Publications by authors named "John J Greer"

75 Publications

Countering Opioid-induced Respiratory Depression in Male Rats with Nicotinic Acetylcholine Receptor Partial Agonists Varenicline and ABT 594.

Anesthesiology 2020 05;132(5):1197-1211

From the Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.

Background: Opioids can induce significant respiratory depression when administered as analgesics for the treatment of acute, postoperative, and chronic pain. There are currently no pharmacologic means of reversing opioid-induced respiratory depression without interfering with analgesia. Further, there is a growing epidemic of opioid overdose that could benefit from therapeutic advancements. The aim of this study was to test the ability of two partial agonists of α4β2 nicotinic acetylcholine receptors, varenicline (used clinically for smoking cessation) and ABT 594 (tebanicline, developed as an analgesic), to reduce respiratory depression induced by fentanyl, remifentanil, morphine, and a combination of fentanyl and diazepam.

Methods: Whole body plethysmographic recordings, nociception testing, and righting reflex testing were used to examine ventilation, analgesia, and sedation in adult male Sprague-Dawley rats.

Results: Pre-, co-, or postadministration of varenicline or ABT 594 did not alter baseline breathing but markedly reduced opioid-induced respiratory depression. Varenicline had no effect on fentanyl-induced analgesia and ABT 594 potentiated fentanyl-induced analgesia. Specifically, 10-min administration of fentanyl induced a decrease in respiratory rate to 43 ± 32% of control in vehicle group, which was alleviated by preadministration of varenicline (85 ± 14% of control, n = 8, P < 0.001) or ABT 594 (81 ± 36% of control, n = 8, P = 0.001). ABT 594 or varenicline with a low dose of naloxone (1 µg/kg), but not varenicline alone, partially reversed fentanyl-induced lethal apnea, but neither compound provided the very rapid and complete reversal of apnea achieved with high doses of naloxone (0.03 to 1 mg/kg). Administration of varenicline (n = 4, P = 0.034) or ABT 594 (n = 4, P = 0.034) prevented lethal apneas induced by the combination of fentanyl and diazepam.

Conclusions: Activation of α4β2 nicotinic acetylcholine receptors by varenicline and ABT 594 counters opioid-induced respiratory depression without interfering with analgesia.
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http://dx.doi.org/10.1097/ALN.0000000000003128DOI Listing
May 2020

Late Rescue Therapy with Cord-Derived Mesenchymal Stromal Cells for Established Lung Injury in Experimental Bronchopulmonary Dysplasia.

Stem Cells Dev 2020 03 10;29(6):364-371. Epub 2020 Feb 10.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Sinclair Center for Regenerative Medicine, Ottawa, Canada.

Bronchopulmonary dysplasia (BPD), the main complication of extreme prematurity, has lifelong consequences for lung health. Mesenchymal stromal cells (MSCs) prevent lung injury in experimental BPD in newborn rodents when given in the immediate neonatal period. Whether MSC therapy can restore normal lung growth after established lung injury in adulthood is clinically relevant, but currently unknown. Experimental BPD was achieved by exposing newborn rats to 95% O from postnatal days 4-14. Human umbilical cord-derived MSCs were intratracheally administered to rats (1 × 10cells/kg body weight) as a single dose at 3 or 6 months of age followed by assessment at 5 or 8 months of age, respectively. Lung alveolar structure and vessel density were histologically analyzed. O-exposed rats exhibited persistent lung injury characterized by arrested alveolar growth with airspace enlargement and a lower vessel density at both 5 and 8 months of age compared with controls. Single-dose MSC treatment at 3 months partially attenuated O-induced alveolar injury and restored vessel density at 5 months. Treatment with a single dose at 6 months did not attenuate alveolar injury or vessel density at 8 months. However, treatment with multiple MSC doses at 6, 6.5, 7, and 7.5 months significantly attenuated alveolar injury and improved vessel density at 8 months of age. Treatment of the adult BPD lung with MSCs has the potential to improve lung injury if administered in multiple doses or at an early stage of adulthood.
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http://dx.doi.org/10.1089/scd.2019.0116DOI Listing
March 2020

Regulation of breathing pattern by IL-10.

Am J Physiol Regul Integr Comp Physiol 2019 07 15;317(1):R190-R202. Epub 2019 May 15.

Department of Critical Care and Pulmonary Services and Marianthi Simou Applied Biomedical Research and Training Center, University of Athens Medical School , Athens , Greece.

Proinflammatory cytokines like interleukin-1β (IL-1β) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 οn the control of breathing. IL-10 knockout mice (IL-10, = 10) and wild-type mice (IL-10, = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO-93% O, normoxic hypercapnia 7% CO-21% O, hypoxic hypercapnia 7% CO-10% O, and hypoxic normocapnia 3% CO-10% O. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 μg/kg) was administered intraperitoneally to wild-type mice ( = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10-30 ng/ml, = 8). We found that IL-10 mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10 mice during room air breathing and in all test gases (by 23.62 to 33.2%, < 0.05 and -36.23 to -41.69%, < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10 mice was lower than IL-10 (by -15.67 to -22.74%, < 0.05). The rapid shallow breathing index was higher in IL-10 mice compared with IL-10 mice in all inspired gases (by 50.25 to 57.5%, < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by -12.22 to -29.53 and 32.18 to 45.11%, < 0.05, respectively). IL-10 administration in neonatal rat ( = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing.
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http://dx.doi.org/10.1152/ajpregu.00065.2019DOI Listing
July 2019

Activating α4β2 Nicotinic Acetylcholine Receptors Alleviates Fentanyl-induced Respiratory Depression in Rats.

