Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors

Suppiramaniam, Vishnu; Bahr, Ben A.; Sinnarajah, Srikumar; Owens, Kittra; Rogers, Gary A.; Yilma, Solomon; Vodyanoy, Vitaly

doi:10.1002/syn.1037

Cited by 41 publications

(30 citation statements)

References 41 publications

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“…However, compounds have been developed that potentiate AMPA transmission without binding directly to the agonist binding site. 42 Termed AMPAkines, these drugs stimulate memory-dependent processing in animals, 14 and are currently under development for treatment of cognitive dysfunction in various neuropsychiatric disorders.…”

Section: Modulatory Sitesmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Modulatory Sitesmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss.…”

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confidence: 99%

“…[3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss.…”

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confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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“…These drugs up-regulate AMPAr-mediated electrophysiological responses to glutamate, increase miniature excitatory postsynaptic current frequency and amplitude, and facilitate LTP (Arai et al, , 2002aSuppiramaniam et al, 2001). CX614 increases the amplitude of AMPAr-mediated currents, prolongs the "open-channel" state of the receptor, and increases the frequency and amplitude of miniature excitatory postsynaptic potential.…”

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confidence: 99%

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Jourdi

Lü²,

Yanagihara³

et al. 2005

J Pharmacol Exp Ther

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Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2Љ,1Љ-3Ј,2Ј]1,3-oxazino[6Ј,5Ј-5,4]-benzo[e]1,4-dioxan 10-one], a positive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.AMPA-type glutamate receptors (AMPAr) mediate most of the fast excitatory neurotransmission in the mammalian central nervous system. Several recent studies have implicated the cycling of these receptors into and out of the synaptic compartment in important neurophysiological phenomena such as long-term potentiation (LTP) and long-term depression (LTD) in support of our initial hypothesis (Baudry and

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Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors

Cited by 41 publications

References 41 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

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