Disease relevance of Renazide

• Cyclothiazide selectively enhanced the AMPA/KA receptor-mediated component of ganglion cells EPSCs, suggesting that desensitization of AMPA/KA receptors shape transient L-EPSCs [1].
• Cyclothiazide, which inhibits AMPA receptor desensitization, enhanced steady state current responses to AMPA and increased the toxicity of AMPA [2].
• In particular, coadministration of bicuculline (118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered continuous self-sustaining seizures (status epilepticus; SE) [3].

High impact information on Renazide

• At the endbulb of Held, a fast central calyceal synapse in the auditory pathway, cyclothiazide (CTZ) abolished marked paired pulse depression (PPD) by acting presynaptically to enhance transmitter release, rather than by blocking postsynaptic receptor desensitization [4].
• The sensitivity for attenuation of desensitization by cyclothiazide for homomeric GluR-A was solely dependent upon exchange of Ser-750 (flip) and Asn-750 (flop), and was unaffected by mutagenesis of other divergent residues [5].
• Modulation by cyclothiazide was abolished by mutation of Ser-750 to Gin, the residue found at the homologous site in kainate-preferring subunits, whereas introduction of Ser at this site in GluR6 imparted sensitivity to cyclothiazide [5].
• Further experiments demonstrated that cyclothiazide, previously thought to affect only AMPA receptor kinetics, also enhances synaptic release [6].
• AMPA receptors were found to be directly involved in intracellular Ca2+ and NGFI-A mRNA regulation, because the effects of kainate were greatly enhanced by cyclothiazide, an allosteric modulator that selectively suppresses desensitization of AMPA but not kainate receptors [7].

Chemical compound and disease context of Renazide

• In isolated ganglion cells, cyclothiazide (10 microM), which blocks desensitization in non-NMDA receptors, enhanced both the amplitude and the duration of currents evoked by puffs of AMPA or glutamate [1].
• Cyclothiazide-treated cultures were now vulnerable to AMPA as well as KA; moreover, AMPA was unable to block KA toxicity completely, suggesting that cyclothiazide impaired AMPA/KA receptor desensitization [8].
• In the presence of cyclothiazide (CTZ), kainate or AMPA was toxic (30 min exposure), or the toxic effect was significantly enhanced (24 h exposure), but in this case LY 303070 did not completely protect the cells against kainate-induced toxicity [9].
• The N-methyl-D-aspartate (NMDA) antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK801) also blocked cyclothiazide-enhanced kainate toxicity, but only partially [10].
• Current responses elicited by puffing glycine onto ganglion cell dendrites were not affected by cyclothiazide, indicating that the enhancement of glycinergic IPSCs was not due to a direct effect on glycine receptors [11].

Biological context of Renazide

• The structure-activity relationships of these compounds are examined and the actions of cyclothiazide (CYZ), the most potent of these compounds, are described in detail [12].
• Glutamate stimulation of GluR4-containing AMPA receptors decreased cell viability, in a calcium-dependent manner, when the receptor desensitisation was prevented with cyclothiazide [13].
• Our results suggest that the flip/flop module could directly contribute to the binding site for cyclothiazide, raising the possibility that this site is located in an extracellular receptor domain [14].
• At heteromeric AMPA receptors, 50 microM cyclothiazide increased the IC50 value for GYKI-52466 significantly [15].
• In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide [16].

Anatomical context of Renazide

• For instance, the electrical activity of the nerve ending, neurotransmitters, hypertonic solutions, neurotoxins, polycations, neurotrophic factors, immunoglobulins, cyclothiazide and psychotropic drugs can all modify the rate of spontaneous release [17].
• Cyclothiazide-enhanced injury varied with the age of astrocyte cultures; the maximal effect occurred at approximately 2 weeks in vitro, and little death was seen after 4 weeks [18].
• L-glutamate and other glutamate receptor agonists evoked currents in islet cells that were blocked by the selective AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione and potentiated by cyclothiazide in a manner indistinguishable from that of neuronal AMPA receptors [19].
• The different sensitivities of native AMPA- and kainate-preferring glutamate receptors to cyclothiazide and concanavalin A should prove useful for the differentiation of glutamate receptor subtypes in other areas of the central nervous system [20].
• The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date [21].

Associations of Renazide with other chemical compounds

• In DRG neurons cyclothiazide and aniracetam had no effect on desensitization and instead produced weak inhibition of responses to kainate [20].
• We have recently demonstrated that chronic stimulation with cyclothiazide (CTZ) or kainic acid (KA) induces robust epileptiform activity in hippocampal neurons both in vitro and in vivo [22].
• alpha-amino-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor in rat cultured microglia were analyzed precisely using flop- and flip-preferring allosteric modulators of AMPA receptors, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA) and cyclothiazide (CTZ), respectively [23].
• CTZ (1.25-5 microM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors [24].
• 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by cyclothiazide, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons [25].

Gene context of Renazide

• In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice [26].
• We found that in the presence of cyclothiazide, AMPA caused a robust and direct (no involvement of NMDA receptors or L-type voltage-sensitive Ca(2+) channels) Ca(2+)-dependent activation of MAPK through MAPK kinase (MEK) [27].
• When AMPA was applied together with cyclothiazide the maximal enhancement of AP-1 binding was reached much faster, within 120 min [28].
• Cyclothiazide and two analogs in which the norbornenyl part was replaced with a cyclohexyl or a cyclohexenyl moiety were examined with regard to their preference for flop vs. flip splice variants of the (+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits GluR2, 3 and 4 [29].
• 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to cyclothiazide, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit [25].

Analytical, diagnostic and therapeutic context of Renazide

• Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices [21].
• Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings [30].
• The effects of desensitization on anesthetic sensitivity were investigated using cyclothiazide and site-directed mutagenesis [31].
• The pharmacology behind this cyclothiazide-enhanced kainate-induced excitotoxicity was characterized in embryonic rat hippocampal cell cultures [10].
• Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates [32].

References