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At least 19 recordsLinked to original sources
PubMed1984

Effects of glutamic acid, kainic acid and aspartic acid on GABA release from rat retina degenerated by kainic acid.

The effects of L-glutamic acid (Glu), kainic acid (KA) and L-aspartic acid (Asp) on 14C-GABA release from the rat retina degenerated by KA were investigated. In the normal rat retina, Glu initially enhanced GABA release and subsequently inhibited it. Both KA and Asp did not have dual effects; KA enhanced GABA release, while Asp inhibited it. In the KA-degenerated retina, the stimulatory effect of Glu or KA on GABA release was markedly suppressed, while the inhibitory effects of Glu or Asp were preserved.

Animals↗
PubMed1994

Regulation of gonadotropin-releasing hormone gene expression by the excitatory amino acids kainic acid and N-methyl-D,L-aspartate in the male rat.

The glutamate analogs N-methyl-D,L-aspartate (NMA) and kainic acid are involved in the regulation of GnRH and LH release in mammals. It has recently been reported that the increase in GnRH release induced by NMA is accompanied by an increase in GnRH mRNA levels, as measured by in situ hybridization. In the present study we assessed the effects of NMA and kainic acid on cytoplasmic mRNA levels using the more quantitative solution hybridization/RNase protection assay. To address the mechanism responsible for these mRNA changes, we also examined changes in heteronuclear RNA transcripts as a reflection of gene transcription. Adult male rats were implanted with a jugular catheter, and 1-2 days later, NMA (14 mg/kg BW), kainic acid (2 mg/kg BW), both NMA and kainic acid, or saline vehicle were injected through the cannula. Rats were killed 15 min or 1 h later by decapitation, blood samples were collected for RIA of LH, brains were removed, and the preoptic area was dissected and frozen. Cytoplasmic and nuclear RNA were extracted and assayed separately by RNase protection assay. Treatment with NMA or NMA plus kainic acid resulted in significantly elevated cytoplasmic mRNA levels 15 min and 1 h later compared to saline control values, with no differences between the two drug treatments observed. Kainic acid stimulated mRNA levels 1 h, but not 15 min after injection. Nuclear RNA transcripts were unaffected by all drug or vehicle treatments. As nuclear primary transcript levels presumably reflect GnRH gene transcription, and these levels are unaltered, the present study indicates that the regulation of GnRH gene expression by excitatory amino acids occurs at a posttranscriptional level. The increase in cytoplasmic GnRH mRNA levels also does not result from an increased translocation of the relatively large nuclear GnRH mRNA pool into the cytoplasm, because nuclear GnRH mRNA levels are also unchanged. Therefore, the elevation of cytoplasmic mRNA levels after excitatory amino acid treatment is probably due to an increase in mRNA stability.

Animals↗
PubMed1994

The activity of opioid analgesics in seizure models utilizing N-methyl-DL-aspartic acid, kainic acid, bicuculline and pentylenetetrazole.

Morphine, fentanyl and pethidine exhibited a biphasic dose response relationship with respect to their effects on seizure thresholds to bicuculline, pentylenetetrazole, N-methyl-DL-aspartate (NMDLA) and kainic acid in mice. The usual pattern was for low doses to be anticonvulsant and higher doses to be proconvulsant. However this pattern was reversed for fentanyl and pethidine when NMDLA was used to induce seizures. The low dose effects of all three opioid drugs was sensitive to 1 mg kg-1 naloxone in all seizure models. The responses to high doses of pethidine were unaffected or enhanced by this dose of naloxone. Naloxone reversed the effects of the higher doses of morphine and fentanyl in all models except bicuculline induced seizures.

Analgesics, Opioid↗
PubMed1986

Effect of seizures induced by intra-amygdaloid kainic acid on kainic acid binding sites in rat hippocampus and amygdala.

