men, 16 women) suffering from both mild or moderate depression and advanced Parkinson's disease (PD). The assessment was performed by a blinded independent observer. Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities of daily living (UPDRS II and VI) and depressive symptoms as measured by Self - Rating Depression Scale by Zung were evaluated in an open-label design. The average value of Zung scores decreased significantly in both groups with no statistical difference between both groups. A significant decrease in the average value of MADRS scores was present only in the PPX group. The average UPDRS scores decreased significantly with no statistical difference between both groups at the comparable average total daily dose of both preparations. In both cases, the total daily dose of L-dopa decreased significantly but the decrease was statistically more pronounced in the PRG group. Our results demonstrate the antidepressant effect of PPX in patients with PD while we can't make any conclusions with regard to antidepressant effect of PRG.

Activities of Daily Living↗

PubMed2002

Sex differences in androgen and estrogen receptor expression in rat substantia nigra during development: an immunohistochemical study.

Gonadal hormones are important regulators of sexual differentiation of the CNS. Exposure to testosterone and estrogen during development causes permanent organizational differences between males and females. We previously described functional sex-related differences of the GABA(A)ergic circuits of the rat substantia nigra pars reticulata (SNR) involved in the control of flurothyl seizures. This sexual differentiation of the SNR is regulated by postnatal testosterone. To assess whether the organizing effects of testosterone in the SNR are mediated via the androgen receptor (AR) and/or estrogen receptors (ER), we used immunohistochemistry to study the ontogeny of AR, ERalpha and ERbeta expression in SNR and substantia nigra pars compacta (SNC) of male and female rats. Rats on the day of birth [postnatal day (PN) 0] and at PN1, PN5, PN15 and PN30 were used. AR- and ERbeta-immunopositive cells were present in SNR and SNC in both sexes and at all ages. ERalpha was not detected in male and female SNC at PN0-PN1. In both substantia nigra (SN) regions, there were developmentally regulated sex differences in AR, ERalpha and ERbeta immunoreactivity. In the SN, each receptor showed specific intracellular localization: AR was present in the nucleus, ERalpha and ERbeta were present both in nuclear and extranuclear compartments. ERalpha was detected also in processes. At PN0-PN1, quantitative analysis revealed sex and regional differences in the distribution of SN cells expressing AR and ERalpha, while ERbeta were equally present in both sexes. The presence of gonadal steroid receptors in the SN suggests that the biological effects of gonadal hormones in the CNS extend beyond reproduction-related functions and may affect and modify motor behaviors (including seizures) in a sex-specific manner. Based on the ontogeny of SNR ERbeta, we hypothesize that postnatal injections of testosterone may regulate the nigral GABA(A) system through the aromatization pathway and activation of ERbeta.

Animals↗

PubMed2001

Sexual dimorphism and developmental regulation of substantia nigra function.

The substantia nigra is an important brain nucleus involved in the expression of movement disorders and seizures. The two most common movement disorders affecting the substantia nigra, Parkinson's disease and Tourette syndrome, show gender differences and age-related onset. To assess the substrates for the gender and age specificity of substantia nigra-related disorders, we determined the functional properties of the substantia nigra gamma-aminobutyric acid (GABAA) system along its anterior-posterior axis, using localized microinfusions of muscimol (a GABAA agonist) and susceptibility to motor seizures in rats. In the substantia nigra, there are sex-specific differences in the topographic segregation and functionality of GABAA systems. In mature male rats there are two distinct regions mediating opposite effects on seizures; in female rats there is only one region that can affect seizures. In the neonatal period, the presence of circulating testosterone is essential for the development of a substantia nigra region that exerts proconvulsant effects throughout the rat's life, a unique feature of the male substantia nigra. The final maturation of the substantia nigra occurs in the peripubertal period, and is in part regulated by testosterone as well. The recognition of the existence of distinct sex- and age-specific substantia nigra features can be translated into new cures of disorders affecting the substantia nigra.

