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1. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain

Author

Dongfang Li, Guo-Fang Xue, Guanglai Li, Lijun Cao, Peng Feng, Christian Hölscher, and Lin Li

Subjects
Male, 0301 basic medicine, Agonist, endocrine system, medicine.medical_specialty, Parkinson's disease, Tyrosine 3-Monooxygenase, medicine.drug_class, Incretin, Substantia nigra, Striatum, Neuroprotection, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, Antiparkinson Agents, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Animals, Analysis of Variance, Dose-Response Relationship, Drug, business.industry, General Neuroscience, MPTP, Calcium-Binding Proteins, Microfilament Proteins, Brain, MPTP Poisoning, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, nervous system, chemistry, Exploratory Behavior, Peptides, business, Locomotion, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery
Abstract

The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.

Published
2016
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2. A novel dual-glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist is neuroprotective in transient focal cerebral ischemia in the rat

Author

Ling Han, Guanglai Li, Christian Hölscher, Guo-Fang Xue, and Dongfang Li

Subjects
Male, 0301 basic medicine, Agonist, endocrine system, medicine.medical_specialty, medicine.drug_class, Drug Evaluation, Preclinical, Ischemia, Nitric Oxide Synthase Type II, Apoptosis, Motor Activity, Neuroprotection, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, Rats, Sprague-Dawley, Lipopeptides, Random Allocation, 03 medical and health sciences, 0302 clinical medicine, Bcl-2-associated X protein, Glucagon-Like Peptide 1, Internal medicine, medicine, Animals, Receptor, bcl-2-Associated X Protein, Neurons, biology, business.industry, Cerebral infarction, General Neuroscience, Neurodegeneration, Brain, Infarction, Middle Cerebral Artery, medicine.disease, Glucagon-like peptide-1, Disease Models, Animal, Neuroprotective Agents, 030104 developmental biology, Endocrinology, Ischemic Attack, Transient, Nerve Degeneration, biology.protein, business, hormones, hormone substitutes, and hormone antagonists, 030217 neurology & neurosurgery
Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

Published
2016
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3. Neuroprotective role of (Val8)GLP-1-Glu-PAL in an in vitro model of Parkinson's disease

Author

Christian Hölscher, Juan Zhao, Ke Liu, Lin Li, Yue-Ze Liu, and Guanglai Li

Subjects
0301 basic medicine, endocrine system, caspase-3, Parkinson's disease, Caspase 3, Pharmacology, Neuroprotection, lcsh:RC346-429, rotenone, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, neurodegenerative disease, Developmental Neuroscience, Downregulation and upregulation, Medicine, Glucose homeostasis, Bcl-2, nerve regeneration, lcsh:Neurology. Diseases of the nervous system, cellular culture, business.industry, Neurogenesis, Neurodegeneration, digestive, oral, and skin physiology, apoptosis, Rotenone, medicine.disease, humanities, 030104 developmental biology, chemistry, business, GLP-1, neural regeneration, Neuroscience, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Research Article
Abstract

The growth factor glucagon-like peptide-1 (GLP-1) is neuroprotective in several animal models of neurodegeneration. Here, we analyzed the neuroprotective effects of a novel protease-resistant GLP-1 analogue, (Val 8 )GLP-1-Glu-PAL, which has advantages over older analogues, such as improvement of hippocampal neurogenesis, glucose homeostasis, and insulin secretion. We established an in vitro model of Parkinson's disease using the mitochondrial stressor rotenone in primary cultured mouse neurons pretreated with (Val 8 )GLP-1-Glu-PAL. (Val 8 )GLP-1-Glu-PAL alone did not affect neuronal viability, but prevented the rotenone-induced reduction in cell viability in a dose-dependent manner. In addition, (Val 8 )GLP-1-Glu-PAL pretreatment prevented rotenone-induced proapoptotic changes manifesting as downregulation of procaspase-3 and Bcl-2 and upregulation of cleaved caspase-3. These results demonstrate that the novel agent (Val 8 )GLP-1-Glu-PAL shows promise as a drug treatment for Parkinson's disease.

Published
2016

4. Geniposide prevents rotenone-induced apoptosis in primary cultured neurons

Author

Yan-qing Han, Juan Zhao, Guanglai Li, Ke Liu, Lin Li, and Yue-Ze Liu

Subjects
Agonist, caspase-3, medicine.drug_class, Caspase 3, Pharmacology, Neuroprotection, lcsh:RC346-429, geniposide, rotenone, chemistry.chemical_compound, Developmental Neuroscience, Lactate dehydrogenase, Medicine, Bcl-2, Receptor, nerve regeneration, lcsh:Neurology. Diseases of the nervous system, biology, cell apoptosis, business.industry, Rotenone, Alzheimer's disease, biology.organism_classification, Alzheimer′s disease, neural regeneration, Gardenia, chemistry, Apoptosis, business, Neuroscience, Research Article
Abstract

Geniposide, a monomer extracted from gardenia and widely used in Chinese medicine, is a novel agonist at the glucagon-like peptide-1 receptor. This receptor is involved in neuroprotection. In the present study, we sought to identify an anti-apoptotic mechanism for the treatment of neurodegenerative diseases. Primary cultured neurons were treated with different concentrations of rotenone for 48 hours. Morphological observation, cell counting kit-8 assay, lactate dehydrogenase detection and western blot assay demonstrated that 0.5 nM rotenone increased lactate dehydrogenase release, decreased the expression of procaspase-3 and Bcl-2, and increased cleaved caspase-3 expression in normal neurons. All these effects were prevented by geniposide. Our results indicate that geniposide diminished rotenone-induced injury in primary neurons by suppressing apoptosis. This may be one of the molecular mechanisms underlying the efficacy of geniposide in the treatment of neurodegenerative diseases.