Anesthesiology 2019 06;130(6):1017-1031

From the Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.

Background: Opioid analgesics are widely used for treatment of acute, postoperative, and chronic pain. However, activation of opioid receptors can result in severe respiratory depression. There is an unmet clinical need to develop a pharmacologic therapy to counter opioid-induced respiratory depression without interfering with analgesia. Further, additional advances to confront accidental lethal overdose with the use of fentanyl and other opioids are needed. Here, the authors test the hypothesis that activation of nicotinic receptors expressed within respiratory rhythm-generating networks would counter opioid-induced respiratory depression without compromising analgesia.

Methods: Respiratory neural discharge was measured using in vitro brainstem-spinal cord and medullary slice rat preparations. In vivo, plethysmographic recording, nociception testing, and righting reflexes were used to examine respiratory ventilation, analgesia, and sedation, respectively.

Results: The administration of nicotine, selective α4β2 nicotinic receptor agonist A85380, but not α7 nicotinic receptor agonist PNU282987, reversed opioid-induced respiratory depression in neonatal pups in vitro and in vivo. In adult rats in vivo, administration of A85380 (0.03 mg/kg), but not PNU282987, provides a rapid and robust reversal of fentanyl-induced decrease in respiratory rate (93.4 ± 33.7% of control 3 min after A85380 vs. 31 ± 20.5% of control after vehicle, n = 8 each, P < 0.001), without marked side effects. The coadministration of A85380 (0.06 mg/kg) with fentanyl or remifentanil markedly reduced respiratory depression and apneas, and enhanced the fentanyl-induced analgesia, as evidenced by increased paw withdrawal latency in Hargreaves plantar test (14.4 ± 2.8 s vs. vehicle: 11.3 ± 2.4 s, n = 8 each, P = 0.013) and decreased formalin-induced nocifensive duration (2.5 ± 2.4 min vs. vehicle: 5.4 ± 2.7 min, n = 8 each, P = 0.029).

Conclusions: The novel strategy of targeting α4β2 nicotinic acetylcholine receptors has the potential for advancing pain control and reducing opioid-induced respiratory depression and overdose.
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http://dx.doi.org/10.1097/ALN.0000000000002676DOI Listing
June 2019

Cardiorespiratory pathogenesis of sickle cell disease in a mouse model.

Sci Rep 2017 08 17;7(1):8665. Epub 2017 Aug 17.

Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.

The nature and development of cardiorespiratory impairments associated with sickle cell disease are poorly understood. Given that the mechanisms of these impairments cannot be addressed adequately in clinical studies, we characterized cardiorespiratory pathophysiology from birth to maturity in the sickle cell disease SAD mouse model. We identified two critical phases of respiratory dysfunction in SAD mice; the first prior to weaning and the second in adulthood. At postnatal day 3, 43% of SAD mice showed marked apneas, anemia, and pulmonary vascular congestion typical of acute chest syndrome; none of these mice survived to maturity. The remaining SAD mice had mild lung histological changes in room air with an altered respiratory pattern, seizures, and a high rate of death in response to hypoxia. Approximately half the SAD mice that survived to adulthood had an identifiable respiratory phenotype including baseline tachypnea at 7-8 months of age, restrictive lung disease, pulmonary hypertension, cardiac enlargement, lower total lung capacity, and pulmonary vascular congestion. All adult SAD mice demonstrated impairments in exercise capacity and response to hypoxia, with a more severe phenotype in the tachypneic mice. The model revealed distinguishable subgroups of SAD mice with cardiorespiratory pathophysiology mimicking the complications of human sickle cell disease.
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http://dx.doi.org/10.1038/s41598-017-08860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561125PMC
August 2017

Mechanistic Studies of Capsaicin-Induced Apnea in Rodents.

Am J Respir Cell Mol Biol 2017 Feb;56(2):252-260

Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.

