Search results for "Kainate receptor"
showing 7 items of 27 documents
Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors
2007
Antagonists for kainate receptors (KARs), a family of glutamategated ion channels, are efficacious in a number of animal models of neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities for kainate receptors, we generated three sets of analogs related to the natural marine convulsant neodysiherbaine (neoDH), and we characterized their pharmacological profiles. Radioligand displacement assays with recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KARs demonstrated that functional groups at two positions on the neoDH molecule are critical pharmacological determinants; only binding to the glutamate receptor …
Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion
2000
1. This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cyclic GMP in the acute inhibitory effects of low doses of peripheral endotoxin on pentagastrin-stimulated acid production. 2. Vagotomy or intracisternal (i.c.) microinjections of the NO-inhibitor, N(G)-nitro-L-arginine methyl esther (L-NAME; 200 microg rat(-1)) restored acid secretory responses in endotoxin (10 microg kg(-1), i.v.)-treated rats. 3. The acid-inhibitory effect of i.v. endotoxin (10 microg kg(-1), i.v.) was prevented by prior i.c. administration of the NMDA receptor antagonists, dizocilpine maleate (MK-801; 10 nmol rat(-1)) and D-2-amino-5-phosphono-valeric acid (AP-5; 20…
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine
2010
Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited ∼100-fold selectivi…
Exploring kainate receptor pharmacology using molecular dynamics simulations
2010
Ionotropic glutamate receptors (iGluRs) are enticing targets for pharmaceutical research; however, the search for selective ligands is a laborious experimental process. Here we introduce a purely computational procedure as an approach to evaluate ligand–iGluR pharmacology. The ligands are docked into the closed ligand-binding domain and during the molecular dynamics (MD) simulation the bi-lobed interface either opens (partial agonist/antagonist) or stays closed (agonist) according to the properties of the ligand. The procedure is tested with closely related set of analogs of the marine toxin dysiherbaine bound to GluK1 kainate receptor. The modeling is set against the abundant binding data …
The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis.
2007
Endocannabinoids are lipid signaling mediators that exert an important neuromodulatory role and confer neuroprotection in several types of brain injury. Excitotoxicity and stroke can induce neural progenitor (NP) proliferation and differentiation as an attempt of neuroregeneration after damage. Here we investigated the mechanism of hippocampal progenitor cell engagement upon excitotoxicity induced by kainic acid administration and the putative involvement of the CB1 cannabinoid receptor in this process. Adult NPs express kainate receptors that mediate proliferation and neurosphere generation in vitro via CB1 cannabinoid receptors. Similarly, in vivo studies showed that excitotoxicity-induce…
Model-specific effects of bumetanide on epileptiform activity in the in-vitro intact hippocampus of the newborn mouse.
2007
The immature brain has a higher susceptibility to develop seizures, which often respond poorly to classical pharmacological treatment. It has been recently suggested that bumetanide, which blocks Na(+)-dependent K(+)-Cl(-)-cotransporter isoform 1 (NKCC1) and thus attenuates depolarizing GABAergic responses, could soothe epileptiform activity in immature nervous systems. To evaluate whether bumetanide consistently attenuates epileptiform activity, we investigated the effect of 10 microM bumetanide in five different in-vitro epilepsy models using field potential recordings in the CA3 region of intact mouse hippocampal preparations at postnatal day 4-7. Bumetanide reduced amplitude and frequen…
Early developmental alterations of low-Mg2+ -induced epileptiform activity in the intact corticohippocampal formation of the newborn mouse in vitro.
2005
Abstract The generation, propagation and pharmacological properties of low-Mg 2+ -induced epileptiform activity were examined in the intact corticohippocampal formation (CHF) of the newborn (P0–4) mouse in vitro. Multi-site field potential recordings in dentate gyrus (DG), CA3, CA1, entorhinal cortex (EC) and temporal cortex (TC) revealed in 0.2 mM Mg 2+ -containing ACSF a stable pattern of spontaneous epileptiform activity consisting of recurrent ictal-like events (ILEs) and interictal events (IEs). Although this activity could be consistently observed as early as P0, ILEs were smaller in amplitude, less frequent and showed a slower onset in P0–2 as compared to P3–4 animals. In all age gro…