Aging↗

PubMed2001

The effects of N-methyl-D-aspartate antagonist 2-amino-7-phosphonoheptanoic acid microinfusions into the adult male rat substantia nigra pars reticulata are site-specific.

We examined the effects of regional infusions of 2-amino-7-phosphonoheptanoic acid (AP7) into the substantia nigra pars reticulata (SNR) in adult male rats on flurothyl-induced clonic seizures. AP7 infusions in the SNR had dose- and region-specific effects. In the SNR(anterior), both doses of AP7 (0.1 and 5 nmol) produced an anticonvulsant effect. In the SNR(posterior), the lower dose (0.1 nmol) did not influence the seizure threshold whereas the higher dose (5 nmol) of AP7 had a proconvulsant effect. The data indicate that there are two distinct regions within the SNR which differentially respond to pharmacological manipulations of the glutamatergic system. The region-specific effects in the SNR may provide an explanation for the previous conflicting reports regarding infusions of N-methyl-D-aspartate antagonists into this structure.

2-Amino-5-phosphonovalerate↗

PubMed2000

Prenatal morphine exposure alters susceptibility to bicuculline seizures in a sex- and age-specific manner.

Bicuculline was used to investigate seizure susceptibility in pre- and peripubertal male and female rats exposed prenatally to morphine. Morphine-exposed males showed increased seizure susceptibility at prepubertal and decreased susceptibility at peripubertal ages. There was no difference in seizure susceptibility in morphine-exposed females at either age. Therefore, the present data suggest that males are more vulnerable than females to morphine-induced insults during prenatal brain development.

Age Factors↗

PubMed2000

Prenatal methotrexate exposure decreases seizure susceptibility in young rats of two strains.

Effects of prenatal exposure to methotrexate (MTX) administered in Sprague-Dawley (one 5 mg/kg dose of MTX on gestational day 15; E15) or Wistar (one 5 mg/kg dose of MTX on E14 or E15 or two such doses on E15) pregnant rat dams were studied in developing offspring. Young Sprague-Dawley rats were subjected to rapid kindling on postnatal days (PN) 15 and 16, and to flurothyl seizures on PN 15 and PN 30. Offspring of the Wistar strain were tested in flurothyl on PN 30. In Sprague-Dawley rats, prenatal exposure to MTX decreased susceptibility to kindling-induced seizures on PN 15 and to flurothyl-induced clonic seizures on PN 30. In Wistar rats, a single dose of MTX on E15 was ineffective, but two doses significantly decreased susceptibility to flurothyl-induced seizures. Additionally, due to a shorter duration of pregnancy in Wistar rats, exposure to a single dose of MTX on E14 also decreased susceptibility to flurothyl seizures. MTX, as folic acid antagonist, interferes with DNA synthesis. However, unlike other treatments that suppress DNA synthesis (such as methylazoxymethanol exposure or X-ray radiation), MTX exposure results in anticonvulsant effects in surviving offspring. The data suggest that not all prenatal impairments of DNA have proconvulsant features postnatally.

Animals↗

PubMed2000

Effect of ganaxolone on flurothyl seizures in developing rats.

PURPOSE: To determine the effects of a newly synthesized epalon, ganaxolone (GNX), on primarily generalized seizures in rats of various ages during development. Epalons are classified as neuroactive steroids that interact at unique site of the GABAA receptor-Cl- channel complex in the central nervous system. METHODS: Sprague-Dawley male rats were used at 9, 15, 30, and 60 postnatal days (PN). GNX dissolved in 2-hydroxypropylbeta-cyclodextrine was administered intraperitoneally in different doses at various time points before flurothyl testing. The incidence and threshold of clonic and tonic-clonic flurothyl seizures were evaluated. Behavioral changes were also assessed. RESULTS: In all age groups, the effects of GNX were dose dependent and more prominent 10 min after its administration. In PN 60 and PN 30 rats, GNX had dose-dependent anticonvulsant effects; tonic-clonic seizures were more sensitive to GNX treatment than clonic seizures. In PN 15 and PN 9 rats, GNX demonstrated dose-and time-dependent anticonvulsant effects against both types of flurothyl-induced seizures. GNX was more effective in PN 15 rats than in other age groups, but at doses that altered motor behavior. CONCLUSIONS: GNX has anticonvulsant effects against flurothylinduced seizures in all age groups tested. Its effects are more prominent in the two younger age groups, especially in PN 15 rats, but are associated with motor side effects.