Published
2015

5. Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes)

Author

J. Donald Easton, Maria Aunes, Gregory W. Albers, Pierre Amarenco, Sara Bokelund-Singh, Hans Denison, Scott R. Evans, Peter Held, Marianne Jahreskog, Jenny Jonasson, Kazuo Minematsu, Carlos A. Molina, Yongjun Wang, K.S. Lawrence Wong, S. Claiborne Johnston, Sebastiá F. Ameriso, Geoffrey Donnan, Robin Lemmens, Ayrton Massaro, Ekaterina Titianova, Michael D. Hill, Pablo Lavados, David Skoloudik, Joachim Röther, Szegedi Norbert, Giancarlo Agnelli, Natan Bornstein, Norio Tanahashi, Angel Arauz Góngora, Edwin Pretell, Maria Cristina Z. San Jose, Anna Czlonkowska, Ovidiu Bajenaru, Ludmila Stakhovskaya, Miroslav Brozman, Jong-Sung Kim, Nils Wahlgren, Patrik Michel, Tsong Hai Lee, Nijasri Charnnarong Suwanwela, Kursad Kutluk, Sergii Moskovko, Scott Kasner, Daniel Laskowitz, Wayne Clark, Huy Thang Nguyen, Sebastian Ameriso, Sandra Lepera, Marina Romano, David Paulon, Pablo Ioli, Cristina Zurru, Guadalupe Bruera, Lorena Jure, Francisco Klein, Guillermo Povedano, Christopher Levi, Thanh Phan, Romesh Markus, Craig Anderson, Arman Sabet, Stephen Davis, Andrew Lee, Timothy Kleinig, Andrew Wong, Martin Krause, Jim Jannes, Tissa Wijeratne, Dimitri Hemelsoet, André Peeters, Philippe Tack, Peter Vanacker, Patrice Laloux, William Van Landegem, Geert Vanhooren, Philippe Desfontaines, Marc Van Orshoven, Fabio Oliveira, Mauricio Friedrich, Rosane Brondani, Rubens Gagliardi, Soraia Fabio, Marianna Dracoulakis, Rodrigo Bazan, Luiz Marrone, Octavio Pontes Neto, Gisele Silva, Pedro Kowacs, Paraskeva Stamenova, Marin Daskalov, Ivan Staikov, Dimo Baldaranov, Dimitar Maslarov, Hristo Lilovski, Plamen Petkov, Neli Petrova, Radoslav Mavrov, Veska Markova, Valeria Petrova, Tanya Beleva, Borislav Kralev, Nikolay Sotirov, Veska Lekova, Dimcho Hristov, Vera Ermenkova, Lyudmil Mateev, Rumeliya Mitkova, Liybomir Haralanov, Rosen Ikonomov, Margarita Mihailova, Ivan Georgiev, Ashfaq Shuaib, Vladimir Hachinski, Jean-Martin Boulanger, Sharan Mann, Ayman Hassan, Ariane Mackey, Bijoy Menon, Jeffrey Minuk, Muzaffar Siddiqui, Marsha Eustace, Lucia Vieira, Daniel Selchen, Michel Beaudry, Grant Stotts, Angel Castro, Kristo Gasic, Rodrigo Rivas, Pablo Sanchez, Andres Roldan, Ingrid Grossmann, Christian Figueroa, Jimei Li, Xiaolin Xu, Huisheng Chen, Xiaohong Li, Yi Yang, Chunsheng Zhang, Baojun Wang, Guanglai Li, Dong Wang, Hong Lin, Yamei Tang, Anding Xu, Yanjiang Wang, Wenke Hong, Zhi Song, Xu Zhang, Xiaoping Jin, Yun Xu, Fuling Yan, Weihong Zheng, Xiaoping Wang, Qiang Dong, Zhongxin Zhao, Baorong Zhang, Wangtao Zhong, Guoqiang Wen, Jun Xu, Guozhong Li, Xueshuang Dong, Xiangyang Tian, Zhaohui Zhang, En Xu, Kaixiang Liu, Jun Chen, Ondrej Skoda, Edvard Ehler, Daniel Vaclavik, Daniel Sanak, Sylva Klimosova, Eva Vitkova, Jan Fiksa, Robert Mikulik, Jiri Neumann, Richard Plny, Didier Leys, Igor Sibon, Jean-Louis Mas, Sonia Alamowitch, Fernando Pico, Hassan Hosseini, Marie-Hélène Mahagne, Emmanuel Touze, Wilfried Vadot, Stéphane Vannier, Norbert Nighoghossian, Yves Samson, Pierre Garnier, Emmanuel Ellie, Benoît Guillon, Serge Timsit, Maurice Giroud, Frédéric Philippeau, Aude Bagan-Triquenot, Valérie Wolff, Nicolas Raposo, Michel Obadia, Severine Debiais, Jérôme Grimaud, Stéphane Illouz, Didier Smadja, Cédric Urbanczyk, Jörg Berrouschot, Christian Weimar, Georg Gahn, Hassan Soda, Sven Klimpe, Darius Nabavi, Jörg Glahn, Martin Köhrmann, Lars Krause, Christoph Terborg, Peter Urban, Thorsten Steiner, Andreas Ferbert, Rainer Dziewas, Günter Seidel, Götz Thomalla, Richard Li, Wing Chi Fong, Raymond Cheung, Norbert Szegedi, Krisztián Pozsegovits, Attila Valikovics, Gyula Pánczél, Csilla Rózsa, László Németh, Péter Diószeghy, Csaba Óváry, Attila Csányi, Levente Kerényi, Valéria Nagy, Sámuel Komoly, Dániel Bereczki, Sándor Molnár, István Kondákor, David Tanne, Guy Raphaeli, Gregory Telman, Ronen Leker, Yair Lampl, Francesco Corea, Stefano Ricci, Donata Guidetti, Giovanni Malferrari, Simona Marcheselli, Giuseppe Micieli, Andrea Zini, Vincenzo Di Lazzaro, Carlo Gandolfo, Andrea Salmaggi, Rossana Tassi, Maurizia Rasura, Giovanni Orlandi, Giancarlo Comi, Michelangelo Mancuso, Marialuisa Delodovici, Paolo Bovi, Domenico Consoli, Kimiaki Utsugisawa, Tsuneo Fujita, Hideyuki Kurihara, Chikashi Maruki, Takeshi Hayashi, Tsuneaki Ogiichi, Morio Kumagai, Katsunobu