Some effects of piracetam (UCB 6215 nootropyl) on chronic schizophrenia

Dimond, Stuart J.; Scammell, Robert; Pryce, I. G.; Huws, D; Gray, Colin

doi:10.1007/bf00427522

Cited by 22 publications

(4 citation statements)

References 10 publications

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“…The relationship between thickness and metabolic rate has unfortunately not been studied. Several studies of callosum transfer functioning in schizophrenia have also suggested deficits more clearly consistent with reduced metabolism [34][35][36][37][38][39], Jaynes [40] presented a theory sug gesting that the disconnection of the hemispheres in the bicameral mind of early man later became more inte grated as consciousness developed. He suggested that schizophrenia may represent vestiges of bicamerality.…”

Section: Discussionmentioning

confidence: 99%

Explorations in the Relationship of Dream Sleep to Schizophrenia Using Positron Emisson Tomography

Ma¹,

et al. 1990

Neuropsychobiology

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This study explored the relationship between rapid eye movement (REM) sleep and schizophrenia using positron emission tomography. Glucose use was compared between 49 schizophrenics, 30 awake controls and 12 controls in REM sleep. Assessment of the frequency and locations of brain areas showing significant differences suggested that REM did not resemble schizophrenia. Schizophrenics were between the higher awake controls and lower REM controls in corpus callosum glucose use. Hallucinating schizophrenics showed lower left caudate glucose use.

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Section: Discussionmentioning

confidence: 99%

Explorations in the Relationship of Dream Sleep to Schizophrenia Using Positron Emisson Tomography

Ma¹,

et al. 1990

Neuropsychobiology

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“…Support for the therapeutic potential of AMPA receptor modulators has come from preclinical studies demonstrating that modulators, including biarylpropylsulfonamides, improve performance of animals on a variety of cognitive tasks that require multiple types of mnemonic processes (Staubli et al, 1994a;Hampson et al, 1998;. More importantly, several clinical studies have demonstrated that allosteric modulators can enhance cognitive function in both healthy and aged subjects, as well as in patients with Parkinson's disease and schizophrenia (Dimond et al, 1979;Oepen et al, 1985;Ingvar et al, 1997). Collectively, these data support the possibility that positive modulation of AMPA receptors may be a novel therapeutic approach for cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling.…”

Section: Structural Implications For Ly404187 Modulationmentioning

confidence: 99%

Multiple Molecular Determinants for Allosteric Modulation of Alternatively Spliced AMPA Receptors

Quirk

Nisenbaum

2003

J. Neurosci.

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Positive allosteric regulation of glutamate AMPA receptors involves conformational changes that can attenuate receptor desensitization and enhance ion flux through the channel pore. Many allosteric modulators (e.g., cyclothiazide and aniracetam) preferentially affect the flip (i) or flop (o) alternatively spliced isoform of AMPA receptors, implicating residues in the flip-flop domain as critical determinants of splice variant sensitivity. Indeed, previous mutational analyses have demonstrated that the differential sensitivity to cyclothiazide and aniracetam depends on a single amino acid, Ser (flip) and Asn (flop), suggesting that this residue may be solely responsible for differences in modulation of AMPA receptor isoforms. The present studies tested this hypothesis by investigating the molecular determinants of modulation of AMPA receptor splice variants by a structurally distinct compound, LY404187, which displays strikingly different and opposing kinetics of allosteric regulation characterized by a time-dependent enhancement in potentiation of homomeric GluR1-GluR4i and a time-dependent reduction in potentiation of GluR1-GluR4o. Site-directed mutagenesis of residues in the flip-flop domain of GluR2 revealed that, although exchange of Asn775 for Ser in GluR2o was sufficient to confer the GluR2i phenotype of potentiation, the corresponding mutation, Ser775Asn, in GluR2i did not impart the GluR2o response. In fact, the GluR2o kinetics of modulation depended on a novel set of substitutions in GluR2i, including Thr765Asn, Pro766Ala, and Val779Leu in combination with Ser775Asn. Collectively, these results show that, unlike cyclothiazide and aniracetam, the residues that confer splice variant differences in modulation by LY404187 are not identical and indicate that allosteric regulation of AMPA receptors can arise from multiple molecular determinants.

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“…Support for the therapeutic potential of AMPA receptor potentiators comes from early clinical studies with the pyrrolidinone compounds, piracetam and aniracetam. These studies showed promising results in treating cognitive deficits associated with several neurological diseases, including Parkinson's disease, Alzheimer's disease, and schizophrenia (20,53,76). The cognitive enhancing effects of these drugs prompted their informal classification as "nootropic agents" (i.e., compounds that facilitate learning and memory).…”

Section: Introductionmentioning

confidence: 99%

LY404187: A Novel Positive Allosteric Modulator of AMPA Receptors

Quirk¹,

Nisenbaum²

2002

CNS Drug Reviews

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LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. In addition, LY404187 potentiates the flip splice variant of these AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native AMPA receptors, potentiation by LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these ion channels. LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of AMPA receptor function, as well as an indirect recruitment of voltage-dependent NMDA receptor activity. Enhanced calcium influx through NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of NMDA receptor activity, LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity. Although the therapeutic efficacy of AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression. 255

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Some effects of piracetam (UCB 6215 nootropyl) on chronic schizophrenia

Cited by 22 publications

References 10 publications

Explorations in the Relationship of Dream Sleep to Schizophrenia Using Positron Emisson Tomography

Explorations in the Relationship of Dream Sleep to Schizophrenia Using Positron Emisson Tomography

Multiple Molecular Determinants for Allosteric Modulation of Alternatively Spliced AMPA Receptors

LY404187: A Novel Positive Allosteric Modulator of AMPA Receptors

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