Disease relevance of Digenic acid

• JunAA mice are viable and fertile, smaller than controls and resistant to epileptic seizures and neuronal apoptosis induced by the excitatory amino acid kainate [1].
• This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX) [2].
• We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis [3].
• Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis [3].
• These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease [2].

Psychiatry related information on Digenic acid

• During the critical period for experience-dependent plasticity, the kainate-receptor contribution to transmission decreases; a similar decrease occurs when long-term potentiation is induced in vitro [4].
• Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder [5].
• Highly specific regulation of kainate receptor action may provide a novel route for treatment of drug addiction and epilepsy [6].
• The enhancement of locomotor activity in the kainate group was significantly correlated with the density of hippocampal CA1 neurons [7].
• The integrity of kainate receptors was studied in several brain regions from six patients who had died of Alzheimer's disease and from six closely matched control subjects [8].

High impact information on Digenic acid

• Our results provide evidence that JNP is dispensable for mouse development, and identify c-Jun as the essential substrate of JNK signalling during kainate-induced neuronal apoptosis [1].
• GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells [9].
• Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons [9].
• There are three classes of ionotropic glutamate receptor, namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic plasticity have been identified for two of these [10].
• Recent work on the physiological function of kainate receptors has focused on the hippocampus, where repetitive activation of the mossy-fibre pathway generates a slow, kainate-receptor-mediated excitatory postsynaptic current (EPSC) [11].

Chemical compound and disease context of Digenic acid

• Further investigation revealed that neurons containing NADPH-d were also resistant to the toxicity of N-methyl-D-aspartate itself but were selectively vulnerable to the toxicity of either kainate or quisqualate [12].
• Three recent reports demonstrate that parkin can protect neurons from diverse cellular insults, including alpha-synuclein toxicity, proteasomal dysfunction, Pael-R accumulation, and kainate-induced excitotoxicity [13].
• Our findings are in accord with the concept that both a depression of GABA inhibition and a dysfunction of the KAI-receptor system maintain a high neuronal excitability that results in epileptic seizures [14].
• This effect was partially prevented by the AMPA receptor antagonist GYKI 52466 and was completely abolished by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that both AMPA and kainate receptors mediate the observed kainate toxicity [15].
• Patch-clamp recordings of CA1 interneurons and pyramidal cells were performed in hippocampal slices from kainate- or pilocarpine-treated rat models of temporal lobe epilepsy [16].

Biological context of Digenic acid

• The selectively high expression of KA-1 messenger RNA in the CA3 region of the hippocampus closely corresponds to autoradiographically located high-affinity kainate binding sites [17].
• The modulation of synaptic transmission by kainate receptors and their synaptic activation in a variety of brain regions have been reported [4].
• Addition of the NMDA-receptor-channel blocker AP-5 prevents upregulation of the NR2C subunit by neuregulin, whereas an AMPA/kainate-receptor antagonist does not [18].
• We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus [19].
• We have isolated a complementary DNA clone by screening a rat brain cDNA library for expression of kainate-gated ion channels in Xenopus oocytes [20].

Anatomical context of Digenic acid

• Regulation of glutamate release by presynaptic kainate receptors in the hippocampus [21].
• We cloned 52 cDNAs of genes induced by the glutamate analogue kainate in the hippocampus dentate gyrus [22].
• Here we show that high-intensity single-shock stimulation (of duration 200 microseconds) of primary afferent sensory fibres produces a fast, kainate-receptor-mediated EPSC in the superficial dorsal horn of the spinal cord [11].
• Kainate receptors are present both on neuronal and glial cell membranes where they regulate the gating of a voltage-independent ion channel [23].
• Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity [2].

Associations of Digenic acid with other chemical compounds

• Our experiments show that glial cells possess quisqualate- and kainate-receptor channels but lack receptors for NMDA [24].
• When expressed in Xenopus oocytes the homomeric GluR6 receptor is activated by kainate, quisqualate and L-glutamate but not by AMPA, and the apparent affinity for kainate is higher than for receptors from the GluR1-GluR4 class [25].
• Glutamate, the major excitatory neurotransmitter in the central nervous system, activates three different receptors that directly gate ion channels, namely receptors for AMPA (alpha-amino-3-hydroxy-5-methyl isoxozole propionic acid), NMDA (N-methyl-D-aspartate), and kainate, a structural analogue of glutamate [11].
• We have examined these possibilities in cerebellar neurons by analysing the single-channel currents activated by L-glutamate, L-aspartate, NMDA, quisqualate and kainate in excised membrane patches [26].
• Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate [19].
• Sustained kainate or transient N-methyl-d-aspartate application resulted in a slow decrease of base-line surface KAR levels [27].

Gene context of Digenic acid

• Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4) [28].
• The coexpression of GluR-K2 with either GluR-K3 or GluR-K1 results in the formation of channels whose current-voltage relationships differ from those of the individual subunits alone and more closely approximate the properties of kainate receptors in neurons [29].
• SAP90 binds and clusters kainate receptors causing incomplete desensitization [30].
• Transcripts of the GluR7 gene are evident in brain areas that bind [3H]kainate and are susceptible to kainate-induced neurotoxicity [31].
• Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP [32].

Analytical, diagnostic and therapeutic context of Digenic acid

• Intracellular perfusion of cultured hippocampal neurons with peptides derived from the conserved kinase binding region of AKAPs prevented the protein kinase A-mediated regulation of AMPA/kainate currents as well as fast excitatory synaptic currents [33].
• We recently purified a kainate-binding protein (KBP) from frog (Rana pipiens berlandieri) brain by domoic acid (a high-affinity kainate analogue) affinity chromatography, and showed that the kainate-binding activity was associated with a protein of relative molecular mass 48,000 (Mr 48 K) [34].
• This single-dose vaccine was associated with strong anti-epileptic and neuroprotective activity in rats for both a kainate-induced seizure model and also a middle cerebral artery occlusion stroke model at 1 to 5 months following vaccination [35].
• This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the neurological score of animals with experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis), indicates that oligodendrocyte excitotoxicity could be involved in the pathogenesis of demyelinating disorders [36].
• Electrical stimulation of excitatory afferents generates kainate receptor-mediated excitatory postsynaptic currents (EPSCs) and action potentials in identified interneurons that project to the dendrites and somata of pyramidal neurons [37].

References