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C Nyakas

Publications and source records attributed to C Nyakas.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mechanisms of beta-amyloid neurotoxicity: perspectives of pharmacotherapy.

One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta-amyloid peptides (Abeta) in neuritic plaques. Experimental data indicate that different molecular forms of Abeta affect a wide array of neuronal and glial functions and thereby may lead to neuronal death in the nervous system. Whereas the fatal outcome of Abeta overproduction in transgenic cell lines, and of exogenous Abeta administration in numerous neurotoxicity models, is well established, particular facets of a complex molecular cascade by which Abeta attack neural cells are still elusive. In the present review we summarize recent knowledge on mechanisms of Abeta aggregation, its role in Abeta neurotoxicity, and binding of Abeta peptides to putative neuronal and glial receptors. Additionally, an integrative view on the interactions of Ca2+ -mediated excitotoxicity and free radical-induced oxidative stress in Abeta toxicity is provided. Furthermore, we survey advances of pharmacological investigations attempting to prevent and antagonize Abeta toxicity, or to promote neuronal regeneration following Abeta-induced neurotoxic insults. We distinguish two major classes of therapeutic approaches: conventional pharmacotherapy that employs blockade of known receptors, signal transduction pathways, and re-uptake of neurotransmitters, and direct targeting of neurotoxic Abeta by means of beta-sheet breakers, functional anti-Abeta peptides, and antibodies. Although a clinically relevant neuroprotective strategy is not yet available, sequential combination of drug regimens may provide prospects for effective antagonism of late-life Abeta burden and subsequent development of dementia.

Alzheimer Disease↗
PubMed1999

Propionyl-IIGL tetrapeptide antagonizes beta-amyloid excitotoxicity in rat nucleus basalis.

A putative tetrapeptide beta-amyloid (Abeta) antagonist (propionyl-Ile-Ile-Gly-Leu [Pr-IIGL]) based on the [31-34] sequence of Abeta was previously shown to rescue astrocytes from Abeta-induced membrane depolarization and subsequent long-term elevations of the intracellular Ca2+ concentration in vitro. Here we provide in vivo evidence that the Pr-IIGL tetrapeptide effectively attenuates the excitotoxic action of Abeta(1-42) on cholinergic neurons of the rat magnocellular nucleus basalis (MBN). We also demonstrate by means of microdialysis that administration of Pr-IIGL abolished Abeta(1-42)-induced increases in extracellular aspartate and glutamate concentrations in the MBN, which coincide with a significant preservation of cholinergic MBN neurons and their cortical projections. This neuroprotective effect was associated with preserved exploratory behavior in an open-field paradigm, and improved memory retention in a step-through passive avoidance task. Our data presented here indicate for the first time the efficacy of short, modified functional Abeta antagonists in ameliorating Abeta excitotoxicity in vivo.

Acetylcholinesterase↗
PubMed1999

Delayed neuronal migration of protein kinase Cgamma immunoreactive cells in hippocampal CA1 area after 48 h of moderate hypoxemia in the near term ovine fetus.

The brain is uniquely sensitive to disturbances in energy and oxygen supply, particularly during the early stage of life. Since hypoxemia can indirectly activate the intracellular messenger protein kinase C (PKC), we studied the PKCgamma-immunoreaction in the fetal hippocampal CA1 region of naive (n=4), instrumented control (n=7), and instrumented hypoxemic fetuses (n=14), at a mean gestational age of 127 days. Forty-eight hours of mild to moderate hypoxemia, were followed by a 48-h recovery period. Hypoxemia resulted in an increase in carotid blood flow (137% of control), and a shift towards a higher percentage of high-voltage electrocortical activity. After recovery, the fetal brain was fixated by perfusion of both carotid arteries, sectioned and immunostained for PKCgamma. The distribution of PKCgamma-immunoreactive cells was significantly changed after 48 h of hypoxemia in that the migration of cells (from the ventricular region towards the stratum pyramidale) was delayed (p<0.01) compared to naive and instrumented control animals. In contrast to the distribution, the relative total optical density of PKCgamma-ir cells and fibres in the CA1 hippocampal area was not significant different between the animal groups. We conclude that hypoxemia delayed migration of PKCgamma-ir cells, without neuronal degeneration.

Animals↗
PubMed1999

N-Methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity.

Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A(1-42) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry. beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes. Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ameliorate beta A toxicity.

Acetylcholinesterase↗
PubMed1999

Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity.

Studies on adult animals and humans have shown that the ACTH4-9 analog ORG 2766 influences cognitive performance and possibly has neurotrophic effects. For this reason we studied the effect of ORG 2766 applied in early postnatal life when brain structures and neuronal pathways are still developing. Our aim was to see whether such treatment during development would result in permanent changes in adult behavioural performance. Pups received subcutaneous injections of 1 microg/g bodyweight ACTH4-9 analog ORG 2766 on day 1, 3 and 5 after birth. Control animals in the same nest received saline injections. When the animals had reached an adult age of 3 months they were subjected to a series of tests to measure their behavioural performance. In the first experiment, behavioural stress responses and anxiety were measured by subjecting the rats to the following tests: open field, defensive burying, elevated plus maze, and conditioned fear test. In a second experiment, adult cognitive function was measured in the Morris water-maze, a hippocampus-related spatial learning test, and in the active avoidance test, a more amygdala-related nonspatial test. The results showed that animals treated with ORG 2766 during early postnatal life learned faster in the spatial Morris water-maze. The treatment had a positive effect on performance during the acquisition phase of the learning task, while memory retrieval was not affected. Learning in the nonspatial active avoidance task did not change due to the postnatal ACTH4-9 treatment. In addition, there were no differences in the open field test, the defensive burying test, elevated plus maze and the conditioned fear test. The latter supports the conclusion that the differences in water-maze performance was due to a difference in learning speed, rather than a difference in anxiety or behavioural stress reactivity. Analysis of [3H]CORT binding capacity measured after the learning tests revealed no differences in the hippocampal MR and GR concentration between non-treated and treated animals.

Adrenocorticotropic Hormone↗
PubMed1999

Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity: relevance to Alzheimer's disease.

1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition and processing, and memory formation. A beta fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary conservation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isotope-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions. During the past decade, acute injection, prolonged mini-osmotic brain perfusion approaches or A beta infusions into the blood circulation were developed in order to investigate the effects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed primary targets of acute neurotoxicity screening, but functional consequences of A beta infusions were primarily demonstrated following either intracerebroventricular or basal forebrain (medial septum or magnocellular basal nucleus (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta is located within the beta(25-35) sequence, the flanking peptide regions influence not only the folding properties of the A beta fragments, but also their in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neuron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a critical role for N-methyl-D-aspartate (NMDA) receptors was postulated in the neurotoxic processes. Additionally, A beta s might become internalized, either after their selective binding to cell-surface receptors or after membrane association in consequence of their highly lipophilic nature, and induce free radical generation and subsequent oxidative injury. Ca(2+)-mediated neurotoxic events and generation of oxygen free radicals may indeed potentiate each other, or even converge to the same neurotoxic events, leading to cell death. 6. Neuroprotection against A beta toxicity was achieved by both pre- and post-treatment with NMDA receptor channel antagonists. Moreover, direct radical-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity with high efficacy. Interestingly, combined drug treatments did not necessarily result in additive enhanced neuroprotection. 7. Similarly to the blockade of NMDA receptors, the neurotoxic action of A beta s could be markedly decreased by pharmacological manipulation of voltage-dependent Ca(2+)-channels, serotonergic IA or adenosine A1 receptors, and by drugs eliciting membrane hyperpolarization or indirect blockade of Ca(2+)-mediated intracellular consequences of intracerebral A beta infusions. 8. A beta neurotoxicity might be dose-dependently modulated by trace metals. In spite of the fact that zinc (Zn) may act as a potent inhibitor of the NMDA receptor channel, high Zn doses accelerate A beta fibril formation, stabilize the beta-sheet conformation and thereby potentiate A beta neurotoxicity. Combined trace element supplementation with Se, Mn, or Mg, which prevails over the expression of detoxifying enzymes or counteracts intracellular elevations of Ca2+, may reduce the neurotoxic impact of A beta s. 9. Alterations in the regulatory functions of the hypothalamo-pituitary-adrenal axis may contribute significantly to neurodegenerative changes in the brain. Furthermore, AD patients exhibit substantially increased circadia

Alzheimer Disease↗
PubMed1999

The effect of exercise training on oxidative damage of lipids, proteins, and DNA in rat skeletal muscle: evidence for beneficial outcomes.

