Article
Neurosciences
Lara Costa, Alessandra Tempio, Enza Lacivita, Marcello Leopoldo, Lucia Ciranna
Summary: The study demonstrates that Cdk5 modulates hippocampal synaptic plasticity, with 5-HT7 receptors requiring Cdk5 to regulate synaptic plasticity and rescue abnormal plasticity in Fmr1 KO neurons. This suggests that Cdk5 could be a novel target in Fragile X Syndrome.
EUROPEAN JOURNAL OF NEUROSCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Jieon Lee, Diana Avramets, Byungsun Jeon, Hyunah Choo
Summary: Recent studies suggest that 5-HT7R could be a potential therapeutic target for the treatment of neurodevelopmental disorders by affecting neuronal morphology and modulating behavioral symptoms, offering a new approach to treating NDDs.
Review
Neurosciences
Luis A. Milla, Lucia Corral, Jhanpool Rivera, Nolberto Zuniga, Gabriela Pino, Alexia Nunez-Parra, Christian A. Cea-Del Rio
Summary: Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by the mutation and silencing of the FMR1 gene, leading to loss of FMRP expression. FXS is characterized by abnormal regulation of neuronal development, resulting in cognitive and behavioral phenotypes. This review highlights the importance of therapeutically targeting critical developmental periods, such as early postnatal stages, and discusses the past and current clinical trials in FXS. The potential benefits, limitations, and disadvantages of pharmacological approaches are also discussed based on preclinical and clinical research.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Kouji Fukuyama, Eishi Motomura, Motohiro Okada
Summary: This study investigates the effects of Brexpiprazole on protein expression, intracellular signaling, and cAMP levels in astrocytes and rat hypothalamus. The results suggest that Brexpiprazole has complex pharmacological features, with partial agonistic action on 5-HT1AR and inverse agonist-like action on 5-HT7R. The suppressive effects of Brexpiprazole on 5-HT7R play an important role in its antidepressive and mood-stabilizing actions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Scheila Daiane Schmidt, Carolina Garrido Zinn, Lorena Evelyn Cavalcante, Flavia Fagundes Ferreira, Cristiane Regina Guerino Furini, Ivan Izquierdo, Jociane De Carvalho Myskiw
Summary: Social recognition, crucial for social group establishment, reproduction, and species survival, relies on the consolidation of social stimuli in long-term memory. This study reveals the involvement of specific serotonin receptors in the consolidation of social recognition memory, shedding light on the molecular mechanisms underlying this process.
Article
Biochemistry & Molecular Biology
Luisa Speranza, Kardelen Dalim Filiz, Sarah Goebel, Carla Perrone-Capano, Salvatore Pulcrano, Floriana Volpicelli, Anna Francesconi
Summary: Structural, functional, and molecular alterations in excitatory spines are common in neurodevelopmental disorders. The researchers developed a method using DiI and immunofluorescence to characterize spines in native brain tissue. They found that mutant mice with Fragile X Syndrome displayed dysgenesis of spines, including an overabundance of abnormally elongated thin spines and cup-shaped spines.
Article
Neurosciences
B. Di Marco, P. Dell'Albani, S. D'Antoni, M. Spatuzza, C. M. Bonaccorso, S. A. Musumeci, F. Drago, B. Bardoni, M. V. Catania
Summary: The study found a novel modulatory role of mGlu5 receptor in SGs formation, providing new perspectives for understanding cellular response to stress in FXS pathophysiology.
NEUROBIOLOGY OF DISEASE
(2021)
Review
Genetics & Heredity
Aadil Yousuf, Nadeem Ahmed, Abrar Qurashi
Summary: Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X syndrome (FXS) are distinct disorders caused by abnormal expansion of CGG repeats. FXTAS is a neurodegenerative disorder characterized by gene hyperexpression, while FXS is a neurodevelopmental disorder characterized by gene silencing. Non-canonical DNA and RNA structures formed from CGG repeat expansions can disrupt cellular processes and have different effects in these two disorders.
FRONTIERS IN GENETICS
(2022)
Article
Neurosciences
Jesus David Urbano-Gamez, Juan Jose Casanas, Itziar Benito, Maria Luz Montesinos
Summary: Down syndrome (DS) is associated with memory deficits due to hippocampal-related issues, with experimental models showing alterations in synaptic plasticity pathways. Enhanced mGluR-LTD and increased mushroom spines in hippocampal neurons in Ts1Cje mice contribute to memory deficits. Prenatal rapamycin treatment shows positive effects on both phenotypes, suggesting therapeutic potential for DS intellectual disability.