[3H]Kainic acid binding sites with a slow dissociation rate in the rat limbic system were investigated in detail. Extensively washed membranes prepared from the hippocampal formation and from the region comprising the amygdala and the piriform cortex yielded non-linear Scatchard plots. Microdissection showed that the high-affinity component (affinity constant around 1 nM) was present in the hippocampal CA3 region (4.2 fmol/mg wet tissue) and the amygdaloid complex (4.6 fmol/mg wet tissue), whereas the remaining part of the hippocampal formation and the piriform lobe contained the low-affinity component (affinity constant 5-20 nM; 11.6 and 11.3 fmol/mg wet tissue, respectively). In the lateral + medial septum we detected only the low-affinity component. Severe limbic seizures, induced by unilateral injection of 0.7 or 0.8 microgram kainic acid in 0.3 microliter of phosphate-buffered saline into the amygdala, reduced kainic acid binding sites in the ipsilateral amygdala and CA3 region. The decline of kainic acid binding sites in the injected amygdala was followed by a similar effect in the contralateral amygdala ("mirror focus") and later by a moderate loss also in the contralateral CA3 region. Kainic acid receptor autoradiography demonstrated that binding sites were lost from the stratum lucidum in hippocampus. Septal lesion had no effect on kainic acid binding sites in the hippocampus. Comparison with previous results on the histopathological changes after this lesion shows that high-affinity kainic acid binding sites are preferentially located on neurons that undergo selective degenerations after severe kainic acid-induced seizures.

Amygdala↗
PubMed1979

Effects of L-glutamic acid and kainic acid on central cardiovascular control.

L-Glutamic acid and kainic acid injected into the cisterna magna of dogs, produced a dose-dependent increase in blood pressure and a decrease in heart rate. In contrast, intravenous injection of both compounds was ineffective. The hypertension was probably due to an increase in sympathetic tone as guanethidine prevented the rise in blood pressure induced by central administration of L-glutamic acid and kainic acid. Kainic acid was 1 000 fold more potent than L-glutamic acid.

Animals↗
PubMed1998

Effects of N-methyl-D-aspartic acid and kainic acid on prolactin secretion in hyper- and hypoprolactinaemic conditions.

OBJECTIVE: The stimulatory and inhibitory effects of N-methyl-D-aspartic acid (NMDA) and kainic acid on prolactin (PRL) secretion have been correlated with the serum prolactin concentrations before drug administration. In the present experiments, we analysed the role of NMDA and kainic acid in PRL secretion in females with different serum concentrations of PRL. METHODS: Hypoprolactinaemic females were obtained by ovariectomy or after administration of diethyldithiocarbamate (an inhibitor of dopamine-beta-hydroxylase). Chronic hyperprolactinaemia was induced by neonatal administration of testosterone or oestradiol and acute hyperprolactinaemia was induced either by administration of alpha-methyl-p-tyrosine (an inhibitor of tyrosine hydroxylase) or by ether exposure. To analyse the role of dopamine in the effects of NMDA, we measured pituitary concentrations of dopamine after NMDA treatment and the effects of pretreatment with domperidone. RESULTS: (1) NMDA, but not kainic acid, stimulated PRL release in cyclic females. This effect was independent of serum PRL concentrations and was not accompanied by a decrease in pituitary concentrations of dopamine. (2) NMDA did not change PRL secretion in neonatally androgenized females, whereas NMDA and kainic acid inhibited PRL release in neonatally oestrogenized females. The inhibitory effects of NMDA and kainic acid were blocked by domperidone. (3) Kainic acid inhibited PRL secretion in prepubertal hyper- and hypoprolactinaemic rats. (4) Hyperprolactinaemia induced by ether stress was counteracted by administration of NMDA and kainic acid. CONCLUSIONS: (a) NMDA has a dual effect on prolactin secretion that is independent of prior prolactin concentrations and of dopamine activity, but kainic acid is only inhibitory. (b) The stimulatory or inhibitory effects of NMDA and kainic acid on PRL secretion were not strictly related to basal PRL concentrations and necessarily involved a change in the secretion of prolactin releasing factors, as no correlations were observed between changes in pituitary concentrations of dopamine and serum PRL concentrations. (c) Females rendered hyperprolactinaemic by neonatal administration of testosterone or oestradiol responded differently after NMDA administration. (d) NMDA and kainic acid blocked the mechanisms involved in stress-induced PRL secretion.

