Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Kainic acid (KA) is a known potent neuroexcitotoxin, although the biochemical mechanism producing its underlying neurotoxic effect is not quite clear. Histopathological examination of gerbil brains 24 h after systemic injection of KA revealed severe neuronal lesions in different regions of the brain, especially the cerebellar and hippocampal areas. We have detected free radical formation in the brain 1 h after KA administration by using an in vivo spin trapping technique. We have also observed increased lipid peroxidation in the brain after KA-treatment by analyzing thiobarbituric acid reactive substances and conjugated diene formation. Diminished brain specific (Na+, K+)-ATPase activity was also found 2 h after KA injection and persisted to 24 h. It is possible that the free radical reaction is a primary cause of neuronal degeneration after KA administration.
Mol Chem Neuropathol 1992 Aug
PMID:The biochemical mechanisms of the excitotoxicity of kainic acid. Free radical formation. 132 73

We have investigated by in situ hybridization changes in the content of mRNAs encoding for chromogranin B, secretogranin II, synaptin/synaptophysin and p65 after kainic acid-induced seizures and pentylenetetrazol kindling. Kainic acid seizures resulted in marked but transient increases in secretogranin II mRNA concentrations in the granule cell layer and throughout the pyramidal cell layers of the hippocampus (by 100-500%) as well as in various areas of the cerebral cortex (by up to 900%) and the thalamus (up to 300%) 12 h after injection of the toxin. Chromogranin B mRNA concentrations were persistently increased in granule cells (but not in pyramidal cells) of the hippocampus (suprapyramidal blade, 450%) and in cortical areas (250%) at all time intervals after kainic acid injection (12 h to 60 days). Accordingly chromogranin B immunoreactivity was enhanced in the terminal field of mossy fibers and in the inner part of the molecular layer 30 days after kainic acid. Secretogranin II immunoreactivity was also markedly increased in CA1, the paraventricular thalamic nucleus and in the central amygdala. In rats kindled with pentylenetetrazol only chromogranin B (by 200%) but not secretogranin II mRNA was increased in dentate granule cells. In contrast to the mRNAs of these secretory proteins concentrations of mRNAs encoding synaptin/synaptophysin and p65, two membrane proteins of synaptic vesicles, were not altered in any of these brain structures. These data demonstrate that in brain the biosynthesis of chromogranin B and secretogranin II is regulated like that of neuropeptides which is consistent with a role of these secretory polypeptides as precursors of functional peptides. Activation of neurons induces an increased synthesis of neuropeptides but not a concomitant synthesis of membrane proteins of synaptic vesicle. This might lead to an increased quantal content available for transmission.
Brain Res Mol Brain Res 1992 Nov
PMID:Temporal lobe epilepsy of the rat: differential expression of mRNAs of chromogranin B, secretogranin II, synaptin/synaptophysin and p65 in subfield of the hippocampus. 133 87

Expression of inducible heat shock protein-70 mRNA (hsp-70 mRNA) was studied in the rat brain following systemic administration of different convulsant agents: an L-type voltage-dependent calcium channel agonist, (+/-)-BAY K 8644 (BAY-K); the excitotoxic glutamate agonists kainic acid and N-methyl-D-aspartic acid (NMDA); and the GABAA receptor complex antagonists pentylenetetrazole (PTZ) and lindane (gamma-hexaclorocyclohexane). BAY-K induced minimal hsp-70 mRNA expression in the hippocampus of convulsant rats, localized in the dentate gyrus and the pyramidal cell layer of Ammon's horn. Kainic acid treatment in rats, showing severe limbic convulsions, caused intense expression of hsp-70 mRNA and protein (HSP-70). Expression was localized in select cerebral regions, notably the pyramidal cell layer of the hippocampal CA3 field of Ammon's horn and the piriform cortex, and also the subicular complex and the amygdala, and, to a lesser extent, the entorhinal cortex, the pyramidal cell layer of CA1, several thalamic nuclei, and the parietal cortex. In contrast, systemic administration of NMDA, PTZ or lindane led to no detectable induction of hsp-70 mRNA in the rat brain, despite producing convulsions. Histological examination revealed cell injury only following kainic acid treatment. Damage was most apparent in the piriform and entorhinal cortices, pyramidal cell layer of the CA1 field, and cortical amygdaloid nuclei. BAY-K, NMDA, PTZ and lindane did not lead to any observable histopathological changes. These results show that convulsions of different aetiology do not inevitably induce hsp-70 mRNA expression or cell damage. Intense expression of hsp-70 mRNA was generally associated with regions that later showed variable degrees of nerve cell damage, although hsp-70 mRNA expression was not always predictive of subsequent cell death or survival.
Brain Res Mol Brain Res 1994 Nov
PMID:Regional expression of inducible heat shock protein-70 mRNA in the rat brain following administration of convulsant drugs. 753 33