Inhalation of capsaicin-based sprays can cause central respiratory depression and lethal apneas. There are contradictory reports regarding the sites of capsaicin action. Furthermore, an understanding of the neurochemical mechanisms underlying capsaicin-induced apneas and the development of pharmacological interventions is lacking. The main objectives of this study were to perform a systematic study of the mechanisms of action of capsaicin-induced apneas and to provide insights relevant to pharmacological intervention. In vitro and in vivo rat and transient receptor potential vanilloid superfamily member 1 (TRPV1)-null mouse models were used to measure respiratory parameters and seizure-like activity in the presence of capsaicin and compounds that modulate glutamatergic neurotransmission. Administration of capsaicin to in vitro and in vivo rat and wild-type mouse models induced dose-dependent apneas and the production of seizure-like activity. No significant changes were observed in TRPV1-null mice or rat medullary slice preparations. The capsaicin-induced effects were inhibited by the TRPV1 antagonist capsazepine, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonists CNQX, NBQX, perampanel, and riluzole, a drug that inhibits glutamate release and increases glutamate uptake. The capsaicin-induced effects on breathing and seizure-like activity were accentuated by positive allosteric modulators of the AMPA receptors, CX717 and cyclothiazide. To summarize, capsaicin-induced apneas and seizure-like behaviors are mediated via TRPV1 activation acting at lung afferents, spinal cord-ascending tracts, and medullary structures (including nucleus tractus solitarius). AMPA receptor-mediated conductances play an important role in capsaicin-induced apneas and seizure-like activity. A pharmaceutical strategy targeted at reducing AMPA receptor-mediated glutamatergic signaling may reduce capsaicin-induced deleterious effects.
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http://dx.doi.org/10.1165/rcmb.2016-0228OCDOI Listing
February 2017

Ampakine CX1942 attenuates opioid-induced respiratory depression and corrects the hypoxaemic effects of etorphine in immobilized goats (Capra hircus).

Vet Anaesth Analg 2016 Sep 1;43(5):528-38. Epub 2016 Mar 1.

Brain Function Research Group, Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Parktown, South Africa.

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. Respiratory rate, ventilation and tidal volume were measured continuously. Arterial blood samples for the determination of PaO2 , PaCO2 , pH and SaO2 were taken 2 minutes before and then at 5 minute intervals after drug administration for 25 minutes.

Results: Doxapram corrected etorphine-induced respiratory depression but also led to arousal and hyperventilation at 2 minutes after its administration, as indicated by the low PaCO2 (27.8 ± 4.5 mmHg) and ventilation of 5.32 ± 5.24 L minute(-1) above pre-immobilization values. CX1942 improved respiratory parameters and corrected etorphine's hypoxaemic effects more gradually than did doxapram, with a more sustained improvement in PaO2 and SaO2 in comparison with the control trial.

Conclusions: CX1942 attenuated opioid-induced respiratory depression and corrected the hypoxaemic effects of etorphine in immobilized goats.

Clinical Relevance: Ampakines potentially offer advantages over doxapram, a conventional treatment, in reversing etorphine-induced respiratory depression without causing unwanted side effects, particularly arousal, in immobilized animals.
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http://dx.doi.org/10.1111/vaa.12358DOI Listing
September 2016

Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes.

Hum Mol Genet 2016 09 19;25(17):3798-3809. Epub 2016 Jul 19.

Department of Medical Genetics

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.
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http://dx.doi.org/10.1093/hmg/ddw225DOI Listing
September 2016

Novel Therapies for the Treatment of Central Sleep Apnea.

Sleep Med Clin 2016 Jun;11(2):227-39

University of Alberta, Edmonton, Alberta, Canada.

Neurophysiologically, central apnea is due to a temporary cessation of respiratory rhythmogenesis in medullary respiratory networks. Central apneas occur in several disorders and result in pathophysiological consequences, including arousals and desaturation. The 2 most common causes in adults are congestive heart failure and chronic use of opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea may improve quality of life, morbidity, and mortality. This article discusses recent developments in the treatment of central sleep apnea in heart failure and opioids use.
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http://dx.doi.org/10.1016/j.jsmc.2016.01.004DOI Listing
June 2016

Developmental plasticity of phrenic motoneuron and diaphragm properties with the inception of inspiratory drive transmission in utero.

Exp Neurol 2017 Jan 12;287(Pt 2):137-143. Epub 2016 May 12.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, United States. Electronic address:

The review outlines data consistent with the hypothesis that inspiratory drive transmission that generates fetal breathing movements (FBMs) is essential for the developmental plasticity of phrenic motoneurons (PMNs) and diaphragm musculature prior to birth. A systematic examination during the perinatal period demonstrated a very marked transformation of PMN and diaphragm properties coinciding with the onset and strengthening of inspiratory drive and FBMs in utero. This included studies of age-dependent changes of: i) morphology, neuronal coupling, passive and electrophysiological properties of PMNs; ii) rhythmic inspiratory activity in vitro; iii) FBMs generated in vivo detected by ultrasonography; iv) contractile and end-plate potential properties of diaphragm musculature. We also propose how the hypothesis can be further evaluated with studies of perinatal hypoglossal motoneuron-tongue musculature and the use of Dbx1 null mice that provide an experimental model lacking descending inspiratory drive transmission in utero.
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http://dx.doi.org/10.1016/j.expneurol.2016.05.017DOI Listing
January 2017

G-protein-gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids.

Anesthesiology 2016 Mar;124(3):641-50

From the Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada (G.M., H.L., R.L.H.); Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada (J.R., J.J.G.); and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota (N.C.V., K.W.).

Background: Drugs acting on μ-opioid receptors (MORs) are widely used as analgesics but present side effects including life-threatening respiratory depression. MORs are G-protein-coupled receptors inhibiting neuronal activity through calcium channels, adenylyl cyclase, and/or G-protein-gated inwardly rectifying potassium (GIRK) channels. The pathways underlying MOR-dependent inhibition of rhythmic breathing are unknown.

