Seizure activity and lesions after intrahippocampal quinolinic acid injection (original) (raw)
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European Journal of Neuroscience, 1991
In this study we examined whether the potency of quinolinic acid (Quin) in inducing neurodegeneration in vivo was dependent on the exposure time of the tissue to the excitotoxin. The effect of chronic infusion of Quin into rat striatum and hippocampus was examined at the light microscopic level and by cell count on 40 pm Cresyl violet stained brain sections. Continuous infusion was at a constant speed (0.5 pllh) for various times (15 h-2 weeks) by osmotic minipumps (Alzet 2002). No build up of [3HlQuin occurred in the tissue during infusion; this was assessed by measuring the radioactivity 3-14 days after minipump placement. lntrastriatal infusion of 6 and 10 nmollh Quin, but not of nicotinic acid, for 1 week induced a dose-dependent neurodegeneration (70 and 90% loss of neurons, respectively, compared to the contralateral striatum) extending 1.2-2 mm from the centre of the injection. The onset of the neurotoxicity caused by 10 nmollh Quin was >24 h. One week's infusion of 4 nmollh Quin did not induce neurotoxicity, but a 40% drop of neurons, compared to the contralateral side, occurred after 2 weeks. One week's intrahippocampal infusion of 2.4 and 6 nmollh Quin, but not of nicotinic acid, caused a dose-dependent neurodegeneration with a radius of-1-1.5 mm around the injection track. The onset of the neurotoxicity induced by 2.4 nmol/h Quin was <15 h. The pattern of nerve cell loss induced by 1.2 nmol/h Quin after 1 week (CA4 cells lost in 50% of the rats) did not differ from that observed after 2 weeks of infusion. Nerve cell loss caused by Quin in the striatum and in the hippocampus was restricted to the injected area and antagonized by coinfusion with D(-)-2-amino-7-phosphonoheptanoic and kynurenic acids in molar ratios of 1 :0.1 and 1 :3, respectively. These data show that Quin's potency in inducing neurodegeneration in the striatum, but not in the hippocampus, depends on the exposure time of the tissue to the excitotoxin. In addition, neurodegeneration is induced faster by Quin in the hippocampus than in the striatum. The usefulness of this model to study the sequelae of the neurotoxic process in vivo will be discussed.
Bulletin of Experimental Biology and Medicine, 1989
The results of recent experimental investigations show that quinolinic acid (QA), one of the strongest neuroactive products of the kynurenin metabolism of tryptophan, has a marked excitatory, convulsant, and neurodegenerative action [11, 14]. This action of QA is similar in many respects with the effects of excitatory amino acids (glutamate, aspartate) and of their exogenous analogs (N-methyl-D-aspartate, ibothenate, quisqualate, cainate, etc.). As it has been shown [4, 12, 14], the QA concentration in various brain structures rises during aging and also in epilepsy, senile dementias, Alzheimer's disease, Huntington's chorea, and hepatic coma, and this may be one of the causes of destruction of neurons. Identification and study of the mechanisms of action of QA antagonists is thus an urgent problem. Soem of the investigations to be described below were conducted on dissociated cultures of cells from various brain structures, by means of which the destructive action of QA and its analogs on living neurons could be studied at the cellular level and the protective effect of putative antagonists of this action revealed [8, 13]. Experiments to study the anticonvulsant action of these compounds in situ by their systemic administration and injection into the cerebral ventricles, preceding injection of cytotoxins, are another traditional and effective method of identifying antagonists [1, 6]. The aim of the investigation was to compare the effects of various antagonists on the neurodegenerative action of QA in dissociated cultures of hippocampal cells and on its convulsant action in situ.
