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C Nyakas

Publications and source records attributed to C Nyakas.

At least 19 recordsLinked to original sources
PubMed1998

Beta-amyloid(Phe(SO3H)24)25-35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation.

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of beta-amyloid(Phe(SO3H)24)25-35 peptide in rat nucleus basalis magnocellularis (nbm). The beta-amyloid peptide used in these experiments contained the original beta-amyloid 25-35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and 'Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of beta-amyloid(Phe(SO3H)24)25-35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. Beta-amyloid(Phe(SO3H)24)25-35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, beta-amyloid(Phe(SO3H)24)25-35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of beta-amyloid(Phe(SO3H)24)25-35 infusion.

Acetylcholinesterase↗
PubMed1998

Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: reversal by NMDA receptor blockade.

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex. In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells. In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid(1-42) or beta-amyloid(25-35) infusion into the rat nucleus basalis. The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity. We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.

Amyloid beta-Peptides↗
PubMed1997

Permanent upregulation of hippocampal mineralocorticoid receptors after neonatal administration of ACTH-(4-9) analog ORG 2766 in rats.

The development of brain corticosteroid receptors may be permanently modified by perinatal hormone treatments, in particular by hormones of the hypothalamic-pituitary-adrenal axis. Changes in binding characteristics of corticosteroid receptors were investigated in rats treated subcutaneously with 1 microg/g body wt of the ACTH-(4-9) analog peptide ORG 2766 once daily at postnatal days 1, 3 and 5. [3H]Corticosterone (CORT) binding capacity (Bmax) and affinity (Kd) were determined at 1-, 2- and 3-weeks old and adult ages in the hippocampal cytosol by using saturation analysis. Mineralocorticoid type receptor (MR) and glucocorticoid receptor (GR) sites were measured separately with single-point analysis applying a selective glucocorticoid ligand RU 28362 saturating GR. An increase in [3H]CORT binding capacity was found during postnatal development which remained permanently high up to adult age. Separate analysis of MR and GR expression indicated that the increment in the number of corticoid receptor sites was due to an increase in number of MRs in both the young and adult rats. It was concluded that neonatal injections of ACTH-(4-9) peptide resulted in a permanent and selective upregulation of hippocampal MRs, which may underlie the previously observed increased vigilance and novelty-induced behavioral reactivity of the peptide-treated adult rats (Felszeghy, K., Sasvari, M. and Nyakas, C., Horm. Behav., 27 (1993) 380-396).

Adrenocorticotropic Hormone↗
PubMed1997

Chronic ethanol ingestion-induced changes in open-field behavior and oxidative stress in the rat.

The effects of chronic ethanol intoxication on the open-field behavior, on antioxidant enzyme activities, and the degree of lipid peroxidation were investigated. Rats consuming a liquid diet containing 7% ethanol for 4, 7, 14, or 21 days exhibited a significantly decreased ambulation activity, accompanied by a reduced frequency and duration of explorative rearing in an open-field task 4, 7, and 14 days after chronic ethanol ingestion, whereas presumed adaptation to the neurologic effects of ethanol was observed on day 21. Changes in the activities of glutathione peroxidase (GSH-Px): glutathione reductase (GSH-R), and catalase, and in the content of reduced glutathione (GSH) in blood samples were determined by means of biochemical methods. The degree of lipid peroxidation was measured via thiobarbituric acid assays. Chronic ethanol ingestion elicited a significant increase in GSH-Px activity (by a maximum of approximately 32% on day 14), whereas opposite alterations in GSH-R and catalase activities were recorded (49% of the control value on day 4 and 17% on day 21, respectively). Highly elevated contents of thiobarbituric acid reactive substances reflected extensive lipid peroxidation processes throughout the experiment. These changes indicate that ethanol toxicity induces profound changes in explorative behavior, mediated, at least partly, by changes in the free radical metabolism.