Methods: By using a combination of genetic, pharmacological, and physiological tools in rodents in vivo, the authors aimed to identify the role of GIRK channels in MOR-mediated inhibition of respiratory circuits.

Results: GIRK channels were expressed in the ventrolateral medulla, a neuronal population regulating rhythmic breathing, and GIRK channel activation with flupirtine reduced respiratory rate in rats (percentage of baseline rate in mean ± SD: 79.4 ± 7.4%, n = 7), wild-type mice (82.6 ± 3.8%, n = 3), but not in mice lacking the GIRK2 subunit, an integral subunit of neuronal GIRK channels (GIRK2, 101.0 ± 1.9%, n = 3). Application of the MOR agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO) to the ventrolateral medulla depressed respiratory rate, an effect partially reversed by the GIRK channel blocker Tertiapin-Q (baseline: 42.1 ± 7.4 breath/min, DAMGO: 26.1 ± 13.4 breath/min, Tertiapin-Q + DAMGO: 33.9 ± 9.8 breath/min, n = 4). Importantly, DAMGO applied to the ventrolateral medulla failed to reduce rhythmic breathing in GIRK2 mice (percentage of baseline rate: 103.2 ± 12.1%, n = 4), whereas it considerably reduced rate in wild-type mice (62.5 ± 17.7% of baseline, n = 4). Respiratory rate depression by systemic injection of the opioid analgesic fentanyl was markedly reduced in GIRK2 (percentage of baseline: 12.8 ± 15.8%, n = 5) compared with wild-type mice (72.9 ± 27.3%).

Conclusions: Overall, these results identify that GIRK channels contribute to respiratory inhibition by MOR, an essential step toward understanding respiratory depression by opioids.
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http://dx.doi.org/10.1097/ALN.0000000000000984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755838PMC
March 2016

Ampakines enhance weak endogenous respiratory drive and alleviate apnea in perinatal rats.

Am J Respir Crit Care Med 2015 Mar;191(6):704-10

Neuroscience and Mental Health Research Institute, Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.

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. We also provide a systematic study of the effects of caffeine for comparison.

Methods: Respiratory neural activity was recorded from brainstem-spinal cord in vitro perinatal rat preparations, and [Formula: see text]e was recorded in newborn rat pups using whole-body plethysmography under normoxic and hypoxic conditions.

Measurements And Main Results: Using in vitro brainstem-spinal cord preparations, we found that CX1739 (10-100 μM) dose-dependently increases the frequency of respiratory activity generated by fetal and newborn rat preparations under normoxic and hypoxic conditions. Plethysmographic recordings in vivo from Postnatal Day 0 rats demonstrated that CX1739 (10 mg/kg) increases the frequency and regularity of ventilation, reduces apneas, and protects against hypoxia-induced respiratory depression.

Conclusions: The net effect of ampakine enhancement of respiratory drive in perinatal rodents is a marked increase in ventilation and the regularity of respiratory patterns in perinatal rat preparations. Importantly, from the perspective of clinical applications, CX1739 readily crosses the blood-brain barrier, is metabolically stable, and has passed through phase I and II clinical trials in adults.
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http://dx.doi.org/10.1164/rccm.201410-1898OCDOI Listing
March 2015

Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.

Am J Respir Cell Mol Biol 2015 Sep;53(3):326-35

3 Department of Physical Therapy, College of Public Health and Health Professions.

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. Using a murine Pompe model with the most severe clinical genotype (the Gaa(-/-) mouse), our primary objective was to test the hypothesis that ampakines can stimulate respiratory motor output and increase ventilation. Our second objective was to confirm that neuropathology was present in Pompe mouse medullary respiratory control neurons. The impact of ampakine CX717 on breathing was determined via phrenic and hypoglossal nerve recordings in anesthetized mice and whole-body plethysmography in unanesthetized mice. The medulla was examined using standard histological methods coupled with immunochemical markers of respiratory control neurons. Ampakine CX717 robustly increased phrenic and hypoglossal inspiratory bursting and reduced respiratory cycle variability in anesthetized Pompe mice, and it increased inspiratory tidal volume in unanesthetized Pompe mice. CX717 did not significantly alter these variables in wild-type mice. Medullary respiratory neurons showed extensive histopathology in Pompe mice. Ampakines stimulate respiratory neuromotor output and ventilation in Pompe mice, and therefore they have potential as an adjunctive therapy in Pompe disease.
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http://dx.doi.org/10.1165/rcmb.2014-0374OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566070PMC
September 2015

5-HT1A receptor agonist Befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats.

Anesthesiology 2015 Feb;122(2):424-34

From the Department of Physiology, Neuroscience, and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada (J.R., X.D., J.J.G.); and the Alberta Innovates Health Sciences Foundation, Edmonton, Alberta, Canada (J.J.G.).

Background: There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT1A receptor agonist without anesthesia.

Methods: Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively.

Results: Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and "behavioral syndrome" in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem-spinal cord and medullary slice preparations.