Age Factors↗

PubMed2000

Neuroprotective effects of estrogens on hippocampal cells in adult female rats after status epilepticus.

PURPOSE: Estrogens have neuroprotective effects in ischemia, stroke, and other conditions leading to neuronal cell death (e.g., Alzheimer's disease). The present study examined whether estrogens may have neuroprotective effects after seizures. METHODS: The kainic acid model was used to determine if estrogens protect hippocampal cells after status epilepticus in adult female rats. Rats were ovariectomized 1 week before hormone replacement. beta-Estradiol benzoate (EB; 2 microg in 0.1 mL of oil) was injected subcutaneously 48 and 24 hours before seizure testing. We administered kainic acid (16 mg/kg intraperitoneally) and behaviorally monitored the rats for 5 hours. After this time, all rats were injected with pentobarbital (50 mg/kg intraperitoneally) irrespective of seizure severity. Some rats received two additional doses of EB, one immediately and one 24 hours after the seizures. Another group of rats received only these two doses of EB after the seizures, and yet another group of rats received pretreatment with the intracellular EB receptor antagonist tamoxifen before each of four EB injections. Control rats received oil instead of EB. Rats were killed 48 hours after seizures. Neuronal damage was evaluated in silver-impregnated and Nissl-stained sections. RESULTS: Estrogen treatment before kainic acid administration significantly delayed the onset of kainic acid-induced clonic seizures, whereas it did not change the onset of status epilepticus compared with oil-treated controls. Furthermore, estrogen treatment significantly protected against kainic acid-induced seizure-related mortality. In control rats, examination of Nissl-stained and silver-impregnated slides revealed severe neuronal damage in the vulnerable pyramidal neurons of the hippocampal CA3 subfield and in the hilus of the dentate gyrus. Estrogen pretreatment, as well as the combination of pretreatment and posttreatment, significantly reduced the number of argyrophilic neurons in both the CA3 and the dentate gyrus. Posttreatment only had no protective effects. The data indicate that intracellular EB receptors mediate this type of neuroprotective effect, because the tamoxifen pretreatment abolished EB neuroprotection. CONCLUSIONS: Our results suggest that estrogens can be beneficial in protecting against status epilepticus-induced hippocampal damage. Hormonal conditions may have differential effects on underlying epileptic state in some patients. Therefore, more studies are necessary to determine the prospective therapeutic advantage of hormonal treatment in seizure-related damage.

Animals↗

PubMed2000

Malnutrition increases dentate granule cell proliferation in immature rats after status epilepticus.

PURPOSE: Nutritional insults early in life have a profound and often permanent effect on the development of the central nervous system. A direct relationship between malnutrition and epilepsy has not been established; however, it is believed that inadequate nutrition may predispose the brain to seizures. This study was designed to determine whether neonatally malnourished rats are different from nourished rats in terms of flurothyl seizure susceptibility at postnatal day (P)15, in the behavioral manifestations of seizures, and in status epilepticus-induced hippocampal injury. METHODS: Sprague-Dawley rat pups were maintained on a starvation regimen from P2 until P17. Age-matched control rats were not exposed to starvation. At P15, all animals were exposed to flurothyl-induced status epilepticus. At P17, the rats received a single injection of bromodeoxyuridine (50 mg/kg intraperitoneal) to determine the extent of genesis of new cells in the dentate gyrus. At P18, the rats were killed, and the brains were processed for histology and immunohistochemistry. RESULTS: Preliminary analysis indicates that early malnutrition did not modify flurothyl seizure susceptibility or the behavioral manifestations of seizures at P15. Histological assessment did not reveal any evidence of hippocampal cell loss after status epilepticus in either group. Malnutrition per se induced an increase in the genesis of new cells in the anterior dentate granule cell layer. Although exposure to status epilepticus augmented the expression of new cells in the dentate gyrus in both groups, this expression was more pronounced in the malnourished group. CONCLUSIONS: The findings suggest that malnutrition early in life alters dentate plasticity but not the susceptibility to flurothyl seizures. Although status epilepticus can increase the expression of new cells in the dentate gyrus in immature rats, malnutrition followed by status epilepticus further increases dentate granule cell proliferation.

