Article
Chemistry, Medicinal
Takahiro Akasaka, Hiroyuki Watanabe, Sho Kaide, Shimpei Iikuni, Masato Hasegawa, Masahiro Ono
Summary: Aggregation of alpha-synuclein (alpha-syn) is involved in neurodegenerative diseases, but the underlying mechanisms are not fully understood. This study developed and synthesized four radioiodinated phenylbenzofuranone (PBF) derivatives as potential alpha-syn imaging probes. Although these compounds showed high binding affinity for alpha-syn aggregates, their uptake in the brain was insufficient for in vivo imaging. Further modifications are needed to improve brain uptake, but PBF derivatives have the potential as alpha-syn imaging probes.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Xianwei Sun, Prasad Admane, Zbigniew A. Starosolski, Jason L. Eriksen, Ananth Annapragada, Eric A. Tanifum
Summary: The study focused on developing new imaging agents for in vivo detection of alpha-synuclein pathologies by designing and synthesizing novel derivatives. The results showed that two lead compounds exhibited high affinity and selectivity for alpha-syn fibrils, selectively labeling all forms of alpha-syn on PD brain tissue sections.
Article
Chemistry, Medicinal
Qi Zeng, Sen Liu, Mengchao Cui
Summary: In this study, a series of cyano-substituted indole derivatives were synthesized and evaluated for their binding potency to α-syn fibrils. Compound 51 showed promising affinity to α-syn fibrils and exhibited moderate brain uptake in normal mice. These results suggest that [I-125]51 has potential as an α-syn imaging probe, but further development is necessary.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Anton B. Matiiv, Svetlana E. Moskalenko, Olga S. Sergeeva, Galina A. Zhouravleva, Stanislav A. Bondarev
Summary: The NOS1AP gene encodes a protein that binds to nNOS and is associated with various disorders. It interacts with alpha-synuclein, suggesting its involvement in synucleinopathies and the relationship between Parkinson's disease and schizophrenia. The molecular mechanisms of these disorders may involve aggregation and misfolding of NOS1AP.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Jiang Bian, Yi-Qi Liu, Jie He, Xin Lin, Chen-Yang Qiu, Wen-Bo Yu, Yan Shen, Ze-Yun Zhu, De-Yong Ye, Jian Wang, Yong Chu
Summary: Parkinson's disease is the second most common neurodegenerative disorder, and early diagnosis remains a challenge in clinical practice. Research on novel alpha-synuclein aggregates ligands has shown promising potential for early diagnosis. Synthesized styrylaniline derivatives displayed good potency to alpha-synuclein aggregates, suggesting their use in further development for in vivo imaging agents.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Radiology, Nuclear Medicine & Medical Imaging
Laura Kuebler, Sabrina Buss, Andrei Leonov, Sergey Ryazanov, Felix Schmidt, Andreas Maurer, Daniel Weckbecker, Anne M. Landau, Thea P. Lillethorup, Daniel Bleher, Ran Sing Saw, Bernd J. Pichler, Christian Griesinger, Armin Giese, Kristina Herfert
Summary: The newly developed MODAG-001 PET tracer based on anle138b showed high affinity in vitro and good penetration and stability in the mouse brain. However, no detectable binding to aggregated alpha SYN was found in human brain sections of LBD cases, possibly due to low abundance of aggregated alpha SYN against background protein.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2021)
Article
Clinical Neurology
Laura Calo, Eric Hidari, Michal Wegrzynowicz, Jeffrey W. Dalley, Bernard L. Schneider, Martyna Podgajna, Oleg Anichtchik, Emma Carlson, David Klenerman, Maria Grazia Spillantini
Summary: Aggregation of alpha-synuclein at the synapse is associated with reduced levels of synaptic CSP alpha, impacting neurotransmission and synaptic function. Interventions involving CSP alpha can rescue the related phenotypes, suggesting CSP alpha as a potential therapeutic target for early-stage Parkinson's disease.