The effects of kainic acid (15 mg/kg i.p.) on alpha subunits of the Gs and Go protein mRNA levels in the rat hippocampal formation were investigated. An in situ hybridization study showed an increase in the Gs alpha mRNA level in the dentate gyrus at 3 h (by ca. 17%), 24 h (by ca. 75%), 72 h (by ca. 89%) and 30 days (by ca. 59%) after kainic acid administration. An emulsion autoradiography revealed enhancement in the Gs alpha mRNA signal intensity over granular cells of the dentate gyrus and over some hilar cells adjacent to the granule cell layer, most likely in GABA interneurons. The Gs alpha mRNA showed a slight tendency to increase in the CA1 and CA3 pyramidal cell layers at 3 h after kainic acid administration, but it decreased after 24 h, 72 h and 30 days. The latter decrease correlated well with the pyramidal cells loss in those areas. Kainic acid differently influenced the Go alpha mRNA level in the dentate gyrus: it had no effect after 3 h, while after 24 h the mRNA level tended to decrease (by ca. 16%); then it increased after 72 h (by ca. 20%) and, to a lesser extent, after 30 days (by ca. 12%). The Go alpha mRNA level in CA1 and CA3 tended to decrease at 3 h after kainic acid administration; the signal completely disappeared after 24, 72 h as well as after 30 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1994 Jul
PMID:Seizure-induced expression of G proteins in the rat hippocampus. 796 78

Steroid sex hormones have an organizational role in gender-specific brain development. Aromatase, converting testosterone (T) to oestradiol-17 beta (E2), is a key enzyme in the brain and the regulation of this enzyme is likely to determine availability of E2 effective for neural differentiation. In rodents, oestrogens are formed very actively during male perinatal brain development. This paper reviews work on the sexual differentiation of the brain aromatase system in vitro. Embryonic day 15 mouse hypothalamic culture aromatase activity (AA: mean Vmax = 0.9 pmol/h/mg protein) is several times greater than in the adult, whereas apparent Km is similar for both (approximately 30-40 nM). Using microdissected brain areas and cultured cells of the mouse, sex differences in hypothalamic AA during both early embryonic and later perinatal development can be demonstrated, with higher E2 formation in the male than in the female. The sex differences are brain region-specific, since no differences between male and female are detectable in cultured cortical cells. AA quantitation and immunoreactive staining with an aromatase polyclonal antibody both identify neuronal rather than astroglial localizations of the enzyme. Kainic acid eliminates the gender difference in hypothalamic oestrogen formation indicating, furthermore, that this sex dimorphism is neuronal. Gender-specific aromatase regulation is regional in the brain. Oestrogen formation is specifically induced in cultured hypothalamic neurones of either sex by T, since androgen has no effect on cortical cells. Androgen is clearly involved in the growth of hypothalamic neurones containing aromatase. It appears that differentiation of the brain involves maturation of a gender-specific network of oestrogen-forming neurones.
J Steroid Biochem Mol Biol 1994 Jun
PMID:Brain formation of oestrogen in the mouse: sex dimorphism in aromatase development. 804 7

The glutamate analogue kainic acid was injected into the hippocampus of intact or 6-hydroxydopamine deafferented rats to investigate the influence of hippocampal neurons on the expression of dopamine D1 and D2 receptor mRNAs in subregions of the striatal complex and possible modulation by dopaminergic neurons. Quantitative in situ hybridization using 35S-labeled oligonucleotide probes specific for dopamine D1 and D2 receptor mRNAs, respectively, were used. It was found that an injection of kainic acid into the hippocampal formation had alone no significant effect on dopamine D1 or D2 receptor mRNA levels in any of the analyzed striatal subregions in animals analyzed 4 h after the injections. Kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion produced an increase in D1 receptor mRNA levels in the ipsilateral medial caudate-putamen, and a bilateral increase in core and shell of nucleus accumbens (ventral striatal limbic regions). A unilateral 6-hydroxydopamine lesion alone caused an increase in D2 receptor mRNA in the lateral caudate-putamen (dorsal striatal motor region) ipsilateral to the lesion and an increase in D1 receptor mRNA in the accumbens core ipsilateral to the lesion. However, in dopamine-lesioned animals, dopamine D1 receptor mRNA levels were increased bilaterally in nucleus accumbens core and shell and in the ipsilateral medial caudate-putamen following kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion. These results indicate a differential regulation of the expression of dopamine D1 and D2 receptor mRNAs by midbrain and hippocampal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1994 Feb
PMID:Expression of mRNAs encoding dopamine receptors in striatal regions is differentially regulated by midbrain and hippocampal neurons. 817 Mar 51