Takenaka, Kazunori Toyoda, Kazuhiro Takamatsu, Ryo Ogami, Shigenari Kin, Takeshi Aoki, Katsumi Takizawa, Shigehiro Omori, Takehiko Umezawa, Yasuyuki Toba, Yutaka Nonoyama, Hidemitsu Nakagawa, Takashi Naka, Masanori Morimoto, Shuichi Matsumoto, Tsutomu Hitotsumatsu, Tatsuya Shingaki, Satoshi Okuda, Mamoru Ota, Nobuyuki Sakai, Takeshi Yamada, Jun Niwa, Hitoshi Fujita, Akihito Moriki, Kimihiro Yoshino, Yoshihisa Fukushima, Takahisa Mori, Atsushi Sato, Yoshikazu Kusano, Michiya Kubo, Masashi Yamazaki, Takao Ooasa, Takafumi Nishizaki, Naoki Kitagawa, Masahiro Yasaka, Yasuhiro Manabe, Akira Yoshioka, Masayuki Ishihara, Takato Kagawa, Toshikazu Ichihashi, Hideki Matsuoka, Yasuhiro Ito, Masahiro Yamasaki, Hitonori Takaba, Hisatoshi Saito, Masahiro Sato, Kazumasa Fukuda, Sumio Endo, Minoru Kidooka, Toshitaka Umemura, Yuriko Kikkawa, Shuta Toru, Kentaro Yamada, Hideki Sakai, Jun Asari, Masayuki Ezura, Hisashi Nitta, Keiko Nagano, Jun Ochiai, Keiichi Sakai, Yasutaka Kobayashi, Yasuhiro Yoshii, Hirotomo Miake, Tomohiro Takita, Hidekazu Taniguchi, Kazuhiko Kuroki, Takamitsu Mizota, Kenichi Yamamoto, Hiroshi Nakane, Takeshi Iwanaga, Kei Chiba, Tetsuyuki Yoshimoto, Tsuyoshi Torii, Takeo Kitagawa, Hiroshi Takashima, Naoki Shirasaki, Makoto Dehara, Naomichi Wada, Kensuke Hamada, Noriyuki Kato, Yoshinori Go, Ichiro Izumi, Hirotomo Ninomiya, Junichiro Kumai, Yoshikazu Nakajima, Yasuhiko Kaku, Yukihiro Isayama, Masahiro Kawanishi, Shinya Noda, Kazuhide Yamamoto, Takanori Hazama, Hiroshi Takahashi, Yohei Tanaka, Takashi Hata, Kiyoshi Kazekawa, Eisuke Furui, Hideki Hondo, Nobuyuki Sato, Katsusuke Kusunoki, Kazunori Nanri, Satoshi Abe, Noboru Sasaoka, Takayuki Kuroyanagi, Hisahiko Suzuki, Kouzou Fukuyama, Kimihiro Nakahara, Fernando Gongora, Carlos Cantú Brito, Jorge Villarreal Careaga, Rosalia Vazquez Alfaro, Geronimo Aguayo Leytte, Percy Berrospi, Carlos Chavez, Liliana Rodriguez, Nilton Custodio, Cesar Castañeda, Julio Perez, Maria Cristina San Jose, Alejandro Baroque, Epifania Collantes, Abdias Aquino, Alejandro Díaz, Artemio Roxas, Johnny Lokin, Joel Advincula, Emerito Calderon, Jose Navarro, John Hiyadan, Arturo Surdilla, Danuta Ryglewicz, Grzegorz Krychowiak, Waldemar Fryze, Piotr Sobolewski, Ryszard Nowak, Urszula Fiszer, Beata Papierowska, Justyna Zielińska-Turek, Anetta Lasek-Bal, Ewa Kołodziejska, Anna Kamińska, Bożena Adamkiewicz, Andrzej Tutaj, Dorota Szkopek, Krzysztof Musiatowicz, Zbigniew Bąk, Sławomir Brzozowski, Waldemar Brola, Antoni Ferens, Marek Zalisz, Konrad Rejdak, Monika Rudzińska, Cristina Panea, Mihaela Simu, Rodica Balasa, Iulian Cuciureanu, Bogdan Popescu, Monica Sabau, Corina Roman-Filip, Leonid Pimenov, Alla Gekht, Anna Milto, Ivan Shchukin, Vladimir Parfenov, Liudmila Stakhovskaya, Mikhail Arkhipov, Nadezhda Sokolova, Enver Bogdanov, Radiy Esin, Dina Khasanova, Konstantin Golikov, Elena Melnikova, Leonid Zaslavskiy, Igor Voznyuk, Alexander Nazarov, Leila Akhmadeeva, Aida Iakupova, Nikolay Shamalov, Galina Belskaya, Svetlana Chuprina, Olga Denisova, Ekaterina Drozdova, Yuliya Karakulova, Ilya Sholomov, Nikolay Spirin, Elena Vostrikova, Elena Mordvintseva, Vera Grigoryeva, Dmitry Zateyshchikov, Vladimir Gorbachev, Zhanna Chefranova, Mikhail Dudarev, Rostislav Nilk, Alexey Rozhdestvenskiy, Ladislav Gurcik, Miloslav Dvorak, Georgi Krastev, Egon Kurca, Juraj Vyletelka, Jong Sung Kim, Hee-Joon Bae, Yong-Won Kim, Joon-Tae Kim, Jae-Kwan Cha, Hyo Suk Nam, Dae-Il Chang, Yong-Seok Lee, Kyungmi Oh, Sung-Wook Yu, Sung-Il Sohn, Jun Lee, Han Jin Cho, Eung-Gyu Kim, Joung-Ho Rha, Seo Hyun Kim, Carlos Molina Cateriano, Joaquín Serena Leal, José Vivancos Mora, Manuel Rodríguez Yañez, Jaume Roquer González, Francisco Purroy García, Meritxell Gomis Cortina, Jaime Masjuan Vallejo, Juan Arenillas Lara, Tomás Segura Martín, José Antonio Egido Herrero, Jose Ignacio Tembl Ferrairó, Jaime Gállego Culleré, Francisco Moniche Álvarez, Anna Steinberg, Margarita Callander, Ann Charlotte Laska, Lena Bokemark, Thomas Mooe, Tor-Björn Käll, Lennart Welin, Lars Sjöblom, Joakim Hambraeus, Jörg Teichert, Hans Wannberg, Johan Sanner, Bo Ramströmer, Bo Ziedén, Stefan Olsson Hau, Claes Gustafsson, Timo Kahles, Philippe Lyrer, Marcel Arnold, Martin Liesch, Friedrich Medlin, Carlo Cereda, Georg Kägi, Andreas Luft, Emmanuel Carrera, Tsong-Hai Lee, Helen L. Po, Chang-Ming Chern, Li-Ming Lien, Lung Chan, Chung-Hsiang