Conclusions: The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior.
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http://dx.doi.org/10.1097/ALN.0000000000000490DOI Listing
February 2015

Glial TLR4 signaling does not contribute to opioid-induced depression of respiration.

J Appl Physiol (1985) 2014 Oct 7;117(8):857-68. Epub 2014 Aug 7.

Department of Physiology, Neuroscience and Mental Health Institute, Women and Children's Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada;

Opioids activate glia in the central nervous system in part by activating the toll-like receptor 4 (TLR4)/myeloid differentiation 2 (MD2) complex. TLR4/MD2-mediated activation of glia by opioids compromises their analgesic actions. Glial activation is also hypothesized as pivotal in opioid-mediated reward and tolerance and as a contributor to opioid-mediated respiratory depression. We tested the contribution of TLR4 to opioid-induced respiratory depression using rhythmically active medullary slices that contain the pre-Bötzinger Complex (preBötC, an important site of respiratory rhythm generation) and adult rats in vivo. Injection with DAMGO (μ-opioid receptor agonist; 50 μM) or bath application of DAMGO (500 nM) or fentanyl (1 μM) slowed frequency recorded from XII nerves to 40%, 40%, or 50% of control, respectively. This DAMGO-mediated frequency inhibition was unaffected by preapplication of lipopolysaccharides from Rhodobacter sphaeroides (a TLR4 antagonist, 2,000 ng/ml) or (+)naloxone (1-10 μM, a TLR4-antagonist). Bath application of (-)naloxone (500 nM; a TLR4 and μ-opioid antagonist), however, rapidly reversed the opioid-mediated frequency decrease. We also compared the opioid-induced respiratory depression in slices in vitro in the absence and presence of bath-applied minocycline (an inhibitor of microglial activation) and in slices prepared from mice injected (ip) 18 h earlier with minocycline or saline. Minocycline had no effect on respiratory depression in vitro. Finally, the respiratory depression evoked in anesthetized rats by tail vein infusion of fentanyl was unaffected by subsequent injection of (+)naloxone, but completely reversed by (-)naloxone. These data indicate that neither activation of microglia in preBötC nor TLR4/MD2-activation contribute to opioid-induced respiratory depression.
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http://dx.doi.org/10.1152/japplphysiol.00534.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199989PMC
October 2014

Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia.

J Clin Invest 2014 Jan 20;124(1):209-21. Epub 2013 Dec 20.

Congenital diaphragmatic hernia (CDH) is a common birth malformation with a heterogeneous etiology. In this study, we report that ablation of the heparan sulfate biosynthetic enzyme NDST1 in murine endothelium (Ndst1ECKO mice) disrupted vascular development in the diaphragm, which led to hypoxia as well as subsequent diaphragm hypoplasia and CDH. Intriguingly, the phenotypes displayed in Ndst1ECKO mice resembled the developmental defects observed in slit homolog 3 (Slit3) knockout mice. Furthermore, introduction of a heterozygous mutation in roundabout homolog 4 (Robo4), the gene encoding the cognate receptor of SLIT3, aggravated the defect in vascular development in the diaphragm and CDH. NDST1 deficiency diminished SLIT3, but not ROBO4, binding to endothelial heparan sulfate and attenuated EC migration and in vivo neovascularization normally elicited by SLIT3-ROBO4 signaling. Together, these data suggest that heparan sulfate presentation of SLIT3 to ROBO4 facilitates initiation of this signaling cascade. Thus, our results demonstrate that loss of NDST1 causes defective diaphragm vascular development and CDH and that heparan sulfate facilitates angiogenic SLIT3-ROBO4 signaling during vascular development.
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http://dx.doi.org/10.1172/JCI71090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871243PMC
January 2014

Control of breathing activity in the fetus and newborn.

Authors:
John J Greer

Compr Physiol 2012 Jul;2(3):1873-88

Department of Physiology, Centre for Neuroscience, Women and Children Health Research Institute, University of Alberta, Edmonton, Alberta, Canada.

Breathing movements have been demonstrated in the fetuses of every mammalian species investigated and are a critical component of normal fetal development. The classic sheep preparations instrumented for chronic fetal monitoring determined that fetal breathing movements (FBMs) occur in aggregates interspersed with long periods of quiescence that are strongly associated with neurophysiological state. The fetal sheep model also provided data regarding the neurochemical modulation of behavioral state and FBMs under a variety of in utero conditions. Subsequently, in vitro rodent models have been developed to advance our understanding of cellular, synaptic, network, and more detailed neuropharmacological aspects of perinatal respiratory neural control. This includes the ontogeny of the inspiratory rhythm generating center, the preBötzinger complex (preBötC), and the anatomical and functional development of phrenic motoneurons (PMNs) and diaphragm during the perinatal period. A variety of newborn animal models and studies of human infants have provided insights into age-dependent changes in state-dependent respiratory control, responses to hypoxia/hypercapnia and respiratory pathologies.
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http://dx.doi.org/10.1002/cphy.c110006DOI Listing
July 2012

Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia.

Authors:
John J Greer

Respir Physiol Neurobiol 2013 Nov 9;189(2):232-40. Epub 2013 May 9.

