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Agnieszka Potasiewicz, Małgorzata Hołuj, Tomasz Kos, Piotr Popik, Hugo R Arias, Agnieszka Nikiforuk
The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist...
October 4, 2016: Neuropharmacology
Priya Revathikumar, Filip Bergqvist, Srividya Gopalakrishnan, Marina Korotkova, Per-Johan Jakobsson, Jon Lampa, Erwan Le Maître
BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) primarily functions through acetylcholine (ACh)-alpha7 nicotinic acetylcholine receptor (α7nAChR) interaction on macrophages to control peripheral inflammation. Interestingly, ACh can also bind α7nAChRs on microglia resulting in neuroprotective effects. However, ACh effects on astrocytes remain elusive. Here, we investigated the effects of nicotine, an ACh receptor agonist, on the cytokine and cholinesterase production of immunocompetent human astrocytes stimulated with interleukin 1β (IL-1β) in vitro...
September 29, 2016: Journal of Neuroinflammation
Jiaxi Ge, Jie Tian, Hao Yang, Lei Hou, Zhankui Wang, Zhengyu He, Xiangrui Wang
OBJECTIVE: Cardiopulmonary bypass (CPB) carries a risk of lung ischemia- reperfusion, leading to acute lung injury (ALI). Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has been implicated in the release of high mobility group box1 (HMGB1), which promotes systemic inflammation in response to ischemia-reperfusion injury. However, the specific role of alpha7nAChR in CPB is poorly understood. This study employed the alpha7nAChR agonist PNU-282987 and a rat model of CPB to determine whether alpha7nAChR was associated with CPB-induced lung damage...
September 22, 2016: Shock
Ann Olincy, Audrey Blakeley-Smith, Lynn Johnson, William R Kem, Robert Freedman
Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor's expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients' attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect...
August 26, 2016: Journal of Autism and Developmental Disorders
Elisa Navarro, Laura Gonzalez-Lafuente, Irene Perez-Liebana, Izaskun Buendia, Elia López-Bernardo, Cristina Sanchez-Ramos, Ignacio Prieto, Antonio Cuadrado, Jorgina Satrustegui, Susana Cadenas, Maria Monsalve, Manuela Garcia Lopez
AIMS: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which leads to low energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases. Glial cells are important for brain homeostasis and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism...
August 23, 2016: Antioxidants & Redox Signaling
Monica M Marcus, Carl Björkholm, Anna Malmerfelt, Annie Möller, Ninni Påhlsson, Åsa Konradsson-Geuken, Kristin Feltmann, Kent Jardemark, Björn Schilström, Torgny H Svensson
Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia...
September 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Linda J Bristow, Amy E Easton, Yu-Wen Li, Digavalli V Sivarao, Regina Lidge, Kelli M Jones, Debra Post-Munson, Christopher Daly, Nicholas J Lodge, Lizbeth Gallagher, Thaddeus Molski, Richard Pieschl, Ping Chen, Adam Hendricson, Ryan Westphal, James Cook, Christiana Iwuagwu, Daniel Morgan, Yulia Benitex, Dalton King, John E Macor, Robert Zaczek, Richard Olson
The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8...
2016: PloS One
Alexandra I Ershova, Alexey N Meshkov, Tatyana A Rozhkova, Maria V Kalinina, Alexander D Deev, Anatoliy N Rogoza, Tatyana V Balakhonova, Sergey A Boytsov
BACKGROUND: The role of plasma cholesterol in impairing arterial function and elasticity remains unclear. We evaluated arterial stiffness, measured locally in the common carotid artery by high-resolution echo-tracking, and aortic stiffness, using carotid-femoral pulse wave velocity (PWV) (the "gold-standard" measurement of arterial stiffness), in treatment-naive patients with heterozygous familial hypercholesterolemia (FH). METHODS: The study included 66 patients with FH (10-66 years old) and 57 first-degree relatives without FH (11-61 years old)...
2016: PloS One
Xi Ling, Hong Zhang, Xi-qin Yi, Jin-feng Wu
OBJECTIVE: To observe the relatively specific effect of electroacupuncture (EA) of "Xiajuxu" (ST 39, the lower hesea paint of the small intestine), etc. on the level of serum TNF-alpha, lnterleukin-1 P (IL-1 P) and high mobility group protein B 1 (HMGB 1) contents, and duodenum a7 nicotinic acetyicholine receptor (nAchR) expression in duodenal ulcer rats, so as to explore its mechanisms underlying improving duodenal ulcer. METHODS: Sixty SD rats were randomly divided into 6 groups: normal control, model, Xiajuxu (ST 39), Zusanli (ST 36), Shangjuxu (ST 37) and Yanglingquan (GB 34)...
April 2016: Zhen Ci Yan Jiu, Acupuncture Research
Sophie Erhardt, Lilly Schwieler, Sophie Imbeault, Göran Engberg
The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments...
May 28, 2016: Neuropharmacology
Sven Rötering, Matthias Scheunemann, Robert Günther, Reik Löser, Achim Hiller, Dan Peters, Peter Brust, Steffen Fischer, Jörg Steinbach
Radiopharmacological investigations of [(18)F]NS14490 have proven that this radiotracer could be a potential PET radiotracer for imaging of alpha7 nicotinic acetylcholine receptor particularly with regard to vulnerable plaques of diseased vessels. For further optimisation of the previously automated one-pot radiosynthesis of [(18)F]NS14490 using a tosylate precursor, precursors with other leaving groups (nosylate and mosylate) were synthesized and compared with the tosylate with respect to their reactivities towards [(18)F]fluoride...