Liu, Shey-Lin Wu, Jiann-Der Lee, Chih-Hung Chen, Huey-Juan Lin, Ruey-Tay Lin, Wei-Hsi Chen, Yu Sun, Tasanee Tantirittisak, Sombat Muengtaweepongsa, Yongchai Nilanont, Somsak Tiamkao, Chesda Udommongkol, Kanokwan Watcharasaksilp, Witoon Jantararotai, Hadiye Sirin, Birsen Ince, Talip Asil, Murat Arsava, Tulay Kurt Incesu, Hulya Tireli, Hayriye Kucukoglu, Fikri Ak, Ali Unal, Serefnur Ozturk, Nevzat Uzuner, Galyna Chmyr, Volodymyr Lebedynets, Vadym Nikonov, Lyudmyla Shulga, Volodymyr Smolanka, Marta Khavunka, Valentyna Yavorska, Nataliya Tomakh, Olexandr Kozyolkin, Galyna Litovaltseva, Maarten Lansberg, Richard Bernstein, David Brown, Jonathan Dissin, Carmelo Graffagnino, Jonathan Harris, William Hicks, Irene Katzan, Jeffrey Kramer, Joshua Willey, Scott Silliman, Sidney Starkman, David Thaler, Margaret Tremwel, Mauricio Concha, Kumar Rajamani, Bhuvaneswari Dandapani, Brian Silver, Nathan Deal, Ira Chang, Ameer Hassan, Steven Rudolph, Kenneth Fischer, Howard Kirshner, William Logan, Sidney Mallenbaum, Hebah Hefzy, Julius Latorre, Steven Levine, Anthony Ciabarra, Rima Dafer, Benjamin Anyanwu, Laurel Cherian, Spozhmy Panezai, Anna Khanna, Jodi Dodds, Michel Torbey, James Gebel, Henry Woo, David Chiu, Xiao Androulakis, William Burgin, Maria Pineda, Engin Yilmaz, Irfan Altafullah, Christine Boutwell, Salvador Cruz-Flores, Biggya Sapkota, Pierre Fayad, Michael Jacoby, Shahid Rafiq, Efrain Salgado, Eugene Lafranchise, Warren Felton, Ramesh Madhavan, Osama Zaidat, Connie Pieper, Ralph Riviello, Aaron Burnett, Michelle Fischer, Nina Gentile, Christopher Calder, Dennis Dietrich, Jonathan Cross, Larry Blankenship, Liliana Montoya, Wendell Grogan, Mark Young, Farrukh Khan, Duane Campbell, Nizar Daboul, Andrey Espinoza, Paul Cullis, Gilberto Concepcion, John Wulff, Haider Afzal, Naseem Jaffrani, William Reiter, Tamjeed Arshad, Timothy Lukovits, James Welker, Fen Lei Chang, Aamir Badruddin, Viken Babikian, Ravi Menon, James Sander, Mellanie Springer, Ashish Nanda, Luis Mas, Raj Rajan, Bruce Silverman, David Huang, David Carpenter, Joni Clark, Marilou Ching, Sunitha Santhakumar, Jeffrey Gould, Vibhav Bansal, Gabriel Vidal, Timothy Mikesell, John Brick, William French, Qaisar Shah, Christine Holmstedt, Nadir Ishag-Osman, John Kostis, Abbas Shehadeh, Pramodkumak Sethi, Asher Imam, Carl Mccomas, Duc Tran, Mehari Gebreyohanns, Brian Wiseman, Maheen Malik, Aron Schwarcz, Dorothea Altschul, John Castaldo, Amer Alshekhlee, Stephen Gancher, Nagesh Krish, Mai Nguyen-Huynh, Margaret Tremwell, Jitendra Sharma, Lance Lee, William Neil, Fazeel Siddiqui, Ali Malek, Charles Romero, Thang Nguyen Huy, Hoa Hoang, Thang Nguyen, Anh Nguyen, Hung Nguyen, Laboratoire de Recherche Vasculaire Translationnelle ( LVTS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), AstraZeneca, National Cerebral and Cardiovascular Center ( NCCC - OSAKA ), Osaka University [Osaka], Department of Neurology ( Dep Neuro - BEIJING ), Tiantan Hospital, University of Melbourne, Faculty of Mathematics and Statistics, Ton Duc Thang University, Ho Chi Minh City, Heidelberg University, Centre hospitalier de Namur, IBM Thomas J. Watson Research Center, IBM, Bulgarian Academy of Sciences, Department of Clinical Neurological Sciences [London, Canada], University of Western Ontario ( UWO ), Servicio de Neurologia ( SANTIAGO - Neurologie ), Universidad de Santiago de Chile [Santiago] ( USACH ) -Universidad del Desarrollo, Institut de Chimie de Clermont-Ferrand - Clermont Auvergne ( ICCF ), Sigma CLERMONT ( Sigma CLERMONT ) -Université Clermont Auvergne ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Universidad de Talca, Shanghai Second Polytechnic University, Northwest Normal University [Lanzhou], Zhongda Hospital, Southeast University [Jiangsu], Cryogenics Laboratory ( CRYOGENICS LABORATORY ), Huazhong University of Science and Technology [Wuhan] ( HUST ) -Wuhan University [China], Centre for Synthetic and Systems Biology, University of Edinburgh-School of Biological Sciences, Duke university [Durham], Fiber Glass, Glass Business and Discovery Center, PPG Industries, National University of Defense Technology [Changsha], School of Oceanography [Seattle], University of Washington [Seattle], Key Laboratory of New Processing Technology for Nonferrous Metals and Materials, Guilin University of Technologie, Laboratoire de Génie Electrique et Ferroélectricité ( LGEF ), Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université de Bordeaux ( UB ), Service de Pédiatrie, Centre Hospitalier Universitaire de Nice ( CHU Nice ) -Hôpital l'Archet, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre Hospitalier de Versailles ( CHV ), Service de neurologie, Hôpital Sainte-Anne, Functional Exploration of Nervous, CHU Grenoble, Service de Neurologie [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière ( NEMESIS-CRICM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Français de Mécanique Avancée ( IFMA ), Neurologie - Côte Basque ( NEUROLOGIE ), Hopital, Laboratoire d'Intégration des Systèmes et des Technologies ( LIST ), Université Paris-Saclay-Direction de Recherche Technologique (CEA) ( DRT (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) ( GGB ), Institut Brestois Santé Agro Matière ( IBSAM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CIC Brest, Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Cavale Blanche, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Strasbourg, Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. ( ISCT ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès ( UT2J ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Neurology, Asklepios Klinik Altona, Department of Neurology and Stroke Center, Universität Duisburg-Essen [Essen], Department of Neurology, University of Mainz, Vivantes Klinikum Neukölln, University of Erlangen, University Hospital Münster, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] ( UKE ), PROTOMED, Neurology Department, Ichilov Medical Center, Internal and Cardiovascular Medicine - Stroke Unit ( PERUGIA - ICM-SU ), Università degli Studi di Perugia ( UNIPG ), University Hospital San Raffaele Milan, Scientific Institute and University Ospedale San Raffaele, Dipartimento di Scienze Fisiche, della Terra e dell'Ambiente., Università degli Studi di Siena ( UNISI ), Department of Education, Yamagata University, Nippon Medical School, Catalan Institute of Ornithology (ICO), Museu de Ciències Naturals (Zoologia), Wroclaw University of Science and Technology, Department of neurology, Jagiellonian University [Krakow] ( UJ ), LInguistique et DIdactique des Langues Étrangères et Maternelles ( LIDILEM ), Université Stendhal - Grenoble 3-Université Grenoble Alpes ( UGA ), Metacohorts Consortium, GenXpro GmBH, Lausanne University Hospital, Lausanne university hospital, Northeastern University [Boston], Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cerebral and Cardiovascular Center (NCCC - OSAKA), Department of Neurology (Dep Neuro - BEIJING), Bulgarian Academy of Sciences (BAS), University of Western Ontario (UWO), Servicio de Neurologia (SANTIAGO - Neurologie), Universidad del Desarrollo, Institut de Chimie de Clermont-Ferrand (ICCF), SIGMA Clermont (SIGMA Clermont)-Institut de Chimie du CNRS (INC)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Shanghai Polytechnic University (SSPU), Cryogenics Laboratory (CRYOGENICS LABORATORY), Huazhong University of Science and Technology [Wuhan] (HUST)-Wuhan University [China], Centre for Synthetic and Systems Biology (Ssynthsys), University of Edinburgh, Duke University [Durham], National University of Defense Technology [China], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Bordeaux (UB), Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier de Versailles André Mignot (CHV), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Français de Mécanique Avancée (IFMA), Neurologie - Côte Basque (NEUROLOGIE), Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Internal and Cardiovascular Medicine - Stroke Unit (PERUGIA - ICM-SU), Università degli Studi di Perugia (UNIPG), Università degli Studi di Siena = University of Siena (UNISI), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurologie - Côte Basque, Centre Hospitalier de la Côte Basque (CHCB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Universität Duisburg-Essen = University of Duisburg-Essen [Essen], Università degli Studi di Perugia = University of Perugia (UNIPG), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-SIGMA Clermont (SIGMA Clermont), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Jagiellonian University [Krakow] (UJ), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weimar, Christian (Beitragende*r), and Calvez, Ghislaine