Animals↗
PubMed1997

Selective decline of 5-HT1A receptor binding sites in rat cortex, hippocampus and cholinergic basal forebrain nuclei during aging.

The effect of aging on 5-HT1A receptor binding in several forebrain areas associated with the basal forebrain cholinergic system was investigated in rats of 3-, 24- and 30-months-old by receptor autoradiography and biochemical binding assay using [3H]8-OH-DPAT as a ligand. Autoradiographic measurements demonstrated a marked region-specific decline of ligand binding in: (i) regions of the basal forebrain cholinergic cell groups, i.e. the medial septum, diagonal band nuclei and magnocellular nucleus basalis, (ii) the frontal and parietal neocortex and (iii) the dentate gyrus of the hippocampus. No change or only a slight decrease of the 5-HT1A receptor density was found in other areas investigated: the CA1 and CA3 sectors of hippocampus, the cingular and perirhinal cerebral cortex and the lateral septum. The autoradiographic findings were substantiated by the biochemical binding assay, which revealed a comparable loss of 5-HT1A receptor in the hippocampus and neocortex at the age of 30 months. The results clearly show that with increasing age the decrement of 5-HT1A receptor binding in the rat forebrain is remarkably region-selective and particularly affects the cholinergic cell groups that innervate cortex and hippocampus. This phenomenon appears to be especially significant in relation to the neuronal substrates underlying the age-related alterations of mood and cognition.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Effect of corticosterone and adrenalectomy on NMDA-induced cholinergic cell death in rat magnocellular nucleus basalis.

The present study demonstrates the effects of adrenalectomy and subcutaneously administered corticosterone on N-methyl-D-aspartate-induced neurodegeneration in the cholinergic magnocellular basal nucleus of the rat. NMDA was unilaterally injected into the nucleus basalis at different plasma corticosterone concentrations in adrenalectomized rats, in adrenalectomized animals with subcutaneously implanted cholesterol-corticosterone pellets containing 25% or 100% corticosterone, and in sham-adrenalectomized controls. The neurotoxic impact of the NMDA injection in the various experimental groups was assessed by the loss of cholinergic fibers stained with acetylcholinesterase histochemistry in the parietal neocortex. Reactive cortical astrocytes as a result of the treatments were detected by glial fibrillary acidic protein immunohistochemistry. Measurements of the densities of astrocytes and cholinergic fibers at the injected side of the brain were carried out by image analysis. Adrenalectomy significantly potentiated the NMDA-induced neurodegeneration by 50%, while chronic administration of corticosterone significantly attenuated the NMDA-neurotoxicity in a dose-dependent manner. Compared to the ADX group, 25% corticosterone application reduced the NMDA damage by 37%, whereas the 100% corticosterone pellet diminished NMDA neurotoxicity by 75%. Both ADX and ADX + corticosterone implantation enhanced the NMDA-induced GFAP immunoreactivity. The increase of GFAP immunoreactivity was most pronounced in the adrenalectomized rats supplied with the 100% corticosterone pellets. The results demonstrate that corticosterone exerts a potent neuroprotective effect on NMDA-induced neurotoxicity in the magnocellular nucleus basalis. The activated astroglia suggest that astrocytes may contribute to the beneficial effect of corticosterone in the neuroprotective mechanisms against excitotoxic neuronal injury.

Acetylcholinesterase↗
PubMed1996

In vivo protection against NMDA-induced neurodegeneration by MK-801 and nimodipine: combined therapy and temporal course of protection.

Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca2+ channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatment before and after NMDA-exposure. NMDA was unilaterally injected in the magnocellular nucleus basalis (MBN). Neuronal damage was assessed 12 days after the NMDA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no drug treatment, NMDA-exposure damaged MBN neurons such that 66% of the cholinergic terminals were lost in the ipsilateral parietal cortex. Pretreatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.) before NMDA-exposure reduced fibre loss by 89% thereby providing a near complete neuroprotection. Combined therapy of MK-801 (5 mg/kg i.p.) and nimodipine (15 mg/kg i.p.) 8 min after NMDA-infusion reduced neuronal injury by 82%, while the same combination given 2 h after the excitotoxic treatment still yielded a 66% protection against neurotoxic damage invoked by NMDA. In conclusion, the present data show that a dual blockade of NMDA-channels and voltage-dependent calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to provide a significant protection against NMDA-neurotoxicity.

Aging↗
PubMed1996

Hypoxia and brain development.

Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous and learning behaviours. Furthermore, it reveals that perinatal hypoxia is an additional threat to neurodegeneration and decline of cognitive and other behaviours during the aging process. Prenatal hypoxia evokes a temporary delay of ingrowth of cholinergic and serotonergic fibres into the hippocampus and neocortex, and causes an enhanced neurodegeneration of 5-HT-ir axons during aging. Neonatal anoxia suppresses hippocampal ChAT activity and up-regulates muscarinic receptor sites for 3H-QNB and 3H-pirenzepine binding in the hippocampus in the early postnatal age. The altered development of axonal arborization and pre- and postsynaptic cholinergic functions may be an important underlying mechanism to explain the behavioural deficits. As far as the cellular mechanisms of perinatal hypoxia is concerned, our primary aim was to study the putative importance of Ca2+ homeostasis of developing neurons by means of pharmacological interventions and by measuring the development of immunoexpression of Ca(2+)-binding proteins. We assessed that nimodipine, an L-type calcium channel blocker, prevented or attenuated the adverse behavioural and neurochemical effects of perinatal hypoxias, while it enhanced the early postnatal development of ir-Ca(2+)-binding proteins. The results are discussed in the context of different related research areas on brain development and hypoxia and ischaemia.

Animals↗
PubMed1996

Long-term selective down-regulation of brain glucocorticoid receptors after neonatal dexamethasone treatment in rats.

The development of corticosteroid receptors may be permanently modified by perinatal hormonal influences. Changes in binding characteristics of corticosteroid receptors were examined in rats treated sc. with 1 microgram/g dexamethasone (DEX) on postnatal day (PND) 1 and subsequently two more times on PND 3 and 5 in several brain areas. [3H]Corticosterone (CORT) binding capacity (Bmax) and affinity (Kd) were determined at 3 weeks old and adult ages by using saturation analysis. The mineralocorticoid type receptor (MR) and the glucocorticoid receptor (GR) sites were measured separately with single point analysis applying a selective glucocorticoid ligand RU 28362 saturating GR. The decrease in CORT binding was due to a selective GR decrement in all structures and the MR concentration was not changed considerably. The basal levels of plasma CORT were not permanently influenced by neonatal DEX. In conclusion, DEX given during the first week of life resulted in long-term and selective down-regulation of GR and this decrement was independent of the actual circulating CORT level.

Animals↗
PubMed1995

Energy homeostasis, autonomic activity and obesity.

Obesity is often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The present paper summarizes the results of a number of studies designed to investigate autonomic functioning in normal, genetically, and experimentally obese rats. Particular emphasis is given to autonomic functioning and dysfunctioning in relation to the processes that are involved in the regulation of peripheral energy substrate homeostasis. It is concluded that alterations in autonomic regulation in obesity are determined by causal factors such as overeating, genetic make-up, age and/or the duration of obesity.

Animals↗
PubMed1995

Cardiac and behavioral responses of long-term obese and lean Zucker rats to emotional stress.