Animals↗

PubMed2000

Laminar and temporal heterogeneity of NMDA/metabotropic glutamate receptor binding in posterior cingulate cortex.

Both N-methyl-D-aspartate (NMDA) and quisqualate/AMPA-insensitive metabotropic glutamate (mGlu) receptors mediate plasticity induction in neocortex, but their interlaminar distribution in cortical microcircuits is largely unknown. We used (+)(3)H-MK801 and (3)H-glutamate binding plus saturating concentrations of NMDA, AMPA, and quisqualate to autoradiographically map NMDA and mGlu receptor sites by lamina in posterior cingulate cortex in adult male rats. Specific binding at NMDA receptor sites in laminae II/III and VI was significantly reduced in comparison to other laminae. Brains prepared from rats killed during dark phase of a 12h/12h light/dark cycle showed a mean 129% increase in overall (+)(3)H-MK801 binding versus light phase brains but retained reduced binding densities in laminae II/III and VI. In contrast to NMDA findings, specific binding at mGlu sites was consistently elevated during light phase in both laminae II/III and VI. Specific (3)H-glutamate binding in dark-phase brains showed an overall 147% increase versus light phase binding but did not retain significant interlaminar heterogeneity. Interpreted in accordance with our physiologically derived models of hippocampo-cortical microcircuitry, these results suggest that spatial and temporal variations in glutamate receptor distribution may play an important role in intracingulate neural processing of afferent input from hippocampus.

Animals↗

PubMed1999

Region-specific modulation of limbic seizure susceptibility by ovarian steroids.

Gonadal steroid hormones can markedly affect seizure susceptibility. Ovariohysterectomized female rats given ovarian steroid hormone supplements were used to evaluate the effects of ovarian steroids on epileptiform activity in hippocampal slices in vitro and on flurothyl-induced seizures in vivo. Seizure susceptibility was compared in the entorhinal cortex (EC) and CA1 regions of the hippocampus perfused with Mg(2+)-free medium, which leads to epileptiform discharges caused by a relief of voltage-dependent NMDA receptor block. After in vivo treatment with 500 microg of progesterone for 2 h prior to slice preparation, the latency to onset of low Mg(2+)-induced epileptiform activity of slices was significantly prolonged compared to slices from controls. In contrast, progesterone replacement accelerated the development of epileptiform activity in the CA1 region. Neither estrogen alone (2 x 2 microg of estradiol benzoate, 48 and 24 h prior to the experiment), nor a combined treatment with estrogen plus progesterone, significantly affected seizure susceptibility in either CA1 or the EC. There were no consistent effects of estrogen or progesterone, alone or in combination, on flurothyl-induced seizures in vivo. The data suggest that in vitro, progesterone alters seizure susceptibility in a site- and seizure model-specific fashion. The differential effects of progesterone may be due to differential expression of progesterone receptor isoforms or metabolites in specific brain areas suggesting that selective modulation of NMDA receptor-dependent epileptiform activity may play a role in hormonal effects on epileptogenesis.

Animals↗

PubMed1999

Prenatal morphine exposure differentially alters seizure susceptibility in developing female rats.

We examined the effect of prenatal morphine exposure (5-10 mg/kg on days 11-18 of gestation) on seizure susceptibility in female rats during development. The effect of morphine exposure on flurothyl-induced seizures was age-dependent. At postnatal day (PN) 15, morphine exposure decreased both clonic and tonic-clonic seizure thresholds compare to saline controls. At PN 25, morphine exposure did not alter the clonic seizure threshold but increased the threshold to tonic-clonic seizure. At PN 38, morphine exposure did not influence either threshold. The data suggest that the effects of prenatal exposure to opioids on seizures are age-related and transient.

