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Gary Lynch – One of the best experts on this subject based on the ideXlab platform.

  • Brain Vacuolation Resulting From Administration of the Type II Ampakine CX717 Is An Artifact Related to Molecular Structure and Chemical Reaction With Tissue Fixative Agents.
    Toxicological sciences : an official journal of the Society of Toxicology, 2017
    Co-Authors: Richard Purcell, Gary Lynch, Steven A. Johnson, Christine M. Gall, Zhong Sheng, Michael Rajesh Stephen, James M. Cook, Robert H. Garman, Bernard S. Jortner, Brad Bolon

    Abstract:

    Ampakines are small molecule positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). One class II (“low impact”) Ampakine, CX717, has been implicated to have a neurotoxic effect based on findings in nonclinical, long-term toxicity studies. The neurotoxicity concerns, which halted the clinical development of the molecule, arose due to a finding of extensive white matter vacuolation in multiple brain regions of animals that were administered high doses of CX717 in several test species (unpublished data). This work characterized the features and a potential mechanism by which Ampakines induce vacuoles in brain tissue. Brain sections from adult rats given CX717 (750 mg/kg BID by oral gavage) exhibited no vacuoles with acute or short-term dosing. However, after 14 or more days of treatment, vacuoles were prominent in cerebellum, globus pallidus, and hippocampus. Vacuole margins were lined by glial fibrillary acidic protein (GFAP), and by transmission electron microscopy were shown to be astrocyte processes. CX717-associated vacuoles occurred in formaldehyde-fixed specimens but not flash-frozen samples. Time-course experiments showed that brain tissue slices from CX717-treated animals exhibit no vacuoles until immersed in formaldehyde fixative, whereupon vacuoles form and expand in a time-dependent manner. Chemical interactions in test tube experiments have demonstrated that the combination of CX717 and formalin in an aqueous solution produces an exothermic reaction. Taken together, the data indicate that CX717 does not induce vacuoles in vivo, but rather is associated with astrocyte vacuolation post mortem, likely as the Ampakine reacts with formalin to produce gas pockets in brain parenchyma.

  • Ampakines promote spine actin polymerization long term potentiation and learning in a mouse model of angelman syndrome
    Neurobiology of Disease, 2012
    Co-Authors: Michel Baudry, Gary Lynch, Eniko A Kramar, Homera Zadran, Stephanie Moreno, Christine M. Gall

    Abstract:

    Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: ‘AS mice’) of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the Ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from Ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from Ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50% in vehicle-treated AS mice but were comparable to values for littermate controls in the Ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment.

  • brief Ampakine treatments slow the progression of huntington s disease phenotypes in r6 2 mice
    Neurobiology of Disease, 2011
    Co-Authors: Danielle A. Simmons, Julie C. Lauterborn, Christine M. Gall, Rishi A. Mehta, Gary Lynch

    Abstract:

    Abstract Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (Ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington’s disease (HD). Here we report that long-term Ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an Ampakine, CX929, with a short half-life. Injected once daily for 4–7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in the neocortex and striatum of R6/2 but not wild-type mice. Moreover, Ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced by 36% the size of intra-nuclear huntingtin aggregates in R6/2 striatum. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.

Christine M. Gall – One of the best experts on this subject based on the ideXlab platform.

  • Brain Vacuolation Resulting From Administration of the Type II Ampakine CX717 Is An Artifact Related to Molecular Structure and Chemical Reaction With Tissue Fixative Agents.
    Toxicological sciences : an official journal of the Society of Toxicology, 2017
    Co-Authors: Richard Purcell, Gary Lynch, Steven A. Johnson, Christine M. Gall, Zhong Sheng, Michael Rajesh Stephen, James M. Cook, Robert H. Garman, Bernard S. Jortner, Brad Bolon

    Abstract:

