Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kainic acid (KA) is a potent neuroexcitatory drug widely used in the experimental study of seizure activity. Subcutaneous injection of KA into rats (10 mg/kg in saline 10 mg/ml; pH 7.0) induced longlasting status epilepticus followed by damage of CNS tissue in the entorhinal/pyriform cortex and in the hippocampus. The studies covered by this report demonstrated the formation of cytotoxic brain edema characterized by massive swelling of perineuronal and perivascular astroglia with microcirculation disturbance after KA injection, resulting in parenchymal necrosis of the affected region; furthermore perivenous hemorrhages and necroses corresponding to herniation lesions of the brain appear. Tracer studies with Na-fluorescein, Evans blue, albumin, and horseradish peroxidase revealed only a mild increase in the permeability of cerebral vessels, topographically unrelated to areas of brain edema. Treatment of brain edema with dexamethasone did not influence the incidence and severity of edematous brain damage. Treatment with mannitol, however, completely prevented the lesion in 54% of animals injected with KA. The present results indicate that brain edema plays an important role in the pathogenesis of epileptic brain damage following systemic KA intoxication. It is suggested that in this model brain edema develops due to massive ionic imbalance caused by KA induced persistent neuronal excitation. In addition the model demonstrates the possible pathogenetic role of selective astrocytic swelling in the production of local hippocampal ischemia followed by herniation and its sequels. Such pathology originating from astrocytes probably may occur also in closed brain injury.
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PMID:Some mechanisms of brain edema studied in a kainic acid model. 213 Jun 48

Glutamate, the major excitatory neurotransmitter in the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). We tested the hypothesis that excessive exposure to glutamate, or related agonists, produces neurotoxicity in enteric neurons. Prolonged stimulation of enteric ganglia by glutamate caused necrosis and apoptosis in enteric neurons. Acute and delayed cell deaths were observed. Glutamate neurotoxicity was mimicked by NMDA and blocked by the NMDA antagonist D-2-amino-5-phosphonopentanoate. Excitotoxicity was more pronounced in cultured enteric ganglia than in intact preparations of bowel, presumably because of a reduction in glutamate uptake. Glutamate-immunoreactive neurons were found in cultured myenteric ganglia, and a subset of enteric neurons expressed NMDA (NR1, NR2A/B), AMPA (GluR1, GluR2/3), and kainate (GluR5/6/7) receptor subunits. Glutamate receptors were clustered on enteric neurites. Stimulation of cultured enteric neurons by kainic acid led to the swelling of somas and the growth of varicosities ("blebs") on neurites. Blebs formed close to neurite intersections and were enriched in mitochondria, as revealed by rhodamine 123 staining. Kainic acid also produced a loss of mitochondrial membrane potential in cultured enteric neurons at sites where blebs tended to form. These observations demonstrate, for the first time, excitotoxicity in the ENS and suggest that overactivation of enteric glutamate receptors may contribute to the intestinal damage produced by anoxia, ischemia, and excitotoxins present in food.
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PMID:Excitotoxicity in the enteric nervous system. 934 49

Kainic acid (KA)-induced status epilepticus (SE) in adult rats results in extensive neuronal damage throughout the limbic system and the loss of selectively vulnerable neuronal populations, particularly CA3 neurons. We investigated the effects of a short episode of seizure activity on neuronal death elicited by a subsequent prolonged SE episode. A short episode of seizure activity was produced by sub-cutaneous (s.c.) injection of KA followed after 1 h by pentobarbital administration. Twenty-four hours later, KA was administered again, and animals were sacrificed 3 days later. Neuronal damage was estimated by visual analysis of neuronal density. Our results show that a short episode of seizure activity did not produce neuronal damage but almost completely protected vulnerable neurons from KA-induced neuronal damage. These results extend to epileptic tolerance the notion of tolerance previously described in the case of ischemia.
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PMID:A short episode of seizure activity protects from status epilepticus-induced neuronal damage in rat brain. 981 46