August 2016: Applied Radiation and Isotopes
Javier Del Pino, Paula Moyano, María José Anadon, José Manuel García, María Jesús Díaz, Gloria Gómez, Jimena García, María Teresa Frejo
Chlorpyrifos (CPF) is an organophosphates insecticide reported to induce, both after acute and repeated exposure, cognitive disorders and basal forebrain cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. This neuronal loss was mediated partially by AChE variants alteration, suggesting other mechanisms are involved. In this regard, CPF induces oxidative stress that is implicated in the induction of cognitive deficits, changes in AChE variants expression and neuronal loss...
April 15, 2016: Toxicology
Da-Wei Wang, Yi-Mei Yin, Yong-Ming Yao
The vagus nerve can sense peripheral inflammation and transmit action potentials from the periphery to the brainstem. Vagal afferent signaling is integrated in the brainstem, and efferent vagus nerves carry outbound signals that terminate in spleen and other organs. Stimulation of efferent vagus nerve leads to the release of acetylcholine in these organs. In turn, acetylcholine interacts with members of the nicotinic acetylcholine receptor (nAChR) family, particularly with the alpha7 nicotinic acetylcholine receptor (α7nAChR), which is expressed by macrophages and other cytokine-producing cells...
April 29, 2016: International Reviews of Immunology
O M Volpina, D O Koroev, T D Volkova, A V Kamynina, M P Filatova, Y V Zaporozhskayva, A N Samokhin, I J Aleksandrova, N V Bobkova
A number of synthetic peptides corresponding to potentially important regions in the sequence of the four membrane proteins known as beta-amyloid cell receptors have been investigated on their ability to improve memory state in experimental model of Alzheimer's disease. Nine fragments repeating all the exposed nonstructural regions of the RAGE protein according to X-ray data, have been synthesized. The activity of these peptides and synthesized earlier immunoprotective fragments of other three proteins (acetylcholine receptor alpha7-type, prion protein and neurotrophin receptor p75) has been investigated under intranasal administration, without immune response to the peptide...
November 2015: Bioorganicheskaia Khimiia
Natalia Gass, Wolfgang Weber-Fahr, Alexander Sartorius, Robert Becker, Michael Didriksen, Tine Bryan Stensbøl, Jesper Frank Bastlund, Andreas Meyer-Lindenberg, Adam J Schwarz
The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns...
July 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Ye He, Zhi-Qiang Ye, Xiang Li, Guo-Song Zhu, Yue Liu, Wei-Feng Yao, Gang-Jian Luo
BACKGROUND: Intestinal ischemia-reperfusion (IIR) could lead to acute lung injury, associated with severe alveolar epithelial cells inflammatory and oxidative injury. Alpha7 nicotinic acetylcholine receptor (α7nAChR) is an essential component of the cholinergic anti-inflammatory pathway. The aim of this study was to investigate the important role of α7nAChR on the lung subjected to IIR. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into four groups (n = 8 in each): sham group (group S), model group (group M), α7nAChR agonist PNU-282987-treated group (group PNU), and specific α7nAChR antagonist methyllycaconitine-treated group (group MLA)...
April 2016: Journal of Surgical Research
Dale Zhou, Peter Gochman, Diane D Broadnax, Judith L Rapoport, Kwangmi Ahn
We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (α7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders...
September 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Ge Li-Sha, Zhao Jing-Lin, Liu Li, Chen Guang-Yi, Li Xiao-Wei, Li Yue-Chun
AIMS: Although excessive sympathetic activation in viral myocarditis and the protective effects of sympathetic inhibition with β-blockers are clear, the effects of enhancing vagal tone on viral myocarditis remain unclear. In several models, vagus nerve activation with the α7 nicotinic acetylcholine receptor (α7-nAChR) agonists has been demonstrated to ameliorate inflammation. This study was therefore designed to examine the effects of cholinergic stimulation with α7-nAChR agonist nicotine in a murine model of acute viral myocarditis...
March 1, 2016: Life Sciences
Fen Li, Yun-bin Zhao, Ding-kun Wang, Xin Zou, Ke Fang, Kai-fu Wang
Berberine (BBR) is an isoquinoline alkaloid extracted from Rhizoma coptidis and has been used for treating type 2 diabetes mellitus (T2DM) in China. The development of T2DM is often associated with insulin resistance and impaired glucose uptake in peripheral tissues. In this study, we examined whether BBR attenuated glucose uptake dysfunction through the cholinergic anti-inflammatory pathway in HepG2 cells. Cellular glucose uptake, quantified by the 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-2-deoxy-D-glucose (2-NBDG), was inhibited by 21% after HepG2 cells were incubated with insulin (10(-6) mol/L) for 36 h...
February 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
Korey P Wylie, Jason Smucny, Kristina T Legget, Jason R Tregellas
Many of the most debilitating symptoms for psychiatric disorders such as schizophrenia remain poorly treated. As such, the development of novel treatments is urgently needed. Unfortunately, the costs associated with high failure rates for investigational compounds as they enter clinical trials has led to pharmaceutical companies downsizing or eliminating research programs needed to develop these drugs. One way of increasing the probability of success for investigational compounds is to incorporate alternative methods of identifying biological targets in order to more effectively screen new drugs...
2016: Current Pharmaceutical Design
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