    Ampakines are small molecule positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). One class II (“low impact”) Ampakine, CX717, has been implicated to have a neurotoxic effect based on findings in nonclinical, long-term toxicity studies. The neurotoxicity concerns, which halted the clinical development of the molecule, arose due to a finding of extensive white matter vacuolation in multiple brain regions of animals that were administered high doses of CX717 in several test species (unpublished data). This work characterized the features and a potential mechanism by which Ampakines induce vacuoles in brain tissue. Brain sections from adult rats given CX717 (750 mg/kg BID by oral gavage) exhibited no vacuoles with acute or short-term dosing. However, after 14 or more days of treatment, vacuoles were prominent in cerebellum, globus pallidus, and hippocampus. Vacuole margins were lined by glial fibrillary acidic protein (GFAP), and by transmission electron microscopy were shown to be astrocyte processes. CX717-associated vacuoles occurred in formaldehyde-fixed specimens but not flash-frozen samples. Time-course experiments showed that brain tissue slices from CX717-treated animals exhibit no vacuoles until immersed in formaldehyde fixative, whereupon vacuoles form and expand in a time-dependent manner. Chemical interactions in test tube experiments have demonstrated that the combination of CX717 and formalin in an aqueous solution produces an exothermic reaction. Taken together, the data indicate that CX717 does not induce vacuoles in vivo, but rather is associated with astrocyte vacuolation post mortem, likely as the Ampakine reacts with formalin to produce gas pockets in brain parenchyma.

  • Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats
    The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016
    Co-Authors: Julie C. Lauterborn, Linda C. Palmer, Yousheng Jia, Danielle T. Pham, Bowen Hou, Weisheng Wang, Brian H. Trieu, Conor D. Cox, Svetlana Kantorovich, Christine M. Gall

    Abstract:

    Positive allosteric modulators of AMPA-type glutamate receptors (Ampakines) have been shown to rescue synaptic plasticity and reduce neuropathology in rodent models of cognitive disorders. Here we tested whether chronic Ampakine treatment offsets age-related dendritic retraction in middle-aged (MA) rats. Starting at 10 months of age, rats were housed in an enriched environment and given daily treatment with a short half-life Ampakine or vehicle for 3 months. Dendritic branching and spine measures were collected from 3D reconstructions of Lucifer yellow-filled CA1 pyramidal cells. There was a substantial loss of secondary branches, relative to enriched 2.5-month-old rats, in apical and basal dendritic fields of vehicle-treated, but not Ampakine-treated, 13-month-old rats. Baseline synaptic responses in CA1 were only subtly different between the two MA groups, but long-term potentiation was greater in Ampakine-treated rats. Unsupervised learning of a complex environment was used to assess treatment effects on behavior. Vehicle- and drug-treated rats behaved similarly during a first 30 min session in the novel environment but differed markedly on subsequent measures of long-term memory. Markov sequence analysis uncovered a clear increase in the predictability of serial movements between behavioral sessions 2 and 3 in the Ampakine, but not vehicle, group. These results show that a surprising degree of dendritic retraction occurs by middle age and that this can be mostly offset by pharmacological treatments without evidence for unwanted side effects. The functional consequences of rescue were prominent with regard to memory but also extended to self-organization of behavior. SIGNIFICANCE STATEMENT Brain aging is characterized by a progressive loss of dendritic arbors and the emergence of impairments to learning-related synaptic plasticity. The present studies show that dendritic losses are evident by middle age despite housing in an enriched environment and can be mostly reversed by long-term, oral administration of a positive allosteric modulator of AMPA-type glutamate receptors. Dendritic recovery was accompanied by improvements to both synaptic plasticity and the encoding of long-term memory of a novel, complex environment. Because the short half-life compound had no evident negative effects, the results suggest a plausible strategy for treating age-related neuronal deterioration.

  • Ampakines promote spine actin polymerization long term potentiation and learning in a mouse model of angelman syndrome
    Neurobiology of Disease, 2012
    Co-Authors: Michel Baudry, Gary Lynch, Eniko A Kramar, Homera Zadran, Stephanie Moreno, Christine M. Gall

    Abstract:

    Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: ‘AS mice’) of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the Ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from Ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from Ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50% in vehicle-treated AS mice but were comparable to values for littermate controls in the Ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment.

Amy Arai – One of the best experts on this subject based on the ideXlab platform.

  • modulation of agonist binding to ampa receptors by 1 1 4 benzodioxan 6 ylcarbonyl piperidine cx546 differential effects across brain regions and glua1 4 transmembrane ampa receptor regulatory protein combinations
    Journal of Pharmacology and Experimental Therapeutics, 2009
    Co-Authors: Kyle Montgomery, Markus Kessler, Amy Arai

    Abstract:

