Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Lauterborn, Julie C.; Truong, Giangsinh T.; Baudry, Michel; Bi, Xiaoning; Lynch, Gary; Gall, Christine M.

doi:10.1124/jpet.103.053694

Cited by 124 publications

(100 citation statements)

References 39 publications

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“…Previous studies by our laboratories indicated that treatment of cultures for 48 h with CX614 decreased AMPAr subunit mRNA and protein levels (Lauterborn et al, 2003). To assess the time course of CX614 on AMPAr protein, cultured slices were incubated with 50 M CX614 for 0, 4, 8, 12, 24, and 48 h (Fig.…”

Section: Treatment Of Cultured Hippocampal Slices With Cx614 Induces mentioning

confidence: 98%

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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Section: Treatment Of Cultured Hippocampal Slices With Cx614 Induces mentioning

confidence: 98%

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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“…In addition, antidepressant strategies which do not directly target the monoamine system, such as electroconvulsive shock therapy, transcranial magnetic stimulation, exercise and the novel a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators and N-methyl-D-aspartic acid (NMDA) antagonists, also increase mRNA or protein BDNF levels in the rat brain. 21,[41][42][43][44][45][46][47][48][49] Although the mechanisms involved in BDNF upregulation remain unknown, SSRI and NARI antidepressants have been reported to increase hippocampal levels of cyclic AMP response binding protein (CREB) in the rat, a nuclear transcription factor known to regulate BDNF expression. 32 …”

Section: Preclinical Evidencementioning

confidence: 99%

“…Human BDNF and TrkB expression are decreased in depressed patients Post-mortem hippocampal mRNA and protein 49 Serum protein from living patients [51][52][53]56 BDNF levels are increased in patients receiving pharmacological antidepressants Post-mortem hippocampal protein 48 Serum protein from living patients [53][54][55][56] BDNF levels refer to mRNA apart from where specified. Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain-derived neurotrophic factor; ECS, electroconvulsive shock; MAOi, monoamine oxidase inhibitor; NARI, noradrenalin reuptake inhibitor; NMDA, N-methyl-D-aspartic acid; SNRI, serotonin and noradrenalin reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TMS, transcranial magnetic stimulation; TrkB, tyrosine kinase receptor B; VTA, ventral tegmental area.…”

Section: Midbrain 27mentioning

confidence: 99%

Is it time to reassess the BDNF hypothesis of depression?

2007

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The brain-derived neurotrophic factor (BDNF) hypothesis of depression postulates that a loss of BDNF is directly involved in the pathophysiology of depression, and that its restoration may underlie the therapeutic efficacy of antidepressant treatment. While this theory has received considerable experimental support, an increasing number of studies have generated evidence which is not only inconsistent, but also directly contradicts the hypothesis. This article provides a critical review of the clinical and preclinical studies which have been responsible for this controversy, outlining pharmacological, behavioural and genetic evidence which demonstrates the contrasting role of BDNF in regulating mood and antidepressant effects throughout the brain. I will also review key studies, both human and animal, which have investigated the association of a BDNF single-nucleotide polymorphism (Val66Met) with depression pathogenesis, and detail the number of inconsistencies which also afflict this novel area of BDNF research. The article will conclude by discussing why now is a critical time to reassess the original BDNF hypothesis of depression, and look towards the formation of new models that can provide a more valid account of the complex relationships between growth factors, mood disorders and their treatment.

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“…They have been associated with enhanced neurogenesis 228 and increased expression of neurotrophic factors such as BDNF. 229,230 The AMPAkine Ampalex exhibited more rapid effect (during the first week of treatment) than fluoxetine (after 2 weeks). 231 Metabotropic glutamate receptors.…”

Section: Glutamatergic Strategiesmentioning

confidence: 99%

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

Carlson¹,

Singh²,

Zarate³

et al. 2006

NeuroRX

136

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Summary:Major depressive disorder and bipolar disorder are severe mood disorders that affect the lives and functioning of millions each year. The majority of previous neurobiological research and standard pharmacotherapy regimens have approached these illnesses as purely neurochemical disorders, with particular focus on the monoaminergic neurotransmitter systems. Not altogether surprisingly, these treatments are inadequate for many individuals afflicted with these devastating illnesses. Recent advances in functional brain imaging have identified critical neural circuits involving the amygdala and other limbic structures, prefrontal cortical regions, thalamus, and basal ganglia that modulate emotional behavior and are disturbed in primary and secondary mood disorders. Growing evidence suggests that mechanisms of neural plasticity and cellular resilience, including impairments of neurotrophic signaling cascades as well as altered glutamatergic and glucocorticoid signaling, underlie the dysregulation in these circuits. The increasing ability to monitor and modulate activity in these circuits is beginning to yield greater insight into the neurobiological basis of mood disorders. Modulation of dysregulated activity in these affective circuits via pharmacological agents that enhance neuronal resilience and plasticity, and possibly via emerging nonpharmacologic, circuitry-based modalities (for example, deep brain stimulation, magnetic stimulation, or vagus nerve stimulation) offers promising targets for novel experimental therapeutics in the treatment of mood disorders.

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Chronic Elevation of Brain-Derived Neurotrophic Factor by Ampakines

Cited by 124 publications

References 39 publications

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

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

Is it time to reassess the BDNF hypothesis of depression?

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

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