Review
Biochemistry & Molecular Biology
Qi Zeng, Mengchao Cui
Summary: The accurate tracking of alpha-Synuclein is crucial for the diagnosis, monitoring, and drug development of neurological disorders such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. However, there is currently a lack of effective alpha-Synuclein targeting probes for clinical application. This overview discusses potential probes that have been reported in the past two decades and provides insights into the current status and future prospects of developing alpha-Synuclein targeting probes.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Hamdam Hourfar, Farhang Aliakbari, Shabboo Rahimi Aqdam, Zahra Nayeri, Hassan Bardania, Daniel E. Otzen, Dina Morshedi
Summary: The blood-brain barrier (BBB) controls the movement of biomolecules and protects the brain, but it can be compromised by the accumulation of alpha-synuclein aggregates (alpha SN-AGs) seen in Parkinson's disease (PD). In this study, in vitro co-culturing models were used to investigate how alpha SN-AGs affect the BBB. The results showed that alpha SN-AGs compromised the endothelial cells, leading to decreased viability, membrane potential, wound healing activity, TEER value, and increased permeability. However, co-culturing with astrocytes or dopaminergic neurons, or treatment with their conditioned media, increased resistance against alpha SN-AGs.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Cell Biology
Fide Sevgi, Eva M. Brauchle, Daniel A. Carvajal Berrio, Katja Schenke-Layland, Nicolas Casadei, Madhuri S. Salker, Olaf Riess, Yogesh Singh
Summary: Parkinson's disease is characterized by the formation of Lewy bodies in the brain, containing aggregated alpha-Synuclein. Raman imaging technology can detect alpha-Synuclein aggregates in colon tissues, showing promise as a useful tool in PD pathology research.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Kelly E. Glajch, Tim E. Moors, Yi Chen, Pascal A. Bechade, Alice Y. Nam, Molly M. Rajsombath, Thomas D. McCaffery, Ulf Dettmer, Andreas Weihofen, Warren D. Hirst, Dennis J. Selkoe, Silke Nuber
Summary: Loss-of-function mutations in GBA1 are strong genetic risk factors for Lewy body disorders, enhancing GCase activity can improve αS dyshomeostasis and reduce lipid-rich aggregates, ameliorating PD-like phenotypes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Peizhou Jiang, Ming Gan, Shu-Hui Yen, Dennis W. Dickson
Summary: Nanoparticles may induce cells to form inclusions of Parkinson's disease-related protein α S, and smaller nanoparticles can lead to more inclusion formation. Additionally, the induction of α S inclusions by nanoparticles may partly depend on endolysosomal impairment and the affinity of α S to nanoparticles.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Biochemical Research Methods
Riza Dervisoglu, Leif Antonschmidt, Evgeny Nimerovsky, Vrinda Sant, Myeongkyu Kim, Sergey Ryazanov, Andrei Leonov, Juan Carlos Fuentes-Monteverde, Melanie Wegstroth, Karin Giller, Guinevere Mathies, Armin Giese, Stefan Becker, Christian Griesinger, Loren B. Andreas
Summary: Small molecules that bind to oligomeric protein species are important for clinical applications. However, determining the binding sites at atomic resolution can be challenging due to low binding stoichiometry. In this study, solid-state NMR with dynamic nuclear polarization (DNP) was used to identify atomic contacts between the protein and the small molecule at sub nm distance. The approach was applied to alpha-synuclein aggregates in complex with the small molecule anle138b, revealing differences in contacts between fibrils and early intermediates.
Article
Chemistry, Physical
Priscila Baltazar Goncalves, Fernando L. Palhano, Yraima Cordeiro, Ana Carolina Renno Sodero
Summary: The misfolding and aggregation of α-synuclein is a pathological hallmark of Parkinson's disease. Epigallocatechin-3-gallate (EGCG) can prevent the formation of toxic aggregates and remodel existing toxic fibrils into non-toxic aggregates. Through molecular docking and dynamics simulations, the study investigates the interactions of oxidized EGCG and Thioflavin T with mature α-syn fibrils.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2023)
Article
Chemistry, Medicinal
Kohei Nakagawa, Hiroyuki Watanabe, Sho Kaide, Masahiro Ono
Summary: Synucleinopathies are characterized by the deposition of alpha-synuclein aggregates before clinical symptoms. In this study, 16 quinoline/quinoxaline derivatives were evaluated to develop an alpha-synuclein imaging probe. Among them, SQ3 showed moderate selectivity for alpha-synuclein aggregates and high binding affinity. [18F]SQ3 exhibited high uptake in a normal mouse brain and has potential as a lead compound for an alpha-synuclein imaging probe.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Clinical Neurology
Daisuke Yoshii, Takashi Ayaki, Takafumi Wada, Akihiko Ozaki, Toru Yamamoto, Yoshimi Miyagi, Hideto Senzaki, Ryosuke Takahashi
Summary: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease with main symptoms of dementia or limb weakness, while some patients may experience encephalitic episodes and transient neurological symptoms. Pathological findings suggest that blood-brain barrier impairment and dysregulation of blood flow may be related to the acute, transient symptoms observed in NIID.