Neuronal apoptosis is induced prominently in the newborn rodent brain by glutamate receptor excitotoxicity and related insults, including trauma and hypoxia-ischemia. However, the molecular mechanisms of this neurodegeneration are unclear. We tested the hypothesis that changes in the subcellular distribution of the proapoptotic protein Bax precede the activation of downstream apoptosis-effector mechanisms such as caspase-3 cleavage and endonuclease activation during the progression of excitotoxic neuronal apoptosis in the striatum of newborn rat. Kainic acid (4 nmol) was injected into striatum of anesthetized 7-day-old rats, and the animals were killed at 2, 6, 12, and 24 h postinsult. Controls were age-matched, vehicle-injected, or naive rats. Counts of ultrastructurally confirmed striatal neuron apoptosis in brain sections were highest at 24 h. Striatal tissue was microdissected and fractionated into cytosolic, mitochondrial-, and nuclear-enriched compartments. Immunoblots showed that Bax translocates from the cytosol fraction to the mitochondrial fraction, with maximal translocation by 2 h in the absence of changes in mitochondrial accumulation. Cleaved caspase-3 levels increase progressively in both cytosolic and mitochondrial fractions between 6 and 24 h. Cleaved caspase-3 accumulates in apoptotic striatal neurons as shown by immunolocalization. Internucleosomal fragmentation of DNA coincides with caspase-3 cleavage. We conclude that rapid translocation of Bax to mitochondria precedes caspase-3 and endonuclease activation during excitotoxic neuronal apoptosis in newborn rat brain and that initiation of this death cascade occurs within 2 h after glutamate receptor activation.
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PMID:Rapid subcellular redistribution of Bax precedes caspase-3 and endonuclease activation during excitotoxic neuronal apoptosis in rat brain. 1218 52

Research into the molecular mechanisms of epileptic brain injury is hampered by the resistance of key mouse strains to seizure-induced neuronal death evoked by systemically administered excitotoxins such as kainic acid. Because C57BL/6 mice are extensively employed as the genetic background for transgenic/knockout modeling in cell death research but are seizure resistant, we sought to develop a seizure model in this strain characterized by injury to the hippocampal CA subfields. Adult male C57BL/6 mice underwent focally evoked seizures induced by intraamygdala microinjection of kainic acid. Kainic acid (KA) effectively elicited ipsilateral CA3 pyramidal neuronal death within a narrow dose range of 0.1-0.3 microg, with mortality < 10%. With employment of the most consistent (0.3 microg) dose, seizures were terminated 15, 30, 60, or 90 min after KA by diazepam. Damage was largely restricted to the ipsilateral CA3 subfield of the hippocampus, but injury was also consistent within CA1, suggesting that this mouse model better reflects the hippocampal neuropathology of human temporal lobe epilepsy than does the rat, in which CA1 is typically spared. Confirming this CA1 injury as seizure specific and not a consequence of ischemia, we used laser-Doppler flowmetry to determine that cerebral perfusion did not significantly change (97% to 118%) over control. Degenerating cells were > 95% neuronal as determined by neuron-specific nuclear protein (NeuN) counterstaining of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeled (TUNEL) brain sections. Furthermore, TUNEL-positive cells often exhibited the morphological features of apoptosis, and small numbers were positive for cleaved caspase-3. These data establish a mouse model of focally evoked seizures in the C57BL/6 strain associated with a restricted pattern of apoptotic neurodegeneration within the hippocampal subfields that may be applied to research into the molecular basis of neuronal death after seizures.
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PMID:Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. 1221 Aug 27

1. Guanosine-5'-monophosphate (GMP) was evaluated as a neuroprotective agent against the damage observed in rat hippocampal slices submitted to an in vitro model of ischemia with or without the presence of the ionotropic glutamate receptor agonist, Kainic acid (KA). 2. Cellular injury was evaluated by MTT reduction, lactate dehydrogenase(LDH) release assay, and measurement of intracellular ATP levels. 3. In slices submitted to ischemic conditions, 1 mM GMP partially prevented the decrease in cell viability induced by glucose and oxygen deprivation and the addition of KA. 4. KA or N-methyl-D-aspartate (NMDA) receptor antagonists, gamma-D-glutamylamino-methylsulfonate (GAMS) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801, 20 microM) also prevented toxicity in hippocampal slices under ischemic conditions, respectively. 5. The association of GMP with GAMS or MK-801 did not induce additional protection than that observed with GMP or that classical glutamate receptor antagonists alone. 6. GMP, probably by interacting with ionotropic glutamate receptors, attenuated the damage caused by glucose and oxygen deprivation in hippocampal slices. This neuroprotective action of GMP in this model of excitotoxicity is of outstanding interest in the search for effective therapies against ischemic injury.
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PMID:Neuroprotective effect of GMP in hippocampal slices submitted to an in vitro model of ischemia. 1246 74