Animals↗

PubMed1999

Age-dependent vulnerability to seizures.

Seizure disorders frequently occur early in life. Seizures are classified as reactive, symptomatic, or idiopathic depending on whether their cause can be identified. Reactive seizures are the result of acute environmental perturbations. Early in life, many stressors can produce seizures and the ultimate outcome may depend on the particular precipitating factor and its intensity. Febrile convulsions are the most common reactive seizures, although they must be differentiated from symptomatic seizures precipitated by fever. Symptomatic seizures are often associated with varying degrees of central nervous system (CNS) insults, including congenital malformations and metabolic storage diseases of the gray matter. These seizures may have age-specific characteristics and may at times be difficult to treat with conventional antiepileptic treatments. To develop a better understanding of the pathophysiology of seizures early in life, we have extensively used animal models of epilepsy. In this chapter, we report our findings with a rat model of developmental cortical dysplasias produced by intrauterine injections of methylazoxymethanol acetate. These rats are more susceptible to kainic acid, flurothyl, and hyperthermic seizures than normal rats. Rats with severe cortical dysplasia are most susceptible to seizures. We have also studied the mechanisms involved in the control of seizures during development because status epilepticus is more prevalent in infants than in adults. Our data suggest that the substantia nigra may play a crucial role in status epilepticus as a function of age. In the adult substantia nigra two regions mediate opposing effects on seizures following infusions of gamma-aminobutyric acid type A (GABAA) agents. One region is located in the anterior substantia nigra, and muscimol infusions in this region mediate anticonvulsant effects. The second region is in the posterior substantia nigra, and here muscimol infusions produce proconvulsant effects. In situ hybridization data demonstrate that, at the cellular level, neurons in the two substantia nigra regions differ in the amount of hybridization grains for GABAA receptor alpha 1 and gamma 2L subunit mRNAs. In developing male rats, only the "proconvulsant" region is present up to the age of 21 days. The transition from the immature to mature substantia nigra mediated seizure control occurs between age 25 and 30 days. The identification of age-dependent functional networks involved in the containment of seizures may lead to possible new pharmacologic strategies to control seizures, thus aiding the development of age-appropriate treatments of seizure disorders.

Aging↗

PubMed1998

GluR2 hippocampal knockdown reveals developmental regulation of epileptogenicity and neurodegeneration.

In adult rats, kainic acid-induced status epilepticus reduces GluR2 subunit expression prior to neurodegeneration of hippocampal CA3 neurons. Increased formation of Ca2+ permeable AMPA receptors may contribute to the delayed neurodegenerative process. In rat pups, highly prone to seizures but resistant to seizure-induced hippocampal damage, GluR2 mRNA and protein expression remain constant in CA3 neurons possibly contributing to their survival. To investigate whether reduced GluR2 expression in hippocampus may lead to enhanced hippocampal vulnerability in an age-dependent manner and whether changes correspond to altered electroencephalography (EEG) patterns, unilateral microinfusion of GluR2 antisense oligodeoxynucleotides (AS-ODNs) into hippocampus was performed at three ages (postnatal (P8), P13, and adult). At P13, GluR2 knockdown resulted in spontaneous seizure-like behavioral manifestations and neurodegeneration of CA3 neurons lateral and distal from the cannula infusion site. EEG recordings revealed high rhythmic activity associated with seizure-like behavior. In P8 pups and adult rats, there were no behavioral manifestations; distant hippocampal damage of the CA3 was not observed. Results indicate that unilateral knockdown of hippocampal GluR2 subunit expression induces age-dependent seizure-like behavioral manifestations, altered EEG recording patterns, and reduces the survival of CA3 neurons in the hippocampus of young rats during a specific postnatal period (3rd week), when GluR2 expression peaks in development and glutamatergic inputs are maturing.

Animals↗