Editorial Material
Cardiac & Cardiovascular Systems
Masafumi Ihara
CIRCULATION RESEARCH
(2022)
News Item
Clinical Neurology
Masafumi Ihara, Yumi Yamamoto
Summary: Single-cell transcriptomic analyses of human brain microvessels have identified transcriptomic signatures and transcriptional changes in the cerebrovasculature in neurodegenerative diseases, which could significantly contribute to our understanding of brain health and disease.
NATURE REVIEWS NEUROLOGY
(2022)
Article
Clinical Neurology
Junpei Koge, Kanta Tanaka, Takeshi Yoshimoto, Masayuki Shiozawa, Yuji Kushi, Tsuyoshi Ohta, Tetsu Satow, Hiroharu Kataoka, Masafumi Ihara, Masatoshi Koga, Noriko Isobe, Kazunori Toyoda
Summary: Tortuosity of the internal carotid artery (ICA) affects the outcomes of mechanical thrombectomy, with lower first pass effect rate and higher risk of intracranial hemorrhage in patients with greater tortuosity.
Article
Clinical Neurology
Kanta Tanaka, Masatoshi Koga, Mayumi Fukuda-Doi, Adnan Qureshi, Haruko Yamamoto, Kaori Miwa, Masafumi Ihara, Kazunori Toyoda
Summary: This study used group-based trajectory modeling to analyze blood pressure changes in patients with acute intracerebral hemorrhage receiving antihypertensive treatment, and found that different blood pressure trajectories were associated with different outcomes. Specifically, the high-to-low SBP group showed increased risks of death or disability and acute kidney injury.
Article
Clinical Neurology
Takeshi Yoshimoto, Kazunori Toyoda, Masafumi Ihara, Hiroshi Inoue, Takeshi Yamashita, Shinya Suzuki, Masaharu Akao, Hirotsugu Atarashi, Takanori Ikeda, Ken Okumura, Yukihiro Koretsune, Wataru Shimizu, Hiroyuki Tsutsui, Atsushi Hirayama, Masahiro Yasaka, Hirofumi Maruyama, Satoshi Teramukai, Tetsuya Kimura, Yoshiyuki Morishima, Atsushi Takita, Takenori Yamaguchi
Summary: The history of stroke/TIA in elderly patients increases the risk of stroke, bleeding, and death. Among patients with prior ischemic stroke/TIA, taking direct oral anticoagulants reduces the risk of bleeding events.
Article
Cardiac & Cardiovascular Systems
Takashi Okada, Takeshi Yoshimoto, Shinichi Wada, Sohei Yoshimura, Tetsuya Chiba, Shuhei Egashira, Shunsuke Kimura, Masayuki Shiozawa, Manabu Inoue, Masafumi Ihara, Kazunori Toyoda, Hiroshi Takashima, Masatoshi Koga
Summary: This study aimed to evaluate the safety of treatment with alteplase at 0.6 mg/kg within 24 hours for patients on direct oral anticoagulants (DOACs) before ischemic stroke onset. The results suggest that intravenous thrombolysis can be safely performed for DOACs patients following the recommendations of the guidelines.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2022)
Review
Clinical Neurology
Yumi Yamamoto, Yi-Chu Liao, Yi-Chung Lee, Masafumi Ihara, Jay Chol Choi
Summary: CADASIL is the most common monogenic disorder of the cerebral small blood vessels, caused by mutations in the NOTCH3 gene. Recent large-scale genomic studies have revealed a high prevalence of pathogenic NOTCH3 variants among the general population, with the highest risk being among Asians. The exact pathogenesis of CADASIL remains unclear, despite various laboratory and clinical observations being made.