Subjects
Male, Risk, Ticagrelor, Adenosine, [SDV]Life Sciences [q-bio], Population, Medizin, Hemorrhage, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Platelet aggregation inhibitors, Physiology (medical), [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Myocardial infarction, education, Stroke, ComputingMilieux_MISCELLANEOUS, Aged, Aspirin, Ischemic attack, Transient, Female, Ischemic Attack, Transient, Purinergic P2Y Receptor Antagonists, Treatment Outcome, Cardiology and Cardiovascular Medicine, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV ] Life Sciences [q-bio], Ischemic Attack, business.industry, medicine.disease, Clopidogrel, [SDV] Life Sciences [q-bio], Anesthesia, Platelet aggregation inhibitor, business, 030217 neurology & neurosurgery, TIMI, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.

Published
2017

6. Recurrent Stroke in Minor Ischemic Stroke or Transient Ischemic Attack With Metabolic Syndrome and/or Diabetes Mellitus

Author

Weiqi Chen, Yuesong Pan, Jing Jing, Xingquan Zhao, Liping Liu, Xia Meng, Yilong Wang, Yongjun Wang, S. Claiborne Johnston, Zhimin Wang, Haiqin Xia, Bin Li, Guiru Zhang, Xudong Ren, Chunling Ji, Guohua Zhang, Jianhua Li, Bohua Lu, Liping Wang, Shutao Feng, Dali Wang, Weiguo Tang, Juntao Li, Hongtian Zhang, Guanglai Li, Baojun Wang, Yuhua Chen, Ying Lian, Bin Liu, Junfang Teng, Rubo Sui, Lejun Li, Zhiling Yuan, Dawei Zang, Zuneng Lu, Li Sun, Dong Wang, Liying Hou, Dongcai Yuan, Yongliang Cao, Hui Li, Xiuge Tan, Huicong Wang, Haisong Du, Mingyi Liu, Suping Wang, Qiuwu Liu, Zhong Zhang, Qifu Cui, Runqing Wang, Jialin Zhao, Jiewen Zhang, Jianping Zhao, Qi Bi, Xiyou Qi, Junyan Liu, Changxin Li, Ling Li, Xiaoping Pan, Junling Zhang, Derang Jiao, Zhao Han, Dawei Qian, Jin Xiao, Yan Xing, Huishan Du, Guang Huang, Yongqiang Cui, Yan Li, Lianyuan Feng, Lianbo Gao, Bo Xiao, Yibin Cao, Yiping Wu, Jinfeng Liu, Zhiming Zhang, Zhengxie Dong, Limin Wang, Li He, Xinchen Wang, Xueying Guo, Ming Wang, Xiaosha Wang, Jiandong Jiang, Renliang Zhao, Shengnian Zhou, Hao Hu, Maolin He, Fengchun Yu, Quping Ouyang, Jingbo Zhang, Anding Xu, Xiaokun Qi, Lei Wang, Fuming Shi, Fuqiang Guo, Jianfeng Wang, Fengli Zhao, Ronghua Dou, Dongning Wei, Qingwei Meng, Yilu Xia, Shimin Wang, Zhangcang Xue, Yuming Xu, Liping Ma, Chun Wang, Jiang Wu, Yifeng Du, Yinzhou Wang, Lijun Xiao, Fucong Song, Wenli Hu, Zhigang Chen, Qingrui Liu, Jiemin Zhang, Mei Chen, Xiaodong Yuan, Zhihui Liu, Guozhong Li, Xiaohong Li, and Tingchen Tian

Subjects
Blood Glucose, Male, Time Factors, 030204 cardiovascular system & hematology, Brain Ischemia, Brain ischemia, 0302 clinical medicine, Recurrence, Risk Factors, Stroke, Original Research, Hazard ratio, Middle Aged, Clopidogrel, Lipids, Ischemic Attack, Transient, Cardiology, Platelet aggregation inhibitor, Female, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, China, Risk Assessment, metabolic syndrome, 03 medical and health sciences, Double-Blind Method, Internal medicine, Diabetes mellitus, medicine, Diabetes Mellitus, Humans, Propensity Score, Aged, Proportional Hazards Models, Ischemic Stroke, Chi-Square Distribution, Proportional hazards model, business.industry, medicine.disease, Logistic Models, Multivariate Analysis, Physical therapy, prognosis, Metabolic syndrome, business, 030217 neurology & neurosurgery, Biomarkers, Platelet Aggregation Inhibitors
Abstract

Background We aimed to determine the risk conferred by metabolic syndrome ( METS ) and diabetes mellitus ( DM ) to recurrent stroke in patients with minor ischemic stroke or transient ischemic attack from the CHANCE (Clopidogrel in High‐risk patients with Acute Non‐disabling Cerebrovascular Events) trial. Methods and Results In total, 3044 patients were included. Patients were stratified into 4 groups: neither, METS only, DM only, or both. METS was defined using the Chinese Diabetes Society ( CDS ) and International Diabetes Foundation ( IDF ) definitions. The primary outcome was new stroke (including ischemic and hemorrhagic) at 90 days. A multivariable Cox regression model was used to assess the relationship of METS and DM status to the risk of recurrent stroke adjusted for potential covariates. Using the CDS criteria of METS , 53.2%, 17.2%, 19.8%, and 9.8% of patients were diagnosed as neither, METS only, DM only, and both, respectively. After 90 days of follow‐up, there were 299 new strokes (293 ischemic, 6 hemorrhagic). Patients with DM only (16.1% versus 6.8%; adjusted hazard ratio 2.50, 95% CI 1.89–3.39) and both (17.1% versus 6.8%; adjusted hazard ratio 2.76, 95% CI 1.98–3.86) had significantly increased rates of recurrent stroke. No interaction effect of antiplatelet therapy by different METS or DM status for the risk of recurrent stroke ( P =0.82 for interaction in the fully adjusted model of CDS ) was observed. Using the METS ( IDF ) criteria demonstrated similar results. Conclusions Concurrent METS and DM was associated with an increased risk of recurrent stroke in patients with minor stroke and transient ischemic attack.

