Disease relevance of Dihydrokainate

• Our study demonstrates that Y-79 human retinoblastoma cells express a single Na+-dependent glutamate uptake system with a Km of 1.7 +/- 0.42 microM that is inhibited by dihydrokainate and DL-threo-beta-hydroxyaspartate (IC50 = 0.29 +/- 0.17 microM and 2.0 +/- 0.43 microM, respectively) [1].
• Dihydrokainate could still inhibit veratridine-induced release during ischemia, showing that conditions during ischemia did not reduce its efficacy [2].
• These results suggest that the toxicity of dihydrokainate in neuronal cultures is due to its ability to block glutamate transport in these cultures, and that dihydrokainate-sensitive neuronal glutamate transport may be important in protecting neurons against the toxicity of synaptically released glutamate [3].
• We tested this by administering dihydrokainic acid (DHK), a non-transported glutamate uptake blocker, into the rat spinal cord by microdialysis in association with contusion spinal cord injury [4].
• Moreover, intraperitoneal injection of dihydrokainate (10 mg/kg), a specific inhibitor of GLT-1, augmented brain swelling [5].

High impact information on Dihydrokainate

• The astroglial transporter GLT-1 is the only subtype that exhibits high sensitivity to the nontransportable glutamate analogue dihydrokainate [6].
• Neuronal electrogenic transport currents in response to D-aspartate applications were occluded by the selective GLT-1 inhibitor dihydrokainate [7].
• Compared with astrocytes expressing only GLAST, the dBcAMP-treated cultures expressing both GLAST and GLT-1 showed an increase in glutamate uptake Vmax, but no change in the glutamate K(m) and no increased sensitivity to inhibition by dihydrokainate [8].
• Inhibition of glutamate transport was observed using inhibitors specific for EAAT2 (kainic acid and dihydrokainic acid) and EAAT3 (cysteine) [9].
• The protective effects could be reversed by inhibiting astrocytic glutamate transport with dihydrokainic acid or pretreating astrocytes with H2O2 [10].

Chemical compound and disease context of Dihydrokainate

• Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or tamoxifen (50 micromol/L), a VRAC inhibitor, were administered continuously via the dialysis probes starting one hour prior to ischemia [11].

Biological context of Dihydrokainate

• In support of this hypothesis, a 20-24 h exposure to 1 mm dihydrokainate reduced cell survival to only 14.8 +/- 9.8% in neuronal cultures (P < 0.001; n = 3), although it had no effect on neuronal survival in astrocyte-rich cultures (P > 0.05; n = 3) [3].
• Esterification of either kainate or dihydrokainate rendered the compounds inactive as did the addition of a benzyloxycarbonyl group on the nitrogen of both compounds [12].
• However, DKA had no significant effect on EEG or evoked potentials [13].
• Quantitative autoradiography of [3H]L-aspartate binding in thaw-mounted sections of rat brain has shown that L-trans-pyrrolidine-2,4-dicarboxylate and D-threo-3-hydroxyaspartate but not DL-2 aminoadipate strongly interacted with the binding sites while dihydrokainate, kainate and beta-aminoadipate produced only weak effects [14].

Anatomical context of Dihydrokainate

• For example, L-trans-pyrrolidine-2,4-dicarboxylate was approximately 5-fold more potent in cortical synaptosomes, and dihydrokainate was approximately 10-fold more potent in cortical synaptosomes than in EAAC1-injected oocytes [15].
• In contrast, dihydrokainate had a poor effect on glutamate levels, but induced clear neuronal damage in the striatum and the hippocampus in both groups of rats [16].
• In contrast, dihydrokainic acid inhibited transport processes in the corpus striatum but was without activity in cerebellar preparations [17].
• The dentate gyrus or CA1 field were perfused through a dialytrode with Krebs-Ringer-bicarbonate or dihydrokainic acid solutions [18].
• In contrast, dihydrokainate exhibited significantly more uptake inhibition in oligodendrocytes than in type-1 astrocytes [19].

Associations of Dihydrokainate with other chemical compounds

• Clear neuronal damage was observed only after dihydrokainate administration, which was partially prevented by intraperitoneal injection of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate or by intrastriatal coinjection of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline [20].
• N-Methyl-D-aspartic acid and dihydrokainate (100 microM) did not stimulate [3H]GABA release from cultured astrocytes [21].
• The inhibition pattern of L-serine-O-sulfate in the presence of a saturating concentration of dihydrokainate was suggestive of [(3)H]4MG also labelling GLAST [22].
• Both dihydrokainic acid and allokainic acid, which have low affinity for the KA receptor, also fail to stimulate Glu and Asp efflux [23].
• Transport in cerebellum was essentially dihydrokainate-insensitive L-alpha-Aminoadipate inhibited transport in forebrain regions with IC50s of approx. 700 microM (range from 590 to 800 microM) and inhibited transport in cerebellum with an IC50 of 40 microM [24].

Gene context of Dihydrokainate

• With regard to the human excitatory amino acid transporter-2 (EAAT2), the inhibitory effect of DL-TBOA (Ki = 5.7 microM) was much more potent than that of dihydrokainate (Ki = 79 microM), which is well known as a selective blocker of this subtype [25].
• These currents were produced by glutamate-aspartate transporters (GLAST) (excitatory amino acid transporter 1) because they were weakly inhibited by dihydrokainate, an antagonist of glutamate transporter-1 (excitatory amino acid transporter 2) and were absent from IPCs in GLAST-/- cochleas [26].
• An intracellular site of action of beta-L-ODAP is proposed because its effect on glutamine synthetase activity could be blocked by the amino acid uptake blocker dihydrokainate [27].
• Compounds inhibiting Glu/Asp reuptake had variable effects: strong depression with dihydrokainic acid (7.5 nmol), or no significant effect (L-threo-3-hydroxyaspartic acid, 2.0 and 10 nmol) [28].
• The effects of dihydrokainate were restricted to the CA1 region and totally prevented by the N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), but not by the non-NMDA receptor antagonist 2,3-dihydro-6-nitro-7-sulphamoyl-benzo(f)-quinoxaline (NBQX) [29].

Analytical, diagnostic and therapeutic context of Dihydrokainate

• It was abolished by the glutamate uptake inhibitor dihydrokainate, but unaffected by perfusion with a low Ca(2+)/high Mg(2+) solution, implicating glutamate transporters [30].
• The effect of an uptake inhibitor (dihydrokainate) on endogenous excitatory amino acids in the lamprey spinal cord as revealed by microdialysis [31].
• Intrathecal injection of dihydrokainate, a selective inhibitor of EAAT type 2, also increased the MAC for isoflurane [32].

References