The present study was directed at evaluating the possible involvement of protein synthesis in excitotoxin-induced neuronal damage and prolonged expression of the proto-oncogene, c-fos. Kainic acid-induced seizure activity elicited varying degrees of neuronal damage and cell loss in selectively vulnerable regions of the adult rat limbic system. Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter behavioral seizure characteristics, but markedly attenuated damage to susceptible neuronal populations. A prolonged increase in c-fos mRNA was observed by in situ hybridization up to 16 h after the onset of seizures in regions exhibiting neuronal death. Pretreatment with cycloheximide did not affect the transient induction of c-fos observed in numerous structures, but significantly reduced the prolonged expression of c-fos mRNA in kainate-vulnerable regions. Despite producing massive seizure activity, systemic kainic acid administration during the early postnatal period did not induce any neuronal death, and did not result in prolonged c-fos expression in any brain structures. The developmental onset of selective neuronal vulnerability coincided with that of prolonged c-fos expression in susceptible neuronal populations. In adult rats, seizure activity induced by pentylenetetrazole did not produce neuronal damage nor did it produce prolonged c-fos expression. These results not only demonstrate that kainate-induced neurotoxicity and the prolonged expression of c-fos are both prevented by cycloheximide, but also strengthen idea that prolonged c-fos expression is a marker of neuronal death.
J Mol Neurosci 1993
PMID:Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain. 829 88

Kainic acid is known to stimulate the release of glutamate (GLU) and aspartate (ASP) from presynaptic neurons. It has been suggested that the enhanced release of these endogenous EAA's plays a significant role in the excitotoxic effects of KA. Domoic acid (DOM), a shellfish toxin, is structurally similar to KA, and has been shown to be 3-8 times more toxic than KA. In this study, effects of KA and DOM on the release of GLU and ASP from rat brain synaptosomes were investigated. Amino acid analysis was performed by the reversed phase HPLC, following derivatization with 9-fluorenylmethyl chloroformate (FMOC). Potassium chloride (40 mM) was used as a positive control, and stimulated GLU release from rat brain synaptosomes in presence or absence of Ca2+. DOM enhanced the release of GLU, whereas KA stimulated the release of both GLU and ASP from synaptosomes in the presence of Ca2+. However, their potency to stimulate GLU and ASP release was enhanced in absence of Ca2+. These results indicate that different mechanisms may be involved in the release of GLU and ASP in response to DOM and KA, and that neurotransmitter release appeared to be highly specific for these agonists. It would appear that DOM and KA may interact with different receptors on the presynaptic nerve terminal, and/or activate different subtypes of voltage-dependent Ca2+ channels to promote influx of Ca2+ which is targeted for different pools neurotransmitters.
Mol Cell Biochem 1995 Oct 04
PMID:The release of glutamate and aspartate from rat brain synaptosomes in response to domoic acid (amnesic shellfish toxin) and kainic acid. 858 13

Seizures have been shown to regulate neurotrophin expression in adult mammalian brain. However, there has been some controversy as to whether seizures affect neurotrophin expression in very immature brain. In the present study, we have examined the effects of seizures induced by pilocarpine following lithium pretreatment or by kainic acid on the expression of brain derived neurotrophic factor (BDNF) mRNA in developing rat brain by in situ hybridization. In adult brain, lithium/pilocarpine treatment resulted in dramatic elevations of hybridization to BDNF cRNA in neocortical and limbic brain structures. In developing brain, lithium/pilocarpine induced elevations of BDNF mRNA in the hippocampus, piriform and entorhinal cortex as early as postnatal day 7 (P7). By P12, the pattern of enhanced expression was similar to that of the adult. Maximal elevations of hybridization were present 2 to 4 h following pilocarpine injection. Electrophysiological recording demonstrated that lithium/pilocarpine treatment resulted in electrographic seizures. Pretreatment with diazepam blocked the seizures as well as the elevation of BDNF mRNA. Kainic acid induced elevations of BDNF mRNA in the CA3 subfield of the hippocampal pyramidal cell layer, but not in other brain areas in pups as young as P7. These data indicate that seizures during the neonatal and early juvenile period of brain development induce elevated BDNF mRNA expression, and that different methods of seizure induction yield different patterns of elevations in hybridization. Furthermore, BDNF may be capable of playing a role in the development of seizure susceptibility in the immature brain.
Brain Res Mol Brain Res 1997 Mar
PMID:Induction of brain derived neurotrophic factor mRNA by seizures in neonatal and juvenile rat brain. 907 63

Kainic acid (KA) administered systemically to rats produces seizures and brain damage. We measured an increase in reactive oxidant species (ROS) during KA-induced seizures in the extracellular fluid (ECF) of the piriform cortex, a brain region known to be subsequently damaged. Intracerebral microdialysis samples were collected and assayed for isoluminol-dependent chemiluminescence before and after injection of KA (16 mg/kg, i.p.). Hydrogen peroxide (H2O2) concentrations were calculated from catalase-sensitive chemiluminescence, the difference between total and catalase-resistant chemiluminescence. During generalized tonic-clonic seizures, both total and catalase-resistant chemiluminescence increased significantly in samples from brain ECF. Catalase-resistant chemiluminescence, most likely produced by ascorbic acid, increased for a full hour during sustained seizure activity. H2O2 concentrations showed a trend towards elevation during seizures. Increased ROS suggest that oxidative stress occurs in brain ECF during sustained seizure activity.
J Mol Neurosci
PMID:Reactive oxidant species in piriform cortex extracellular fluid during seizures induced by systemic kainic acid in rats. 1069 Dec 93


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