    Ampakines are cognitive enhancers that potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents and synaptic responses by slowing receptor deactivation. Their efficacy varies greatly between classes of neurons and brain regions, but the factor responsible for this effect remains unclear. Ampakines also increase agonist affinity in binding tests in ways that are related to their physiological action. We therefore examined 1) whether Ampakine effects on agonist binding vary across brain regions and 2) whether they differ across receptor subunits expressed alone and together with transmembrane AMPA receptor regulatory proteins (TARPs), which associate with AMPA receptors in the brain. We found that the maximal increase in agonist binding (Emax) caused by the prototypical Ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) differs significantly between brain regions, with effects in hippocampus and cerebellum being nearly three times larger than that in thalamus, brainstem, and striatum, and cortex being intermediate. These differences can be explained at least in part by regional variations in receptor subunit and TARP expression because combinations prevalent in hippocampus (GluA2 with TARPs γ3 and γ8) exhibited Emax values nearly twice those of combinations abundant in thalamus (GluA4 with γ2 or γ4). TARPs seem to be critical because GluA2 and GluA4 alone had comparable Emax and also because hippocampal and thalamic receptors had similar Emax after solubilization with Triton X-100, which probably removes associated proteins. Taken together, our data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1–4 as well as TARPs.

  • Pharmacology of Ampakine modulators: from AMPA receptors to synapses and behavior.
    Current drug targets, 2007
    Co-Authors: Amy Arai, Markus Kessler

    Abstract:

    Ampakines are drugs structurally derived from aniracetam that potentiate currents mediated by AMPA type glutamate receptors. These drugs slow deactivation and attenuate desensitization of AMPA receptor currents, increase synaptic responses and enhance long-term potentiation. This review focuses mainly on recent physiological studies and on evidence for two distinct subfamilies. Type I compounds like CX546 are very effective in prolonging synaptic responses while type II compounds like CX516 mainly increase response amplitude. Type I and II drugs do not compete in binding assays and thus presumably act through separate sites. Their differences are likely to have consequences also for synaptic plasticity and behavior. Thus, while all Ampakines facilitated long-term potentiation, only CX546 enhanced long-term depression. Further discussed are studies showing that Ampakine effects vary substantially between neurons, with increases in EPSCs being larger in CA1 pyramidal cells than in thalamus and in hippocampal interneurons. In behavioral tests, Ampakines facilitate learning in many paradigms including odor discrimination, spatial mazes, and conditioning, and they improved short-term memory in a non-matching-to-sample task. Positive results were also obtained in various psychological tests with human subjects. The drugs were effective in correcting behaviors in various animal models of schizophrenia and depression. Lastly, evidence is discussed that Ampakines have few adverse effects at therapeutically relevant concentrations and that they protect neurons against neurotoxic insults, in part by mobilizing growth factors like BDNF. Type II drugs like CX516 in particular appear to be inherently safe since their ability to prolong responses is kinetically limited.

  • Positive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Modulators Have Different Impact on Synaptic Transmission in the Thalamus and Hippocampus
    The Journal of pharmacology and experimental therapeutics, 2004
    Co-Authors: Yan-fang Xia, Markus Kessler, Amy Arai

    Abstract:

    Earlier studies showed that positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors enhance synaptic responses and facilitate synaptic plasticity. Those studies focused mainly on hippocampal functions. However, AMPA receptors have regionally distinct subunit compositions and thus potencies and efficacies of modulators may vary across the brain. The present study compared the effects of CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine], a benzamide-type modulator, on synaptic transmission in neurons of the reticular thalamic nucleus (RTN), which regulates the firing mode of relay cells in other thalamic nuclei, and on hippocampal CA1 pyramidal cells. CX546 greatly prolonged synaptic responses in CA1 pyramidal cells, but at the same concentration it had only weak modulatory effects in RTN neurons. Effects on miniature excitatory postsynaptic currents (EPSCs) were similar to those on EPSCs in both regions, suggesting that variations in neuronal morphology and transmitter release kinetics do not account for the differences. Relay cells in the ventrobasal thalamus also exhibited weak modulatory effects that were comparable with those in RTN neurons. Regionally different effects on response duration were also observed with CX516 [BDP-12, 1-(quinoxalin-6-ylcarbonyl)piperidine], a second benzamide drug. In contrast, 100 μM cyclothiazide produced comparable synaptic enhancements in hippocampus and RTN. The regional selectivity of benzamide drugs (Ampakines) may be explained, at least in part, by a lower potency at thalamic AMPA receptors, perhaps due to the prevalence of the subunits GluR3 and 4. Although regional preferences of the Ampakines were modest in their extent, they may be sufficient to be of relevance when considering future therapeutic applications of such compounds.