Centre for Neuroscience, Department of Physiology, Women and Children's Health Research Institute, 3-020M Katz Building, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address:

This review outlines research that has advanced our understanding of the pathogenesis and etiology of congenital diaphragmatic hernia (CDH). The majority of CDH cases involve incomplete formation of the posterolateral portion of the diaphragm, clinically referred to as a Bochdalek hernia. The hole in the diaphragm allows the abdominal viscera to invade the thoracic cavity, thereby impeding normal lung development. As a result, newborns with CDH suffer from a combination of severe pulmonary hypoplasia and pulmonary hypertension. Despite advances in neonatal intensive care, mortality and serious morbidity remain high. Systematic studies using rat and transgenic mouse models in conjunction with analyses of human tissue are providing insights into the embryological origins of the diaphragmatic defect associated with CDH and abnormalities of developmentally regulated signaling cascades.
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http://dx.doi.org/10.1016/j.resp.2013.04.015DOI Listing
November 2013

Coadministration of the AMPAKINE CX717 with propofol reduces respiratory depression and fatal apneas.

Anesthesiology 2013 Jun;118(6):1437-45

Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada.

Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea.

Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart-brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats.

Results: In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre- or coadministration of CX717 (20-25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg).

Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.
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http://dx.doi.org/10.1097/ALN.0b013e318291079cDOI Listing
June 2013

The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats.

Respir Physiol Neurobiol 2013 Apr 26;186(2):236-53. Epub 2013 Jan 26.

Department of Physiology, 3-020 Katz Bldg, University of Alberta, Edmonton, Alberta, Canada.

Our understanding of the sites and mechanisms underlying rhythmic breathing as well as the neuromodulatory control of respiratory rhythm, pattern, and respiratory motoneuron excitability during perinatal development has advanced significantly over the last 20 years. A major catalyst was the development in 1991 of the rhythmically-active medullary slice preparation, which provided precise mechanical and chemical control over the network as well as enhanced physical and optical access to key brainstem regions. Insights obtained in vitro have informed multiple mechanistic hypotheses. In vivo tests of these hypotheses, performed under conditions of reduced control and precision but more obvious physiological relevance, have clearly established the significance for respiratory neurobiology of the rhythmic slice preparation. We review the contributions of this preparation to current understanding/concepts in respiratory control, and outline the limitations of this approach in the context of studying rhythm and pattern generation, homeostatic control mechanisms and murine models of human genetic disorders that feature prominent breathing disturbances.
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http://dx.doi.org/10.1016/j.resp.2013.01.011DOI Listing
April 2013

Anxiety-related mechanisms of respiratory dysfunction in a mouse model of Rett syndrome.

J Neurosci 2012 Nov;32(48):17230-40

Department of Physiology, Centre for Neuroscience, Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.

Rett syndrome (RTT) is a severe neurological disorder that is associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. RTT patients suffer from mental retardation and behavioral disorders, including heightened anxiety and state-dependent breathing irregularities, such as hyperventilation and apnea. Many symptoms are recapitulated by the Mecp2-null male mice (Mecp2(-/y)). To characterize developmental progression of the respiratory phenotype and explore underlying mechanisms, we examined Mecp2(-/y) and wild-type (WT) mice from presymptomatic periods to end-stage disease. We monitored breathing patterns of unrestrained mice during wake-sleep states and while altering stress levels using movement restraint or threatening odorant (trimethylthiazoline). Respiratory motor patterns generated by in situ working heart-brainstem preparations (WHBPs) were measured to assess function of brainstem respiratory networks isolated from suprapontine structures. Data revealed two general stages of respiratory dysfunction in Mecp2(-/y) mice. At the early stage, respiratory abnormalities were limited to wakefulness, correlated with markers of stress (increased fecal deposition and blood corticosterone levels), and alleviated by antalarmin (corticotropin releasing hormone receptor 1 antagonist). Furthermore, the respiratory rhythm generated by WHBPs was similar in WT and Mecp2(-/y) mice. During the later stage, respiratory abnormalities were evident during wakefulness and sleep. Also, WHBPs from Mecp2(-/y) showed central apneas. We conclude that, at early disease stages, stress-related modulation from suprapontine structures is a significant factor in the Mecp2(-/y) respiratory phenotype and that anxiolytics may be effective. At later stages, abnormalities of brainstem respiratory networks are a significant cause of irregular breathing patterns and central apneas.
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http://dx.doi.org/10.1523/JNEUROSCI.2951-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621869PMC
November 2012

State-dependent modulation of breathing in urethane-anesthetized rats.

J Neurosci 2012 Aug;32(33):11259-70

Department of Physiology, Centre for Neuroscience, and Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.