JOURNAL OF CLINICAL NEUROLOGY
(2023)
Article
Nutrition & Dietetics
Takayuki Inoue, Bin Fu, Miwako Nishio, Miyako Tanaka, Hisashi Kato, Masashi Tanaka, Michiko Itoh, Hajime Yamakage, Kozue Ochi, Ayaka Ito, Yukihiro Shiraki, Satoshi Saito, Masafumi Ihara, Hideo Nishimura, Atsuhiko Kawamoto, Shian Inoue, Kumiko Saeki, Atsushi Enomoto, Takayoshi Suganami, Noriko Satoh-Asahara
Summary: The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) involves metabolic stress and inflammatory stimuli. In this study, we found that Taxifolin treatment effectively prevented hepatic steatosis, chronic inflammation, and liver fibrosis in a NASH murine model. Taxifolin inhibited lipid accumulation in hepatocytes and increased brown adipose tissue activity. Furthermore, Taxifolin treatment after NASH development could prevent the development of liver tumors. These findings indicate the pleiotropic effects of Taxifolin for NASH treatment.
Editorial Material
Biochemistry & Molecular Biology
Hiroyuki Ishiyama, Masafumi Ihara
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Nutrition & Dietetics
Masayo Iwasa, Hisashi Kato, Kaori Iwashita, Hajime Yamakage, Sayaka Kato, Satoshi Saito, Masafumi Ihara, Hideo Nishimura, Atsuhiko Kawamoto, Takayoshi Suganami, Masashi Tanaka, Noriko Satoh-Asahara
Summary: This study found that a high-glucose environment can increase intracellular reactive oxygen species (ROS) levels and trigger inflammation in microglial cells, leading to cognitive impairment in diabetes. However, taxifolin, a natural flavonoid, has been shown to reduce ROS levels and inhibit the activation of the TXNIP-NLRP3 axis, thereby suppressing inflammation and preventing cognitive impairment in diabetes.
Letter
Clinical Neurology
Yoshito Arakaki, Takeshi Yoshimoto, Hiroyuki Ishiyama, Tomotaka Tanaka, Yorito Hattori, Masafumi Ihara
JOURNAL OF MOVEMENT DISORDERS
(2023)
Article
Health Care Sciences & Services
Satoshi Suda, Takehiro Katano, Kazuo Kitagawa, Yasuyuki Iguchi, Shigeru Fujimoto, Kenjiro Ono, Osamu Kano, Hidehiro Takekawa, Masatoshi Koga, Masafumi Ihara, Masafumi Morimoto, Hiroshi Yamagami, Tadashi Terasaki, Keiji Yamaguchi, Seiji Okubo, Yuji Ueno, Nobuyuki Ohara, Yuki Kamiya, Masataka Takeuchi, Yukako Yazawa, Yuka Terasawa, Ryosuke Doijiri, Yoshifumi Tsuboi, Kazutaka Sonoda, Koichi Nomura, Takashi Shimoyama, Akihito Kutsuna, Kazumi Kimura
Summary: This study aims to evaluate the proportion, timing, and characteristics of atrial fibrillation (AF) detection in patients with cryptogenic stroke (CS) using insertable cardiac monitors (ICMs). It also aims to compare patient characteristics and outcomes between those with AF and those without AF. The study has started and the main results are expected to be published in 2023. The findings of this study will contribute to the identification of AF markers and the development of a new and improved screening algorithm for AF detection, as well as aiding in the selection of patients for ICM implantation and the development of diagnostic criteria for CS in Japan.
JMIR RESEARCH PROTOCOLS
(2023)
Article
Clinical Neurology
Takehito Kuroda, Tomotaka Tanaka, Soichiro Abe, Manabu Inoue, Yoshiaki Morita, Takuto Mukaida, Takamasa Iwai, Masafumi Ihara
EPILEPTIC DISORDERS
(2023)
Article
Medicine, General & Internal
Satoshi Suda, Chikako Nito, Masafumi Ihara, Yasuyuki Iguchi, Takao Urabe, Yuji Matsumaru, Nobuyuki Sakai, Kazumi Kimura
Summary: This study aims to evaluate the safety and efficacy of a novel cell-based therapy product called JTR-161 for patients with acute ischemic stroke. The study will be conducted in Japan and will use a randomized, double-blind, placebo-controlled design. The results of the study will be disseminated through informed consent forms and peer-reviewed publication.