Moderate daily exercise is known to be beneficial to health, reducing risks of a number of age-related disorders. Molecular mechanisms that bring about these effects are not clear. In contrast, it has been claimed that some types of prolonged physical exertion are detrimental to health because active oxygen species are generated excessively by enhanced oxygen consumption. Using two age groups of rats, young (4 week) and middle aged (14 months), we investigated the effects of long-term swimming training on the oxidative status of phospholipids, proteins, and DNA. The concentration of thiobarbituric acid reactive substances and 4-hydroxynonenal protein adducts did not differ in the gastrocnemius muscle between exercised and nonexercised animals in the two age groups. The extent of carbonylation in a protein of molecular weight around 29 KDa and the amount of 8-hydroxydeoxyguanosine in nuclear DNA were smaller (p<.05) in the exercised rats than in the sedentary animals. Activities of DT-diaphorase (C1: 29.3+/-1.9; C2: 36.1+/-2.6; E1: 27.2+/-1.3; C2: 33.4+/-2.9 nmol/mg protein) and proteasome, a major proteolytic enzyme for oxidatively modified proteins were significantly higher in the exercised animals of both age groups (p<.05). The adaptive response against oxidative stress induced by moderate endurance exercise constitutes a beneficial effect of exercise.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Long-lasting deficient dexamethasone suppression of hypothalamic-pituitary-adrenocortical activation following peripheral CRF challenge in socially defeated rats.

The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on resting and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0. 5 microg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 microg/kg s.c., 90 min before oCRF injection, 0.5 microg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid-(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR-binding decreased in hippocampus and hypothalamus. No changes were observed in GR-binding in the pituitary nor in MR-binding in any of the regions analysed. Three weeks after defeat GR-binding recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.

Adrenal Cortex↗
PubMed1998

Neuroprotection against N-methyl-D-aspartate-induced excitotoxicity in rat magnocellular nucleus basalis by the 5-HT1A receptor agonist 8-OH-DPAT.

The present study reports the neuroprotective efficacy of the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone against in vivo excitotoxic neuronal injury. Excitotoxic cell death was induced by injections of N-methyl-D-aspartate (NMDA) in the rat magnocellular nucleus basalis. The neurodegenerative effects were quantified by image analysis of the axonal density of the nucleus basalis projection to the somatosensory cortex visualized with acetylcholinesterase histochemistry. Pretreatment with 8-OH-DPAT--but not ipsapirone--1 h prior to NMDA infusion showed significant preservation of cortical cholinergic innervation in all doses tested. Furthermore, 8-OH-DPAT exhibited sustained efficacy under homeothermic conditions in which the body temperature was maintained at 36.8 +/- 0.1 degrees C. These data indicate that selective 5-HT1A receptor activation by 8-OH-DPAT protects against NMDA-induced excitotoxic neuronal damage, probably as a result of 5-HT1A receptor-mediated neuronal hyperpolarization.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Neurotrophin-mediated neuroprotection by solid fetal telencephalic graft in middle cerebral artery occlusion: a preventive approach.

In the present study, embryonic rat neocortex was implanted into the parietal subcortical area of adult naive animals. On the 7th day, the middle cerebral artery was permanently occluded ipsilateral to the graft. Twenty-four hours after middle cerebral artery occlusion, the extent of infarct was visualized by means of 2,3,5-triphenyltetrazolium chloride histochemistry and quantified in four different standardized coronal plains. Subsequently, the effects of fetal tissue grafting and those of transplantation were identified by using glial fibrillary acidic protein and nerve growth factor immunocytochemistry. The grafts integrated well into their new environment and significantly reduced the size of infarct in middle cerebral artery-occluded animals compared with both sham-operated and control rats 24 h postoperation. The underlying mechanism of this phenomenon might be an increased neurotrophic, particularly nerve growth factor, release by the grafted fetal tissue. Moreover, reactive astroglial cells may also trigger the neuroprotection by additional ischemia-induced nerve growth factor release. The present data demonstrate the potential neurotrophin-mediated protective effects of fetal brain tissue implanted into the adult rat brain before unilateral middle cerebral artery occlusion and the beneficial effects of astrocyte activation.

Animals↗
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↗