Respiratory activity is most fragile during sleep, in particular during paradoxical [or rapid eye movement (REM)] sleep and sleep state transitions. Rats are commonly used to study respiratory neuromodulation, but rodent sleep is characterized by a highly fragmented sleep pattern, thus making it very challenging to examine different sleep states and potential pharmacological manipulations within them. Sleep-like brain-state alternations occur in rats under urethane anesthesia and may be an effective and efficient model for sleep itself. The present study assessed state-dependent changes in breathing and respiratory muscle modulation under urethane anesthesia to determine their similarity to those occurring during natural sleep. Rats were anesthetized with urethane and respiratory airflow, as well as electromyographic activity in respiratory muscles were recorded in combination with local field potentials in neocortex and hippocampus to determine how breathing pattern and muscle activity are modulated with brain state. Measurements were made in normoxic, hypoxic, and hypercapnic conditions. Results were compared with recordings made from rats during natural sleep. Brain-state alternations under urethane anesthesia were closely correlated with changes in breathing rate and variability and with modulation of respiratory muscle tone. These changes closely mimicked those observed in natural sleep. Of great interest was that, during both REM and REM-like states, genioglossus muscle activity was strongly depressed and abdominal muscle activity showed potent expiratory modulation. We demonstrate that, in urethane-anesthetized rats, respiratory airflow and muscle activity are closely correlated with brain-state transitions and parallel those shown in natural sleep, providing a useful model to systematically study sleep-related changes in respiratory control.
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http://dx.doi.org/10.1523/JNEUROSCI.0948-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621193PMC
August 2012

Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717.

J Appl Physiol (1985) 2012 Oct 26;113(7):1004-11. Epub 2012 Jul 26.

Department of Physiology, Centre for Neuroscience, University of Alberta, Edmonton, AB, Canada.

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA(A) receptors, which was exacerbated by hypoxic (8% O(2)) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.
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http://dx.doi.org/10.1152/japplphysiol.00752.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487499PMC
October 2012

Ultrahigh sensitivity assays for human cardiac troponin I using TiO2 nanotube arrays.

Lab Chip 2012 Feb 10;12(4):821-8. Epub 2012 Jan 10.

Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB, Canada.

Rapid, highly sensitive troponin assays for the analysis of serum at the point-of-care are particularly desirable for the effective treatment of myocardial infarction (MYI). TiO(2) nanotube arrays constitute a low cost, high surface area, semiconducting architecture with great promise for biosensing applications due to their compatibility with multiple detection techniques. Using TiO(2) nanotube arrays functionalized with highly robust and ordered carboxyalkylphosphonic acid self-assembled monolayers, we have developed a simple and highly sensitive fluorescence immunoassay which can detect concentrations of human cardiac troponin I as low as 0.1 pg ml(-1) without the use of enzymatic amplification. Varying the morphological parameters of the nanotube arrays allows tuning the detection range over 6 orders of magnitude of the troponin concentration from 0.1 pg ml(-1)-100 ng ml(-1).
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http://dx.doi.org/10.1039/c2lc20892jDOI Listing
February 2012

Structural and functional development of the respiratory system in a newborn marsupial with cutaneous gas exchange.

Physiol Biochem Zool 2011 Nov-Dec;84(6):634-49. Epub 2011 Oct 14.

Adaptational and Evolutionary Respiratory Physiology Laboratory, School of Zoology, University of Tasmania, Hobart, Tasmania 7005, Australia.

Marsupials are born with structurally immature lungs and rely, to varying degrees, on cutaneous gas exchange. With a gestation of 13 d and a birth weight of 13 mg, the fat-tailed dunnart (Sminthopsis crassicaudata) is one of the smallest and most immature marsupial newborns. We determined that the skin is almost solely responsible for gas exchange in the early neonatal period. Indeed, fewer than 35% of newborn dunnarts were observed to make any respiratory effort on the day of birth, with pulmonary ventilation alone not meeting the demand for oxygen until approximately 35 d postpartum. Despite the lack of pulmonary ventilation, the phrenic nerve had made contact with the diaphragm, and the respiratory epithelium was sufficiently developed to support gas exchange on the day of birth. Both type I and type II (surfactant-producing) alveolar epithelial cells were present, with fewer than 7% of the cells resembling undifferentiated alveolar epithelial precursor cells. The type I epithelial cells did, however, display thickened cytoplasmic extensions, leading to a high diffusion distance for oxygen. In addition, the architecture of the lung was immature, resembling the early canalicular stage, with alveolarization not commencing until 45 d postpartum. The pulmonary vasculature was also immature, with a centrally positioned single-capillary layer not evident until 100 d postbirth. These structural limitations may impede efficient pulmonary gas exchange, forcing the neonatal fat-tailed dunnart to rely predominately on its skin, a phenomenon supported by a low metabolic rate and small size.
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http://dx.doi.org/10.1086/662557DOI Listing
May 2012

PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.

J Neurosci 2011 Jan;31(4):1292-301

Department of Medicine and Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

The analgesic properties of the opium poppy Papever somniferum were first mentioned by Hippocrates around 400 BC, and opioid analgesics remain the mainstay of pain management today. These drugs can cause the serious side-effect of respiratory depression that can be lethal with overdose, however the critical brain sites and neurochemical identity of the neurons mediating this depression are unknown. By locally manipulating neurotransmission in the adult rat, we identify the critical site of the medulla, the preBötzinger complex, that mediates opioid-induced respiratory depression in vivo. Here we show that opioids at the preBötzinger complex cause respiratory depression or fatal apnea, with anesthesia and deep-sleep being particularly vulnerable states for opioid-induced respiratory depression. Importantly, we establish that the preBötzinger complex is fully responsible for respiratory rate suppression following systemic administration of opioid analgesics. The site in the medulla most sensitive to opioids corresponds to a region expressing neurokinin-1 receptors, and we show in rhythmically active brainstem section in vitro that neurokinin-1 receptor-expressing preBötzinger complex neurons are selectively inhibited by opioids. In summary, neurokinin-1 receptor-expressing preBötzinger complex neurons constitute the critical site mediating opioid-induced respiratory rate depression, and the key therapeutic target for its prevention or reversal.
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http://dx.doi.org/10.1523/JNEUROSCI.4611-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6623620PMC
January 2011

Retinol status of newborn infants is associated with congenital diaphragmatic hernia.

