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Wei Dai, Dian Xiao, Xiang Gao, Xin-Bo Zhou, Tong-Yu Fang, Zheng Yong, Rui-Bin Su
The use of opioid drugs for pain relief can induce life-threatening respiratory depression. Although naloxone effectively counteracts opioid-induced respiratory depression, it diminishes the efficacy of analgesia. Our studies indicate that ampakines, in particular, a brain-targeted compound XD-8-17C, are able to reverse respiratory depression without affecting analgesia at relatively low doses. Mice and rats were subcutaneously or intravenously injected with the opioid agonist TH-030418 to induce moderate or severe respiratory depression...
May 11, 2017: European Journal of Pharmacology
Daniel P Radin, Sheng Zhong, Richard Purcell, Arnold Lippa
Memory loss observed as a consequence of aging is paralleled by a down-regulation of AMPA-type glutamate receptors (AMPARs) that mediate fast excitatory synaptic transmission. Activation of these receptors enhances long-term potentiation (LTP), a neuronal process demonstrated to be crucial for memory storage and thought to be a cellular substrate of learning and memory. In the present studies, we determined that LTP was reduced in aged rats when compared to young rats and that acute treatment with CX1846, a novel AMPAR positive allosteric modulator, fifteen minutes prior to tetanic stimulation completely reversed the significant deficit in LTP observed in aged rats...
December 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Chen Su, Hau Yeuh Lin, Runtao Yang, Duo Xu, Michelle Lee, Natalie Pawlak, Monica Norcini, Alexandra Sideris, Esperanza Recio-Pinto, Dong Huang, Jing Wang
BACKGROUND: AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. METHODS: The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain...
November 2016: Anesthesiology
Anna J Haw, Leith Cr Meyer, John J Greer, Andrea Fuller
OBJECTIVES: To determine whether CX1942 reverses respiratory depression in etorphine-immobilized goats, and to compare its effects with those of doxapram hydrochloride. STUDY DESIGN: A prospective, crossover experimental trial conducted at 1753 m.a.s.l. ANIMALS: Eight adult female Boer goats (Capra hircus) with a mean ± standard deviation mass of 27.1 ± 1.6 kg. METHODS: Following immobilization with 0.1 mg kg(-1) etorphine, goats received one of doxapram, CX1942 or sterile water intravenously, in random order in three trials...
September 2016: Veterinary Anaesthesia and Analgesia
Lianyan Huang, Joseph Cichon, Ipe Ninan, Guang Yang
Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine] to potentiate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia...
June 22, 2016: Science Translational Medicine
S M Turner, M K ElMallah, A K Hoyt, J J Greer, D D Fuller
Glutamatergic currents play a fundamental role in regulating respiratory motor output and are partially mediated by α-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors throughout the premotor and motor respiratory circuitry. Ampakines are pharmacological compounds that enhance glutamatergic transmission by altering AMPA receptor channel kinetics. Here, we examined if ampakines alter the expression of respiratory long-term facilitation (LTF), a form of neuroplasticity manifested as a persistent increase in inspiratory activity following brief periods of reduced O2 [intermittent hypoxia (IH)]...
September 1, 2016: Journal of Neurophysiology
Abigail Benn, Gareth R I Barker, Sarah A Stuart, Eva V L Roloff, Anja G Teschemacher, E Clea Warburton, Emma S J Robinson
UNLABELLED: Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically...
May 4, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dian Xiao, Fan-Hua Meng, Wei Dai, Zheng Yong, Jin-Qiu Liu, Xin-Bo Zhou, Song Li
Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of "lock-in" can be used to solve these problems. A series of thiamine disulfide prodrugs 7a-7f of ampakine compound LCX001 was synthesized and evaluated...
April 14, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Kevin Lee, Lucy Goodman, Chantelle Fourie, Susan Schenk, Beulah Leitch, Johanna M Montgomery
Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction...
2016: Advances in Protein Chemistry and Structural Biology
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, Gary Lynch
UNLABELLED: 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...
February 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Guillaume Fond, Jean-Arthur Micoulaud-Franchi, Lore Brunel, Alexandra Macgregor, Stéphanie Miot, Régis Lopez, Raphaëlle Richieri, Mocrane Abbar, Christophe Lancon, Dimitris Repantis
Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant's action, whose potential effectiveness was assessed in randomized placebo-controlled trials (RCTs). A systematic review was carried out, using the words "attention", "memory", "learning", "executive functions", and "vigilance/wakefulness" combined to "cognitive enhancer" or "smart drug"...
September 30, 2015: Psychiatry Research
David Cavalla, Fabio Chianelli, Alla Korsak, Patrick S Hosford, Alexander V Gourine, Nephtali Marina
Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine...