Neurochemical Research, 2005
Quinolinic acid (QUIN), an endogenous convulsant compound, overstimulates the glutamatergic system stimulating N-methyl-D-aspartate receptors, enhancing glutamate release and inhibiting glutamate uptake. Glutamate releases the neuroprotector adenosine, which in turn reduces glutamate release and depresses the neuronal activity. Additionally, adenine nucleotides are an important source of adenosine, by action of ecto-nucleotidases. Here we evaluated the adenine nucleotide hydrolysis in hippocampal slices of adult rats in different times after seizures induced by QUIN. After 45 min, there was an increase of ATP and ADP hydrolysis. After 5 h, there was an increase of ATP, ADP and AMP hydrolysis. After 12 h, there was an increase only of ATP hydrolysis. After 24 h, all hydrolysis returned to control levels. As slice preparations maintain tissue integrity, this study indicates, more than previously observed with synaptosomal preparations, that the extracellular production of the neuroprotector adenosine may be involved in brain responses to seizures.
Neuroscience, 1991
Changes in endogenous somatostatin after quinolinic and kainic acids were investigated by measuring somatostatin-like peaks by in vivo voltammetry and by assessing the distribution of somatostatin-positive neurons by immunocytochemistry. Kainic acid (0.19 nmol/0.5 microliter) or quinolinic acid (120 nmol/0.5 microliter) in doses inducing comparable electroencephalographic seizure patterns, were injected into the hippocampus of freely moving rats. Somatostatin-like peaks were measured every 6 min for 3 h by a carbon fiber electrode implanted in the proximity of the injection needle. Kainic acid kept somatostatin-like peaks significantly higher than saline from 48 min after the injection till the end of the recording. Somatostatin-like peaks were dramatically elevated by quinolinic acid, reaching a maximum of 482% 60 min after the injection. Three days later, administration of kainic acid resulted in selective degeneration of CA3 pyramidal neurons but did not affect the number of soma...
Brain Research, 2014
Quinolinic acid (QUIN) is a neuroactive metabolite of the kinurenine pathway, considered to be involved in aging and some neurodegenerative disorders, including Huntington's disease. In the present work we have studied the long-lasting effect of acute intrastriatal injection of QUIN (150 nmol/0.5 mL) in 30 day-old rats on the phosphorylating system associated with the astrocytic and neuronal intermediate filament (IF) proteins: glial fibrillary acidic protein (GFAP), and neurofilament (NF) subunits (NFL, NFM and NFH) respectively, until 21 days after injection. The acute administration of QUIN altered the homeostasis of IF phosphorylation in a selective manner, progressing from striatum to cerebral cortex and hippocampus. Twenty four hours after QUIN injection, the IFs were hyperphosphorylated in the striatum. This effect progressed to cerebral cortex causing hypophosphorylation at day 14 and appeared in the hippocampus as hyperphosphorylation at day 21 after QUIN infusion. PKA and PKCaMII have been activated in striatum and hippocampus, since Ser55 and Ser57 in NFL head domain were hyperphosphorylated. However, MAPKs (Erk1/2, JNK and p38MAPK) were hyperphosphorylated/activated only in the hippocampus, suggesting different signaling mechanisms in these two brain structures during the first weeks after QUIN infusion. Also, protein phosphatase 1 (PP1) and 2B (PP2B)-mediated hypophosphorylation of the IF proteins in the cerebral cortex 14 after QUIN injection reinforce the selective signaling mechanisms in different brain structures. Increased GFAP immunocontent in the striatum and cerebral cortex 24 h and 14 days after QUIN injection respectively, suggests reactive astrocytes in these brain regions. We propose that disruption of cytoskeletal homeostasis in neural cells takes part of the long-lasting molecular mechanisms of QUIN toxicity in adolescent rats, showing selective and progressive misregulation of the signaling mechanisms targeting the IF proteins in the striatum, cerebral cortex and hippocampus with important implications for brain function.