Animals↗
PubMed1991

Stimulation of 22Na+ efflux from rat forebrain membrane vesicles by L-glutamic acid, L-aspartic acid and kainic acid.

A glass fiber filter assay method is described for measuring 22Na+ efflux stimulated by L-glutamic acid, L-aspartic acid and kainic acid from osmotically sensitive membrane vesicles prepared from rat brain. L-Glutamic acid and L-aspartic acid showed the greatest efficacy for the stimulation of 22Na+ efflux with EC50 values of 3 microM. Kainic acid produced 28% of the maximal efflux seen with L-glutamic acid or L-aspartic acid with an EC50 value of 1.5 microM. Quisqualic acid never showed statistically significant increases in 22Na+ efflux over control experiments. N-Methyl-D-aspartic acid showed no detectable efflux activity in this preparation. DL-2-Amino-4-phosphonobutyric acid (APB) inhibited up to 40% of the 50 microM L-glutamic acid-stimulated or 50 microM L-aspartic acid-stimulated 22Na+ efflux with an IC50 value of 1.5 nM. Calcium was required for the inhibitory action of APB, but not for the stimulatory actions of L-glutamic, L-aspartic, or kainic acids. L-Glutamic, L-aspartic, and kainic acids at concentrations above 100 microM were found to inhibit rather than to stimulate 22Na+ efflux. Veratridine (1 microM) had no influence on the 22Na+ efflux component which was produced by L-glutamic or kainic acids. We are unable to firmly establish the mechanism for the stimulated 22Na+ efflux.

Animals↗
PubMed1997

Effect of aging on vulnerability of striatal D1 and D2 dopamine receptor-containing neurons to kainic acid.

Kainic acid lesions elicit reductions in ligand binding to both D1 and D2 striata dopamine receptors in young and old rats. Relative reductions are greatest for both receptors in young animals than old. In addition, D1 receptor binding is reduced more than D2 at both ages. These findings support the idea that those dopamine receptor neurons lost during aging may reside in a kainic acid sensitive population.

Aging↗
PubMed1998

Behavioral changes and expression of heat shock protein hsp-70 mRNA, brain-derived neurotrophic factor mRNA, and cyclooxygenase-2 mRNA in rat brain following seizures induced by systemic administration of kainic acid.

Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. However, it is well-known that behavioral responses to the systemic administration of kainic acid are inconsistent between animals. In this study, we examined the relationship between expression of genes, neuropathological damage, and behavioral changes (seizure intensity and body temperature) in rats after systemic administration of kainic acid. The considerable differences in the response to kainic acid-induced seizures were observed in rats after a single administration of kainic acid (12 mg/kg i.p.). There was no detection of the expression of heat shock protein hsp-70 mRNA and HSP-70 protein in brain of vehicle-treated controls and in animals exhibiting weak behavioral changes (stage 1-2). A moderate expression of hsp-70 mRNA was detected throughout all regions (the pyramidal cell layers of CA1-3 and dentate gyrus) of the hippocampus, the basolateral, lateral, central and medial amygdala, the piriform cortex, and the central medial thalamic nucleus of rats that developed moderate seizures (stage 3-4). Marked expression of hsp-70 mRNA was detected in the all regions (cingulate, parietal, somatosensory, insular, entorhinal, piriform cortices) of cerebral cortex and all regions of hippocampus, and the central medial thalamic nucleus of the rats that developed severe seizures (stage 4-5). In addition, marked HSP-70 immunoreactivity was detected in the pyramidal cell layers of CA1 and CA3 regions of hippocampus, all regions (cingulate, parietal, somatosensory, insular, piriform cortices) of cerebral cortex, and the striatum of rats that developed severe seizures (stage 4-5). Furthermore, a marked expression of cyclooxygenase-2 (COX-2) mRNA and brain-derived neurotrophic factor (BDNF) mRNA levels by kainic acid-induced behavioral seizures (stage 3-4 or stage 4-5) was detected in all hippocampal pyramidal cell layers, granule layers of dentate gyrus, piriform cortex, neocortex, and amygdala. The present study suggest that the behavioral changes (seizure intensity and body temperature) and neuropathological damage after systemic administration of kainic acid are inconsistent between animals, and that these behavioral changes (severity of kainic acid-induced limbic seizures) might be correlated with gene expression of hsp-70 mRNA, COX-2 mRNA, and BDNF mRNA in rat brain.