The aim of this study was to validate the ability of postconditioning, used 2 days after kainate intoxication, to protect selectively vulnerable hippocampal CA1 neurons against delayed neuronal death. Kainic acid (8 mg/kg, i.p.) was used to induce neurodegeneration of pyramidal CA1 neurons in rat hippocampus. Fluoro Jade B, the specific marker of neurodegeneration, and NeuN, a specific neuronal marker were used for visualization of changes 7 days after intoxication without and with delayed postconditioning (norepinephrine, 3.1 mumol/kg i.p., 2 days after kainate administration) and anticonditioning (Extract of Ginkgo biloba, 40 mg/kg p.o used simultaneously with kainate). Morris water maze was used on 6th and 7th day after kainate to test learning and memory capabilities of animals. Our results confirm that postconditioning if used at right time and with optimal intensity is able to prevent delayed neuronal death initiated not only by ischemia but kainate intoxication, too. The protective effect of repeated stress-postconditioning was suppressed if extract of Ginkgo biloba (EGb 761, 40 mg/kg p.o.) has been administered together with kainic acid. It seems that combination of lethal stress and antioxidant treatment blocks the activation of endogenous protecting mechanism known as ischemic tolerance, aggravates neurodegeneration and, after repeated stress is able to cause cumulative damage. This observation could be very valuable in situation when the aim of treatment is elimination of unwanted cell population from the organism.
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PMID:Postconditioning and anticonditioning: possibilities to interfere to evoked apoptosis. 1925 8

Insulin-like growth factor I (IGF-I) has been shown to act as a neuroprotectant both in in vitro studies and in in vivo animal models of ischemia, hypoxia, trauma in the brain or the spinal cord, multiple and amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease. In the present study, we investigated the neuroprotective potential of IGF-I in the "kainic acid-induced degeneration of the hippocampus" model of temporal lobe epilepsy. Increased cell death--as detected by FluoroJade B staining--and extensive cell loss--as determined by cresyl violet staining--were observed mainly in the CA3 and CA4 areas of the ipsilateral and contralateral hippocampus, 7 days following intrahippocampal administration of kainic acid. Kainic acid injection also resulted in intense astrogliosis--as assessed by the number of glial fibrillary acidic protein (GFAP) immunopositive cells--in both hemispheres, forming a clear astroglial scar ipsilaterally to the injection site. Heat-shock protein 70 (Hsp70) immunopositive cells were also observed in the ipsilateral dentate gyrus (DG) following kainic acid injection. When IGF-I was administered together with kainic acid, practically no signs of degeneration were detected in the contralateral hemisphere, while in the ipsilateral, there was a smaller degree of cell loss, reduced number of FluoroJade B-stained cells, decreased reactive gliosis and fewer Hsp70-positive cells. Our present results extend further the cases in which IGF-I is shown to exhibit neuroprotective properties in neurodegenerative processes in the CNS.
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PMID:Neuroprotective effects of IGF-I following kainic acid-induced hippocampal degeneration in the rat. 1977 41

Four sphingolipid activator proteins (i.e., saposins A-D) are synthesized from a single precursor protein, prosaposin (PS), which exerts exogenous neurotrophic effects in vivo and in vitro. Kainic acid (KA) injection in rodents is a good model in which to study neurotrophic factor elevation; PS and its mRNA are increased in neurons and the choroid plexus in this animal model. An 18-mer peptide (LSELIINNATEELLIKGL; PS18) derived from the PS neurotrophic region prevents neuronal damage after ischemia, and PS18 is a potent candidate molecule for use in alleviating ischemia-induced learning disabilities and neuronal loss. KA is a glutamate analog that stimulates excitatory neurotransmitter release and induces ischemia-like neuronal degeneration; it has been used to define mechanisms involved in neurodegeneration and neuroprotection. In the present study, we demonstrate that a subcutaneous injection of 0.2 and 2.0 mg/kg PS18 significantly improved behavioral deficits of Wistar rats (n = 6 per group), and enhanced the survival of hippocampal and cortical neurons against neurotoxicity induced by 12 mg/kg KA compared with control animals. PS18 significantly protected hippocampal synapses against KA-induced destruction. To evaluate the extent of PS18- and KA-induced effects in these hippocampal regions, we performed histological evaluations using semithin sections stained with toluidine blue, as well as ordinal sections stained with hematoxylin and eosin. We revealed a distinctive feature of KA-induced brain injury, which reportedly mimics ischemia, but affects a much wider area than ischemia-induced injury: KA induced neuronal degeneration not only in the CA1 region, where neurons degenerate following ischemia, but also in the CA2, CA3, and CA4 hippocampal regions.
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PMID:A prosaposin-derived Peptide alleviates kainic Acid-induced brain injury. 2599 33