Published
2017

7. A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease

Author

Peng Feng, Chenhui Ji, Guo-Fang Xue, Ziyue Yuan, Christian Hölscher, Dongfang Li, and Guanglai Li

Subjects
0301 basic medicine, Agonist, Blood Glucose, Male, medicine.medical_specialty, endocrine system, Parkinson's disease, medicine.drug_class, Dopamine, Substantia nigra, Motor Activity, Neuroprotection, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Glial cell line-derived neurotrophic factor, Medicine, Animals, Glial Cell Line-Derived Neurotrophic Factor, Pharmacology, Inflammation, biology, Tyrosine hydroxylase, Hand Strength, business.industry, Liraglutide, MPTP, Body Weight, Calcium-Binding Proteins, Microfilament Proteins, Brain, Parkinson Disease, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Rotarod Performance Test, biology.protein, business, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, medicine.drug
Abstract

Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25 mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.

Published
2017

8. The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model of stroke

Author

Xiaoyan Yang, Guanglai Li, Dongfang Li, Peng Feng, Chenhui Ji, Rui-Fang Wang, Christian Hölscher, and Xiangjian Zhang

Subjects
0301 basic medicine, medicine.medical_specialty, Doublecortin Protein, Proto-Oncogene Proteins c-jun, Neurogenesis, Glucagon-Like Peptides, Apoptosis, Inflammation, Motor Activity, Hippocampal formation, Hippocampus, p38 Mitogen-Activated Protein Kinases, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Glucagon-Like Peptide 1, Internal medicine, medicine, Animals, Hypoglycemic Agents, Stroke, Mitogen-Activated Protein Kinase Kinases, Neurons, Pharmacology, Mitogen-Activated Protein Kinase 3, Microglia, business.industry, Cerebral infarction, Dentate gyrus, Semaglutide, Transcription Factor RelA, Brain, Infarction, Middle Cerebral Artery, medicine.disease, Rats, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Insulin Receptor Substrate Proteins, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Stroke is a condition with few medical treatments available. Semaglutide, a novel Glucagon-like peptide-1 (GLP-1) analogue, has been brought to the market as a treatment for diabetes. We tested the protective effects of semaglutide against middle cerebral artery occlusion injury in rats. Animals were treated with 10 nmol/kg bw ip. starting 2 h after surgery and every second day for either 1, 7, 14 or 21 days. Semaglutide-treated animals showed significantly reduced scores of neurological impairments in several motor and grip strength tasks. The cerebral infarction size was also reduced, and the loss of neurons in the hippocampal areas CA1, CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and in the activity of the p38 MAPK – MKK – c-Jun- NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX and Caspase-3 was observed. Neurogenesis had also been normalized by the drug treatment as seen in increased neurogenesis (DCX-positive cells) in the dentate gyrus and a normalization of biomarkers for neurogenesis. In conclusion, semaglutide is a promising candidate for re-purposing as a stroke treatment.

Published
2019
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9. A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson′s disease by increasing expression of BNDF

Author

Guo-Fang Xue, Chenhui Ji, Dongfang Li, Peng Feng, Guanglai Li, Cao Lijun, Lin Li, and Christian Hölscher

Subjects
Male, 0301 basic medicine, Agonist, medicine.medical_specialty, endocrine system, Parkinson's disease, Tyrosine 3-Monooxygenase, medicine.drug_class, Incretin, Apoptosis, Substantia nigra, Motor Activity, Neuroprotection, Glucagon-Like Peptide-1 Receptor, Receptors, Gastrointestinal Hormone, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Parkinsonian Disorders, Internal medicine, Animals, Medicine, Muscle Strength, Molecular Biology, Protein kinase B, Neurons, Tyrosine hydroxylase, business.industry, Brain-Derived Neurotrophic Factor, General Neuroscience, MPTP, medicine.disease, Corpus Striatum, Mice, Inbred C57BL, Substantia Nigra, Disease Models, Animal, Neuroprotective Agents, 030104 developmental biology, Endocrinology, chemistry, Rotarod Performance Test, Neurology (clinical), business, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.

Published
2016
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10. Time course of heme oxygenase-1 and oxidative stress after experimental intracerebral hemorrhage

Author

Guanglai Li, Zhitang Sun, Qingping Tang, Weimin Hu, Qidong Yang, Li Wang, Gaiqing Wang, and Dongfang Li

Subjects
Male, medicine.medical_specialty, Time Factors, Antioxidant, medicine.medical_treatment, Pharmacology, medicine.disease_cause, Rats, Sprague-Dawley, Superoxide dismutase, chemistry.chemical_compound, Animals, Medicine, cardiovascular diseases, Heme, Cerebral Hemorrhage, Intracerebral hemorrhage, biology, business.industry, Malondialdehyde, medicine.disease, Rats, nervous system diseases, Surgery, Heme oxygenase, Reverse transcription polymerase chain reaction, Disease Models, Animal, Oxidative Stress, chemistry, Heme Oxygenase (Decyclizing), Nerve Degeneration, biology.protein, Female, Neurology (clinical), business, Oxidative stress
Abstract