Neurochemical Research, 2008
Glutamate uptake into synaptic vesicles is a vital step for glutamatergic neurotransmission. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. Guanine-based purines (GBPs) guanosine 5ยข-monophosphate (GMP and guanosine) have been shown to exert anticonvulsant effects against QA-induced seizures. The aims of this study were to investigate the effects of in vivo administration of several convulsant agents on glutamate uptake into synaptic vesicles and investigate the role of MK-801, guanosine or GMP (anticonvulsants) on glutamate uptake into synaptic vesicles from rats presenting QA-induced seizures. Animals were treated with vehicle (saline 0.9%), QA 239.2 nmoles, kainate 30 mg/kg, picrotoxin 6 mg/kg, PTZ (pentylenetetrazole) 60 mg/kg, caffeine 150 mg/kg or MES (maximal transcorneal electroshock) 80 mA. All convulsant agents induced seizures in 80-100% of animals, but only QA stimulated glutamate uptake into synaptic vesicle. Guanosine or GMP prevented seizures induced by QA (up to 52% of protection), an effect similar to the NMDA antagonist MK-801 (60% of protection). Both GBPs and MK-801 prevented QA-induced glutamate uptake stimulation. This study provided additional evidence on the role of QA and GBPs on glutamatergic system in rat brain, and point to new perspectives on seizures treatment.
Neurotoxicity of quinolinic acid and its derivatives in hypoxic rat hippocampal slices
Brain Research, 1991
The excitotoxlcity of quinolinic acid (2,3-pyndinedicarboxyhc acid), a potent endogenous N-methyl-D-aspartate (NMDA)-type agonist, was charactenzed m the hypoxlc hippocampal slice preparation. A series of other pyndinedicarboxylic acids was also tested in this preparation m order to obtain information about the structural requirements for the interaction between the NMDA receptor and its agonists. Of the 7 pyndinedlcarboxylic acids tested, only quinolinic acid and its anhydride exerted their excitotoxicity by enhancing hypoxic neuronal damage in rat hlppocampal slices at a relatively low concentration (100/~M). Much higher concentration (1 mM) of 3,4-pyridmedlcarboxylic acid was required to exhibit any enhancement of hypoxlc neuronal damage. The rest of the derivatives were innocuous. The effect of quinolinic acid was blocked by DL-2-amino-5-phosphonovalenc acid, by elevated magnesium levels in the incubation medium or by perfuslon with a medium depleted of calcium. Aglycemic damage was also enhanced by quinolinic acad. It appears from the present study that two adjacent carboxylic groups on the pyndine nng, preferably at positions 2 and 3, are a prerequisite for an interaction between the NMDA receptor and its agonlst. However, other factors may have great influence on that interaction as was evident from the total impotency of 6-methyl-qumolinic acid. The hypoxic hippocampal slice preparation and its neuronal function is an inexpensive model system, sensitized to the neurotoxins, and thus, allows the easy screening and evaluation of potentml ligands of the glutamate receptor and its subtypes.
Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model
Experimental Neurology, 2010
Quinolinic acid (QA) is an N-methyl-D-aspartate receptor agonist that also promotes glutamate release and inhibits glutamate uptake by astrocytes. QA is used in experimental models of seizures studying the effects of overstimulation of the glutamatergic system. The guanine-based purines (GBPs), including the nucleoside guanosine, have been shown to modulate the glutamatergic system when administered extracellularly. GBPs were shown to inhibit the binding of glutamate and analogs, to be neuroprotective under excitotoxic conditions, as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizure. In this work, we studied the electrophysiological effects of guanosine against QA-induced epileptiform activity in rats at the macroscopic cortical level, as inferred by electroencephalogram (EEG) signals recorded at the epidural surface. We found that QA disrupts a prominent basal theta (4-10 Hz) activity during peri-ictal periods and also promotes a relative increase in gamma (20-50 Hz) oscillations. Guanosine, when successfully preventing seizures, counteracted both these spectral changes. MK-801, an NMDA-antagonist used as positive control, was also able counteract the decrease in theta power; however, we observed an increase in the power of gamma oscillations in rats concurrently treated with MK-801 and QA. Given the distinct spectral signatures, these results suggest that guanosine and MK-801 prevent QAinduced seizures by different network mechanisms.