August 15, 2015: European Journal of Pharmacology
Andrew N Clarkson, Kim Parker, Michael Nilsson, F Rohan Walker, Emma K Gowing
Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brain-derived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke...
August 2015: Journal of Cerebral Blood Flow and Metabolism
Jun Ren, Xiuqing Ding, John J Greer
RATIONALE: Apnea of prematurity, which is prevalent among infants born at less than 34 weeks gestation, is treated with caffeine, theophylline, or aminophylline. However, not all newborns respond adequately to, or tolerate, methylxanthine administration, and thus alternative pharmacological therapies are required. OBJECTIVES: Rodent models are used to test the hypothesis that the ampakine CX1739, a positive allosteric modulator of amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, strengthens perinatal respiratory drive and reduces apneas...
March 15, 2015: American Journal of Respiratory and Critical Care Medicine
Mai K ElMallah, Silvia Pagliardini, Sara M Turner, Anthony J Cerreta, Darin J Falk, Barry J Byrne, John J Greer, David D Fuller
Pompe disease results from a mutation in the acid α-glucosidase gene leading to lysosomal glycogen accumulation. Respiratory insufficiency is common, and the current U.S. Food and Drug Administration-approved treatment, enzyme replacement, has limited effectiveness. Ampakines are drugs that enhance α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses and can increase respiratory motor drive. Recent work indicates that respiratory motor drive can be blunted in Pompe disease, and thus pharmacologic stimulation of breathing may be beneficial...
September 2015: American Journal of Respiratory Cell and Molecular Biology
Boeke J van Beugen, Xin Qiao, Dana H Simmons, Chris I De Zeeuw, Christian Hansel
Ampakines are allosteric modulators of AMPA receptors that facilitate hippocampal long-term potentiation (LTP) and learning, and have been considered for the treatment of cognition and memory deficits. Here, we show that the ampakine CX546 raises the amplitude and slows the decay time of excitatory postsynaptic currents (EPSCs) at cerebellar parallel fiber (PF) to Purkinje cell synapses, thus resembling CX546 effects described at hippocampal synapses. Using the fluorescent calcium indicator dye Oregon Green BAPTA-2 and an ultra-high-speed CCD camera, we also monitored calcium transients in Purkinje cell dendrites...
December 2014: Learning & Memory
Rutger van der Schier, Margot Roozekrans, Monique van Velzen, Albert Dahan, Marieke Niesters
The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia...
2014: F1000Prime Reports
Alexander M Le, Michelle Lee, Chen Su, Anthony Zou, Jing Wang
BACKGROUND: Novel analgesics that do not suppress the respiratory drive are urgently needed. Glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors plays important roles in central pain circuits. AMPAkines augment AMPA receptor function and have been shown to stimulate the respiratory drive to oppose opioid-induced hypoventilation. However, their role in chronic pain states remains unknown. METHODS: The authors studied AMPAkines (CX546 and CX516) in rat spared nerve injury (SNI) model of neuropathic pain and Complete Freund's Adjuvant (CFA) model of inflammatory pain...
November 2014: Anesthesiology
Juan Gibert-Rahola, Abigail Villena-Rodriguez
It is accepted that both positive and negative symptoms of schizophrenia may be due to hypofunction of glutamatergic pathways leading to altered dopaminergic neurotransmission activity. Specifically, there may be diminished glutamatergic signaling at the level of the NMDA receptors, but direct receptor agonists have no clinical utility due to their nonspecific actions and undesirable side effects. Given the problems of ineffectiveness or side effects of drugs that act directly on ionotropic and metabotropic mGlu2-3 receptors, clinical trials have been conducted with other drugs that have other mechanisms of action, especially indirect mechanisms, such as the co-administration of NMDA agonists (glycine or D-serine), glycine transporter inhibitors (sarcosine bitopertin), ampakines (CX-516), and mGlu5 receptor agonists...
September 2014: Actas Españolas de Psiquiatría
Philip K-Y Chang, George A Prenosil, David Verbich, Raminder Gill, R Anne McKinney
CX 546, an allosteric positive modulator of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type ionotropic glutamate receptors (AMPARs), belongs to a drug class called ampakines. These compounds have been shown to enhance long-term potentiation (LTP), a cellular model of learning and memory, and improve animal learning task performance, and have augmented cognition in neurodegenerative patients. However, the chronic effect of CX546 on synaptic structures has not been examined. The structure and integrity of dendritic spines are thought to play a role in learning and memory, and their abnormalities have been implicated in cognitive disorders...
September 2014: European Journal of Neuroscience
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