Heme oxygenase-1 (HO-1), the rate-limiting enzyme for heme catabolism and iron production, its role in intracerebral hemorrhage (ICH) is controversial. The study was to investigate correlations between brain oxidative injury and HO-1 after experimental ICH.Sprague-Dawley rats received intra-striatal infusions of 100 μl autologous whole blood as ICH models. HO-1 were examined by immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) analysis. Brain oxidative stress was quantitated by malondialdehyde (MDA); antioxidation were measured by copper-zinc superoxide dismutase (Cu/Zn-SOD) activity using RT-PCR assay.The expression of the HO-1 upregulated and reached its peak at days 3 and 7 after ICH (P 0.01). There was a significant increase of MDA and a top at 3-day post-ICH (P 0.01); Cu/Zn-SOD was upregulated post-ICH and reached the top at day 7 (P 0.001); HO-1 was correlated significantly with brain MDA content at days 7 and 14 following ICH (r = 0.435-0.501, P 0.001) but there is no definite correlation between them on 1 to 3 days (P 0.05); conversely, HO-1 was correlated significantly with Cu/Zn-SOD on 1 to 3 days after ICH (r = 0.433-0.621, P 0.001) but there is no definite correlation between them at days 7 and 14 (P 0.05).HO-1 has both antioxidant and prooxidant properties in ICH. The early upregulation of HO-1 possibly fit with the events and be protective against oxidative stress, whereas its overexpression in the late stages may result in its dysfunction and be toxic. So it should be prudent to intervene ICH with the inhibitor/activator of HO-1.

Published
2010
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11. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Author

Jaishree Jalewa, Lin Li, Weizhen Liu, Guanglai Li, Christian Hölscher, and Mohit K. Sharma

Subjects
Male, medicine.medical_specialty, Parkinson's disease, Tyrosine 3-Monooxygenase, Incretin, Apoptosis, Substantia nigra, Motor Activity, Neuroprotection, Basal Ganglia, Mice, Lixisenatide, chemistry.chemical_compound, Parkinsonian Disorders, Internal medicine, medicine, Animals, Catalepsy, Tyrosine hydroxylase, Venoms, business.industry, Liraglutide, Dopaminergic Neurons, General Neuroscience, MPTP, medicine.disease, Mice, Inbred C57BL, Substantia Nigra, Disease Models, Animal, Neuroprotective Agents, Endocrinology, chemistry, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Rotarod Performance Test, Exenatide, Peptides, business, medicine.drug
Abstract

Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a longer biological half-life than exendin-4. We previously showed that these drugs have neuroprotective properties in an animal model of Alzheimer's disease. Here we demonstrate the neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20mg/kg i.p.) for 7 days, and drugs were injected once-daily for 14 days i.p. When comparing exendin-4 (10 nmol/kg), liraglutide (25 nmol/kg) and lixisenatide (10 nmol/kg), it was found that exendin-4 showed no protective effects at the dose chosen. Both liraglutide and lixisenatide showed effects in preventing the MPTP-induced motor impairment (Rotarod, open-field locomotion, catalepsy test), reduction in tyrosine hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, a reduction of the pro-apoptotic signaling molecule BAX and an increase in the anti-apoptotic signaling molecule B-cell lymphoma-2. The results demonstrate that in this study, both liraglutide and lixisenatide are superior to exendin-4, and both drugs show promise as a novel treatment of PD.

Published
2015
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12. Neuroprotective effects of geniposide on Alzheimer's disease pathology

Author

Weizhen Liu, Lin Li, Christian Hölscher, and Guanglai Li

Subjects
Agonist, Neurite, business.industry, medicine.drug_class, General Neuroscience, Type 2 Diabetes Mellitus, Disease, Pharmacology, medicine.disease_cause, Neuroprotection, Neuroprotective Agents, Diabetes Mellitus, Type 2, Alzheimer Disease, Chronic inflammatory response, Medicine, Animals, Humans, Iridoids, Signal transduction, business, Neuroscience, Oxidative stress
Abstract

A growing body of evidence has linked two of the most common aged-related diseases: type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon-like peptide-1 (GLP-1R), which is a newer drug class to treat T2DM, geniposide shows clear effects in inhibiting pathological processes underlying AD, such as promoting neurite outgrowth. In the present article, we review the possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting τ phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD.

Published
2015

13. Diffusion of actin filaments within a thin layer between two walls

Author

Guanglai Li and Jay X. Tang

Subjects
Materials science, business.industry, Microfluidics, Rotational diffusion, Apparent viscosity, Molecular physics, Actins, Diffusion, Solutions, Physics::Fluid Dynamics, Protein filament, Diffusion layer, Motion, Optics, Models, Chemical, Cylinder, Particle, Computer Simulation, Diffusion (business), Hydrodynamic theory, business
Abstract

Diffusion of the protein filaments F -actin confined in a thin layer between two walls is studied using the methods of single filament fluorescence imaging and particle tracking. The translational and rotational diffusion coefficients are measured for F -actin of lengths in the range of 1.5-5 microm. The length dependence of the measured diffusion coefficients is consistent with the predicted two-dimensional projection of the diffusion of a cylinder in an unbounded fluid. Fits based on the formulas for diffusion in the bulk fluid yield higher apparent viscosity values than that of the buffer solution by a factor of 2 for a layer thickness between 0.7 and 1.6 microm. We show that the measured results can be accounted for by correction based on the hydrodynamic theory of a long cylinder between confining walls.

Published
2004
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