Pediatrics 2010 Oct 13;126(4):712-20. Epub 2010 Sep 13.

Department of Pediatric Surgery, Sophia's Children's Hospital, Erasmus Medical Center, University Medical Center Rotterdam, Department of Clinical Chemistry, Building Ee, Room 22-71a, PO Box 2040, 3000 CA Rotterdam, Netherlands.

Objective: Genetic analyses in humans suggest a role for retinoid-related genes in the pathogenesis of congenital diaphragmatic hernia (CDH). The goal of this study was to investigate the vitamin A status of mothers and their newborns in association with CDH.

Methods: We conducted a hospital-based, case-control study with 22 case and 34 control mothers and their newborns. In maternal and cord blood samples, retinol and retinol-binding protein (RBP) levels were measured with high-performance liquid chromatography and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate logistic regression analyses were performed to determine crude and adjusted risk estimates.

Results: Case newborns had significantly lower levels of retinol (0.60 vs 0.76 μmol/L; P=.003) and RBP (5.42 vs 7.11 mg/L; P=.02) than did control newborns. The multivariate logistic regression analysis showed lower levels of retinol and RBP in association with CDH risk; the odds ratio for retinol levels of <15th percentile (<0.61 μmol/L) was 11.11 (95% confidence interval: 2.54-48.66; P=.001), and that for RBP levels of <15th percentile (<4.54 mg/L) was 4.00 (95% confidence interval: 1.00-15.99; P=.05). Retinol and RBP levels were not different between case and control mothers.

Conclusions: CDH is strongly associated with low retinol and RBP levels in newborns, independent of maternal retinol status. This is an important finding supporting the idea that human CDH is linked with abnormal retinoid homeostasis.
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http://dx.doi.org/10.1542/peds.2010-0521DOI Listing
October 2010

Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy.

PLoS One 2010 Jan 19;5(1):e8766. Epub 2010 Jan 19.

Division of Neuroscience, University of Alberta, Edmonton, Canada.

Background: Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of mu-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.

Methodology/principal Findings: A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the mu-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.

Conclusions/significance: The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract mu-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008766PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808240PMC
January 2010

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities.

Proc Natl Acad Sci U S A 2009 Dec 9;106(51):21966-71. Epub 2009 Dec 9.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.
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http://dx.doi.org/10.1073/pnas.0912257106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799790PMC
December 2009

Tripartite purinergic modulation of central respiratory networks during perinatal development: the influence of ATP, ectonucleotidases, and ATP metabolites.

J Neurosci 2009 Nov;29(47):14713-25

Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.

ATP released during hypoxia from the ventrolateral medulla activates purinergic receptors (P2Rs) to attenuate the secondary hypoxic depression of breathing by a mechanism that likely involves a P2Y(1)R-mediated excitation of preBötzinger complex (preBötC) inspiratory rhythm-generating networks. In this study, we used rhythmically active in vitro preparations from embryonic and postnatal rats and ATP microinjection into the rostral ventral respiratory group (rVRG)/preBötC to reveal that these networks are sensitive to ATP when rhythm emerges at embryonic day 17 (E17). The peak frequency elicited by ATP at E19 and postnatally was the same ( approximately 45 bursts/min), but relative sensitivity was threefold greater at E19, reflecting a lower baseline frequency (5.6 +/- 0.9 vs 19.0 +/- 1.3 bursts/min). Combining microinjection techniques with ATP biosensors revealed that ATP concentration in the rVRG/preBötC falls rapidly as a result of active processes and closely correlates with inspiratory frequency. A phosphate assay established that preBötC-containing tissue punches degrade ATP at rates that increase perinatally. Thus, the agonist profile [ATP/ADP/adenosine (ADO)] produced after ATP release in the rVRG/preBötC will change perinatally. Electrophysiology further established that the ATP metabolite ADP is excitatory and that, in fetal but not postnatal animals, ADO at A(1) receptors exerts a tonic depressive action on rhythm, whereas A(1) antagonists extend the excitatory action of ATP on inspiratory rhythm. These data demonstrate that ATP is a potent excitatory modulator of the rVRG/preBötC inspiratory network from the time it becomes active and that ATP actions are determined by a dynamic interaction between the actions of ATP at P2 receptors, ectonucleotidases that degrade ATP, and ATP metabolites on P2Y and P1 receptors.
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http://dx.doi.org/10.1523/JNEUROSCI.2660-09.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666021PMC
November 2009