Animals↗
PubMed1980

The role of epileptic activity in hippocampal and "remote" cerebral lesions induced by kainic acid.

Kainic acid (KA) was injected systemically, intracerebroventricularly (i.c.v.) and focally in the amygdala and other deep brain structures in the rat. EEG and behavioral changes were studied in relation to the neuropathology which developed subsequently. Following intra-amygdaloid KA injection, diazepam blocked the epileptic events induced by the toxin, and abolished the neuronal loss usually seen in the lateral septum, claustrum, and contralateral cortex and hippocampus. The lesions in medial thalamic structures and ipsilateral hippocampus were also reduced by diazepam. Prior transection of the perforant path ipsilateral to the KA injection also decreased the severity of the electrographic and motor effects of the toxin and similarly reduced the extent of distant ("remote") pathological brain damage. Neither diazepam nor perforant path transection reduced the damage at the site of KA injection. Kainic acid (0.4-2 microgram) injected into the bed nucleus of the stria terminalis (BST) or the medial septum produced seizures with a longer latency and little brain damage outside the injection site. In contrast, intrastriatal KA injections were followed by ipsilateral hippocampal lesions. i.c.v. Injection of KA (0.4-1.6 microgram) produced a complex syndrome which included bilateral exophthalmos, mydriasis, foaming, tremor of the vibrissae, and paw and body tremor. The pattern of brain damage resembled that seen following intra-amygdaloid administration of the toxin. In addition, however, there was a bilateral necrosis of the pyriform and prepyriform cortices up to the rhinal fissure. Systemic administration of diazepam (i.p.) reduced the extent of the damage and in particular completely prevented the cortical damage. Systemic administration of KA (9-15 mg/kg i.p.) readily produced motor and EEG seizures similar to those seen after intra-amygdaloid injection of the toxin. The pattern of brain damage was however more symmetrical than that which followed focal i.c.v. injection of the toxin and included necrosis of the pyriform cortex. It is concluded that spread of seizure activity from the injection site plays a crucial role in the induction of "remote" brain damage after focal intracerebral injections.

Afferent Pathways↗
PubMed1997

Relationship between GAP-43 expression in the dentate gyrus and synaptic reorganization of hippocampal mossy fibres in rats treated with kainic acid.

Kainic acid-induced seizures, in adult rats produce neurodegeneration in the hippocampus followed by sprouting of the mossy fibres in the inner molecular layer of the dentate gyrus and changes in GAP-43 expression in the granule cells. In the present study we observed that 4 days after kainic acid injection a dense plexus of silver-impregnated degenerating terminals detected by Gallyas's method and a decrease of GAP-43 immunostaining was observed in the inner molecular layer of the dentate gyrus indicating deafferentiation of this region. This was associated with the formation of an intense GAP-43 immunostained band in the supragranular layer. MK-801, a non-competitive inhibitor of the NMDA receptor, which partially inhibited the behavioural seizures induced by KA, also protected from the inner molecular layer deafferentation and markedly reduced the expression of GAP-43 mRNA in the granule cells and the intense GAP-43 immunostained band in the supragranular layer, suggesting a relationship among these events. Two months after kainic acid injection the intense supragranular GAP-43 positive band was no longer evident but the whole inner molecular layer appeared more labelled in association with the formation of the collateral sprouting of the mossy fibres in the inner molecular layer as detected by Timm's staining. These effects were also markedly reduced by the pretreatment with MK-801. Taken together, these experiments indicate for the first time a direct relationship between the increase of GAP-43 immunostaining in the inner molecular layer of the dentate gyrus and the collateral sprouting of mossy fibres in this district in response to kainic acid induced seizures. This further supports the hypothesis that the early induction of GAP-43 in granule cells may be one of the molecular mechanisms required for the synaptic reorganization of the mossy fibres.

