The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury

  title={The diazoxide derivative IDRA 21 enhances ischemic hippocampal neuron injury},
  author={K. A. Yamada and Douglas F. Covey and C. Y. Hsu and Rong Hu and Y Hu and Y. Y. He},
  journal={Annals of Neurology},
The diazoxide derivative IDRA 21 and other positive modulators of (AMPA)‐type glutamate receptors are considered potential memory‐enhancing agents. However, AMPA receptor activation contributes to CA1 hippocampal neuron damage from global ischemia in rodents, raising the possibility that 7‐chloro‐3‐methyl‐3‐4‐dihydro‐2H‐1,2,4 benzothiadiazine S, S‐dioxide (IDRA 21) or drugs with similar actions may worsen ischemic neuronal injury. Here we demonstrate that glutamate plus IDRA 21 kills cultured… 

Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease

The clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity.

Pharmacology of AMPA/Kainate Receptor Ligands and Their Therapeutic Potential in Neurological and Psychiatric Disorders

Evidence for advantages of AMPA receptor antagonists over N-methyl-D-aspartate (NMDA) receptor antagonists for symptomatic treatment of neurological and psychiatric conditions, and for minimising neuronal loss occurring after acute neurological diseases, are shown in animal models.

Modulating Excitatory Synaptic Neurotransmission: Potential Treatment for Neurological Disease?

This review attempts to synthesize a variety of studies that have utilized these AMPA modulators to gain insight into fundamental as well as clinically relevant AMPA receptor-mediated processes.

Drugs that target ionotropic excitatory amino acid receptors

This chapter will focus on the two main subtypes of ionotropic glutamate receptors, namely those activated by the specific agonists AMPA and NMDA, and the pharmacological intervention which should improve cognition in man.

The Diazoxide Derivative 7-Chloro-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-S,S-dioxide Augments AMPA- and GABA-Mediated Synaptic Responses in Cultured Hippocampal Neurons

At sufficient concentrations, IDRA21 reduced AMPA receptor desensitization and slowed the rate of deactivation, most consistent with full agonist activity with lower potency compared to cyclothiazide.

AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3‐kinase‐dependent activation in extracellular signal‐regulated kinase to upregulate BDNF gene expression

AMPA receptors protect neurons through a mechanism involving BDNF release, TrkB receptor activation, and a signaling pathway involving a PI3‐K dependent activation of MAPK that increases BDNF expression.

Modulation of Ã-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors by a novel organic nitrate ester

GT-21-005 can enhance synaptic responses that may be responsible for encoding rnemory and learning in the hippocampus and has inhibitory effects on N-rnethyl-D-aspartate (NMDA) and y-am inobutryic acid (GABA) receptors in the same concentrations that enhance AMPA receptors.



Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices

The hypothesis that drugs which enhance AMPA receptor-mediated currents facilitate LTP is supported, as at concentrations that facilitated synaptic transmission, IDRA 21 promoted the induction of LTP.

Diazoxide blocks glutamate desensitization and prolongs excitatory postsynaptic currents in rat hippocampal neurons.

The experiments indicate that desensitization plays an important role in terminating excitatory transmission between mammalian central neurons and diazoxide and perhaps related compounds will ultimately help to identify the regions of the AMPA/KA receptor responsible for desensItization.

AMPA receptor activation is rapidly toxic to cortical astrocytes when desensitization is blocked

Although cultured astrocytes express functional glutamate receptors, they are generally resistant to excitotoxic cell death, and the extent of AMPA receptor desensitization may be an important determinant of glial vulnerability to excITotoxic insults.

Postischemic Blockade of AMPA but Not NMDA Receptors Mitigates Neuronal Damage in the Rat Brain following Transient Severe Cerebral Ischemia

  • B. NellgårdT. Wieloch
  • Biology
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 1992
It is demonstrated that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult.

Facilitation of glutamate receptors enhances memory.

Results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements.

The Role of Zinc in Selective Neuronal Death After Transient Global Cerebral Ischemia

The toxic influx of zinc may be a key mechanism underlying selective neuronal death after transient global ischemic insults and could be prevented by the intraventricular injection of a zinc chelating agent.

Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents

  • Kahori YamadaC. Tang
  • Biology
    The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1993
A family of compounds, the benzothiadiazides, is described here that potently inhibit rapid glutamate receptor desensitization, and the actions of cyclothiazide (CYZ), the most potent of these compounds, are described in detail.

Modulation of AMPA/kainate receptors by analogues of diazoxide and cyclothiazide in thin slices of rat hippocampus.

While cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor desensitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptors desensitized preferentially.