Obesity is known as a risk factor in stress-related cardiovascular pathology in man. The length of obesity can be an important interacting variable. Therefore, cardiac and behavioral responses to emotional stress were studied in 1-year-old, genetically obese (fa/fa) and lean(Fa/-) male Zucker rats, a frequently used animal of genetic obesity. An early bradycardic response to emotional stress evoked by stimuli associated with brief previous inescapable foot shock, as observed in lean rats, was absent in the fatty Zuckers. This difference was not due to a learning deficit: obese and lean Zuckers showed the same degree of conditioned behavioral responses to the emotional stress. Furthermore, the magnitude of the novelty induced behavioral arousal was also comparable. As far as the regulation of body temperature is concerned, the fa/fa rats displayed a diminished increment in rectal temperature in response to the emotional stress. In conclusion, the results showed an impairment of phasic change in the parasympathetic drive of heart to emotional stress in the long-term obese animals. The diminished activation of heat production points to a blunted response of certain branches of the sympathetic nervous system to emotional stress. The findings favor the hypothesis that dysfunction of cardiac vagal drive in relation to stress is of pathologic importance in long-term obesity.

Animals↗
PubMed1995

Effects of early postnatal anoxia on adult learning and emotion in rats.

Cognitive functioning, behavioural attention and anxiety were studied in adult male Wistar rats after early postnatal anoxia. Spatial memory performance in the hole board learning task was impaired in anoxic rats when compared with control animals. Attention assessed by the behavioural immobility response to a sudden reduction in background noise was tested in an open field. In anoxic rats this response was reduced compared to controls, which was further reflected in a higher ambulation score in anoxic animals. The emotional state in adult rats after postnatal anoxia was not affected as was demonstrated in the elevated plus-maze and in the shock probe/defensive burying task. The results indicate that adult cognitive deficits after neonatal anoxia are not related to changes in emotional behaviour. Disruption of behavioural attention or the capacity of concentration to task performance may, however, contribute to the observed cognitive impairment.

Animals↗
PubMed1995

Aldehyde fixation differentially affects distribution of diaphorase activity but not of nitric oxide synthase immunoreactivity in rat brain.

The effect of aldehyde fixation on NADPH- and NADH-dependent diaphorase (d) histochemistry and nitric oxide synthase (NOS) immunocytochemistry in the brain was investigated by comparing the distribution of these enzymes in in situ nitrocellulose blots of unfixed brain sections with that in aldehyde-fixed brain sections. Substitution of NADPH by NADH yielded no gross differences in cellular distribution in the native blot, whereas in fixed sections NADH produced nonspecific staining of the entire section. In the in situ blot NADPHd histochemistry therefore visualized general nitroblue tetrazolium reductase (NBTr) activity, which was particularly strong in hippocampal pyramidal neurons and cerebellar Purkinje cells. Aldehyde fixation abolished the anatomical pattern of general NBTr activity and changed the histochemical distribution in that of the NADPHd activity associated with the distribution of NOS-I immunoreactivity (ir). Fixation intensified NADPHd histochem- ical staining in specific neurons, resulting in outstanding, Golgi-like staining of these neurons in several brain regions, whereas the general NBTr activity in pyramidal and Purkinje cells disappeared. In contrast to the histochemical diaphorase distribution, the distribution of NOS-I ir on blots and in aldehyde-fixed brain sections was similar. No NOS was observed in hippocampal pyramidal and cerebellar Purkinje neurons. In regions like cerebral and cerebellar cortex and striatum the applied anti NOS-I serum had a higher affinity for the native protein. It is concluded that aldehydes, rather than to progressively suppress NOS-unrelated enzymes, differentially elicit NADPHd activity in some groups of neurons while leaving NOS-ir unaffected.

Animals↗
PubMed1995

Neuroprotection against NMDA induced cell death in rat nucleus basalis by Ca2+ antagonist nimodipine, influence of aging and developmental drug treatment.