Animals↗
PubMed1998

Kainic acid causes redox changes in cerebral cortex extracellular fluid: NMDA receptor activity increases ascorbic acid whereas seizure activity increases uric acid.

Kainic acid (KA) causes seizures and extensive brain damage in rats. To study the effects of KA on the redox state in cerebral cortex extracellular fluid (ECF), ascorbic and uric acid concentrations were measured in intracerebral microdialysis samples before and after systemic KA administration (ip). During seizures, concentrations of ascorbic and uric acid increased 500 and 100%, respectively. When midazolam was given with KA to prevent seizures, ascorbic acid still increased 400%, but uric acid increased only transiently. When the NMDA receptor antagonist aminophosphonovaleric acid (APV) was included in the microdialysis perfusion media, ascorbic acid levels decreased during baseline perfusion in a concentration-dependent manner. APV then suppressed the KA-induced increase in ascorbic acid levels, without blocking seizure activity. In summary, increased uric acid levels in brain ECF activity after KA administration are related to the induced seizure, but ascorbic acid levels are associated with NMDA receptor activity.

Animals↗
PubMed1992

Morphine differentially affects domoic acid and kainic acid toxicity in vivo.

The effect of systemic injections of morphine on behavioural toxicity and hippocampal (CA3 region) damage produced by both domoic and kainic acids was investigated in mice. Low doses of morphine (2.0 and 4.0 mg kg-1), but not higher doses, significantly antagonized the toxic response to a previously determined TD50 of domoic acid. By contrast, low doses of morphine had either minimal or no effect on the response to an equitoxic dose of kainic acid (TD50), but higher doses (6.0 and 8.0 mg kg-1) resulted in significant potentiation of kainate toxicity. These results provide the first evidence of a pharmacological dissociation between the mechanisms of domoic acid and kainic acid toxicity in vivo, suggesting that these two toxins produce behavioural and hippocampal toxicity via overlapping but non-identical mechanisms.

Animals↗
PubMed1983

Kainic acid selectively stimulates the release of endogenous excitatory acidic amino acids.

Kainic acid (KA) exhibits both neuroexcitatory and neurotoxic actions when applied to the brain. Whereas the neuroexcitatory actions are direct, the neurotoxic effects require the integrity of excitatory afferents. In addition, specific receptors for KA have been demonstrated on both pre- and postsynaptic neuronal elements. In the current study, both KA and KCl are shown to stimulate selectively and in a Ca++-dependent manner the efflux of endogenous Glu and Asp from hippocampal, striatal and cerebellar slices incubated in vitro. Unlike the release of other amino acids, the efflux induced by KCl, but not by KA, is attenuated by tetrodotoxin, suggesting that the action of KA is direct. Furthermore, the action of KA is not mimicked by GABAergic, cholinergic, dopaminergic or serotonergic agonists or antagonists, nor by the excitotoxins N-methyl-DL-aspartic acid or ibotenic acid. Both dihydrokainic acid and allokainic acid, which have low affinity for the KA receptor, also fail to stimulate Glu and Asp efflux. In the case of cerebella from 10-day-old rats, which lack a mature parallel fiber system, KA stimulated the efflux of several amino acids including Asp, but not Glu. Similarly, in slices prepared from adult granulo-prival mice, KA caused an efflux of Asp comparable with that observed in intact cerebellum, whereas the release of Glu was reduced by 75%. On the basis of these studies, the primary source of KA-stimulated Glu efflux in the cerebellar slices appears to be the granule cell-parallel fiber system. A hypothesis is proposed that KA stimulates the release of excitatory amino acids, independent of impulse flow, by activating presynaptic receptors located on excitatory nerve terminals. This additional site of action of KA at excitatory afferents may contribute to the potent but uneven neurotoxic effects of this compound.

Amino Acids↗
PubMed1984

Differentiation of two respiratory areas in the cat medulla using kainic acid.

Kainic acid (KA) was used to destroy neuronal perikarya in different areas of the brainstem. Single KA microinjections were performed in 30 anaesthetized, vagotomized, artificially ventilated cats. Consequences were studied on the phrenic nerve activity (PNA) and blood pressure. We observed changes of the PNA unrelated to blood pressure alteration. Destruction of the dorsal respiratory area (DRA) including the nucleus tractus solitarius at the obex level produced a 40% decrease of the PNA frequency. Destruction restricted to the lateral part of the ventral respiratory area (VRA1) including the ambiguus nucleus induced a 60% decrease of the integrated PNA amplitude followed by a 40% increase of PNA frequency. These latter effects were also observed after destruction inside the infra solitary reticular formation (ISRF). No effect was observed after destruction in other brain structures. We concluded that ISRF and VRA1 form a single ventral bulbar respiratory area. This area controls respiration in a way different from that of the dorsal respiratory area (DRA).

Action Potentials↗
PubMed2001

Changes in the brain protein levels following administration of kainic acid.

Kainic acid (KA), a potent neurotoxin and excitatory amino acid, leads to derangements and modulation of brain proteins. No global brain protein expression pattern induced by KA-treatment has been reported yet. We therefore studied the effect of systemic KA administration on the levels of brain proteins. Rats were injected placebo or KA intraperitoneally and brain was taken after one week. The mitochondrial and cytosolic fractions of the brain proteins were analyzed by proteomics technologies and the levels of selected proteins were quantified using specific software. Heat shock protein HSP 27 was exclusively detected in brains of animals treated with KA, whereas the glucose regulated protein GRP 78 was downregulated. The levels of neurofilaments and alpha-internexin were significantly decreased and a fragment of tubulin alpha-1 chain was manifold increased in KA-brains. The mitochondrial enzymes dihydrolipoamide dehydrogenase, ATP synthase beta chain and isocitrate dehydrogenase were reduced and pyruvate kinase M1 was increased following KA treatment. We conclude that the concomitant determination of the brain proteins indicates altered regulation of heat shock proteins, neuronal death, cytoskeletal disruption, and mitochondrial derangement by systemic KA administration. This report confirms and extends previous studies on the effect of KA on the expression of brain proteins and suggests that our analytical system can serve as a model for neurotoxicological, neurobiological, and neuropathological proteome studies.

Animals↗
PubMed1996

Effect of alpha-MSH upon cyclic AMP levels induced by the glutamatergic agonists NMDA, quisqualic acid, and kainic acid.

This study was carried out to investigate possible interactions between some glutamatergic agonists and the peptide alpha-MSH upon the cyclic AMP levels. We used an in vitro tissue slice preparation incubated in the presence of different glutamatergic agonists such as N-methyl-D-aspartic acid (NMDA), quisqualic acid (QUIS), kainic acid (KA), and the peptide alpha-MSH together with each agonist. Slices containing caudate putamen and accumbens were chosen according to neurochemical data indicating that the striatum contains a moderate amount of MSH binding sites and also receives glutamatergic innervation. Exposure of these slices to either MSH or to the agonists NMDA or QUIS resulted in an increase in the cAMP levels in relation to controls. Nevertheless, incubation with KA resulted in no changes in the nucleotide levels. The combination of MSH/NMDA induced a reduction of cAMP levels in relation to those obtained with NMDA alone. The combinations of QUIS/MSH or KA/MSH also induced variations in the values of nucleotide in relation to the those obtained with the peptide alone or with the corresponding agonist; these changes were related to the dose of agonist used in each case. The results obtained in these experiments suggest the existence of some interaction between the peptide and the agonist used.

Animals↗