In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic impact assessed by measuring cortical cholinergic fibre loss as a percentage of fibre density of the intact control hemisphere. This procedure proved to be a reproducible model in which the degree of damage was almost linearly proportional to the NMDA dose. Neuroprotection by nimodipine was determined in a number of conditions. First, the effect of nimodipine treatment in adult animals starting two weeks prior to neurotoxic injury was compared with neuroprotection provided by perinatal treatment of the mother animals with the calcium antagonist. Surprisingly, the degree of protection was in both cases similar, yielding almost 30% reduction of fibre loss. The neuroprotective effect in adulthood of perinatal nimodipine treatment may be explained by developmentally enhanced calcium binding proteins or persistent developmental changes in calcium channel characteristics. Protection by nimodipine was also investigated in aged, 26 month old rats. Compared to young adult cases, aged animals proved to be less vulnerable to NMDA exposure, while nimodipine application was more potent, thus yielding a reduction of nearly 50% in nerve fibre damage induced by NMDA infusions. Possible mechanisms of differential calcium influx in the various experimental conditions will be discussed.

Aging↗
PubMed1994

Induction of enhanced postnatal expression of immunoreactive calbindin-D28k in rat forebrain by the calcium antagonist nimodipine.

The early postnatal development of immunoreactive calbindin-D28k (CaB-ir) containing neuronal systems in hippocampus and parietal cortex was studied in offspring of Wistar rats chronically treated with either the Ca(2+)-channel antagonist nimodipine or placebo food. The drug was applied to the mother animals during the last week of gestation and continued until the end of the experiment. The CaB-ir was investigated in the period of the highest rate of hippocampal and cortical fiber growth at postnatal days (PD), 5, 7, 10 and 20. In the dorsal hippocampus from PD5 to 20, the dentate granule cells and their mossy fiber connection expressed increasing CaB-ir in a topographically organized manner. In the parietal cortex at PD5, 7 and 10 interneurons and a few pyramidal cells gradually appeared immunoreactive for CaB with progressively increasing intensity and approached their adult-like pattern at PD20. Chronic nimodipine treatment resulted in a transient and markedly enhanced ir-CaB expression up to the age of PD10, which was quantified by cell counts and image analysis. Nimodipine induced a more than twofold increase in the number of CaB-ir neurons in the cortex at PD5-PD10. The developmental enhancement in the hippocampus appeared slightly earlier mainly at PD5 and 7. The findings indicate that the antihypoxic effect of nimodipine, previously found in the perinatal age, may be associated with an increased Ca2+ buffering capacity of neurons due to an enhanced expression of ir-CaB during the early postnatal period.

Animals↗
PubMed1994

Life-spanning behavioural and adrenal dysfunction induced by prenatal hypoxia in the rat is prevented by the calcium antagonist nimodipine.

The long-term behavioural effects of prenatal chronic anaemic hypoxia were investigated in young (5 months old), late adult (19 months) and aged Wistar rats (23-26 months). Sodium nitrite (2 g/l) offered in the drinking water during the second half of pregnancy served to evoke prenatal hypoxia. In parallel to nitrite treatment the Ca2+ channel blocker nimodipine (10 mg/kg) or vehicle alone was administered intragastrically once daily. Open-field activity, intermale social behaviour, learning ability in a black-white discrimination paradigm and fear-induced emotionality were assessed at different ages. Plasma corticosterone response to novelty stress was measured by blood sampling through chronic venous canulas at the age of 28 months. The nitrite-exposed 5-month-old offspring started exploration in a novel open-field with considerable delay. This delayed start-latency was augmented in 19- and 23-month-old rats, pointing to exaggerated suppression of behavioural arousal. Nitrite-induced hypoxia decreased the duration of social interactions during ageing. Aged rats exposed to nitrite were unable to learn a black-white discrimination but showed a normal generalized conditioned fear response (immobility) to the test situation as a whole. The conditioned fear-induced vocalization was more frequent among hypoxic aged animals. The aged hypoxic rats displayed a prolonged plasma corticosterone stress response and had higher adrenal weight than their controls. The abnormal open-field, social, learning and emotional behaviours, as well as the altered plasma corticosterone response, were prevented by prenatal nimodipine treatment.

Adrenal Insufficiency↗