Article
Neurosciences
Kaleb Dee Miles, Caleb Andrew Doll
Summary: Developmental changes in ionic balance play a crucial role in neural circuit formation. The shift of GABAergic neurotransmission from depolarizing to hyperpolarizing output is induced by changes in Cl- gradients and is delayed in Fragile X syndrome (FXS) models. The absence of FMRP protein, which regulates chloride transporter expression, can significantly impact FXS phenotypes. This perspective summarizes the expression of Cl- transporters and discusses the imbalances in inhibitory neurotransmission in FXS, highlighting potential therapeutic strategies.
FRONTIERS IN NEUROSCIENCE
(2022)
Review
Cell Biology
Rob Willemsen, R. Frank Kooy
Summary: Fragile X-related disorders are caused by expanded CGG repeats in the FMR1 gene and can manifest as either neurodegenerative or neurodevelopmental disorders. Mouse models have provided valuable insights into these disorders and their translational value for developing targeted therapies for intellectual disability and autism disorders.
DISEASE MODELS & MECHANISMS
(2023)
Article
Multidisciplinary Sciences
Ha Eun Kong, Junghwa Lim, Alexander Linsalata, Yunhee Kang, Indranil Malik, Emily G. Allen, Yiqu Cao, Lisa Shubeck, Rich Johnston, Yanting Huang, Yanghong Gu, Xiangxue Guo, Michael E. Zwick, Zhaohui Qin, Thomas S. Wingo, Jorge Juncos, David L. Nelson, Michael P. Epstein, David J. Cutler, Peter K. Todd, Stephanie L. Sherman, Stephen T. Warren, Peng Jin
Summary: This study identified Prosbeta5 (PSMB5) as a candidate genetic modifier for FXTAS using a Drosophila model. Knockdown of PSMB5 suppressed CGG-associated neurodegeneration in flies and cells. Additionally, an expression quantitative trait locus variant in PSMB5 was associated with delayed onset of FXTAS in human carriers. These findings suggest a therapeutic strategy for FXTAS by targeting PSMB5.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Neurosciences
Nicole K. Morrill, Aurelie Joly-Amado, Qingyou Li, Sahana Prabhudeva, Edwin J. Weeber, Kevin R. Nash
Summary: This study found that the reduction in Reelin may be related to FXS, and enhancing the Reelin signaling successfully rescued cognitive deficits in FXS mice, providing a feasible therapeutic approach.
EXPERIMENTAL NEUROLOGY
(2022)
Article
Neurosciences
Se Jin Jeon, Huiyoung Kwon, Ho Jung Bae, Edson Luck Gonzales, Junhyeong Kim, Hye Jin Chung, Dong Hyun Kim, Jong Hoon Ryu, Chan Young Shin
Summary: This study found that agmatine can reverse FXS symptoms in Fmr1 KO mouse model, including compulsions, learning and memory deficits, hyperactivity, aberrant social interaction, and communication deficit, while normalizing abnormal long-term potentiation and depression in the hippocampus.
Review
Clinical Neurology
Ramkumar Aishworiya, Dragana Protic, Randi Hagerman
Summary: There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD), with genetic etiology identified in 20-40% of cases. The Fragile X premutation state is a newly discovered disease state associated with various disorders, including ASD, and understanding molecular mechanisms may facilitate targeted treatments in the future.
JOURNAL OF NEUROLOGY
(2022)
Editorial Material
Biochemistry & Molecular Biology
Clinton E. Canal, Marcello Leopoldo
Summary: The molecular characterization of bioactive molecules, such as small molecules targeting G-protein-coupled receptors, is becoming more complex, which affects the meanings of terms like agonist, antagonist, and selective. In the absence of detailed definitions and scientific consensus, these terms can cause confusion in the literature. We discuss this issue and offer straightforward solutions.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Eduardo Penna, Mauro Niso, Sabina Podlewska, Floriana Volpicelli, Marianna Crispino, Carla Perrone-Capano, Andrzej J. Bojarski, Enza Lacivita, Marcello Leopoldo
Summary: The kinetics of drug-target interaction has been a topic of increasing interest in the field of pharmacology. Previous studies have shown the importance of the lipophilicity of a molecule in this process, but there has been limited research on the 5-HT7 receptor (5-HT7R), a GPCR involved in neurodevelopmental and neuropsychiatric disorders. In this study, the researchers explored the structure-kinetics relationships of a specific class of ligands for the 5-HT7R and found that the position of polar groups within the molecule, rather than overall lipophilicity, influenced the interaction kinetics. Additionally, molecular docking and dynamics simulations were used to gain further insights into the relationship between structure and kinetics.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Margherita Mastromarino, Mauro Niso, Carmen Abate, Ewgenij Proschak, Mariam Dubiel, Holger Stark, Marian Castro, Enza Lacivita, Marcello Leopoldo
Summary: Long-chain arylpiperazine scaffold is a versatile template for designing CNS drugs targeting serotonin and dopamine receptors. This study synthesized and evaluated ten new arylpiperazine derivatives with affinity profiles at serotonin and dopamine receptors, aiming to treat ASD or psychosis. The new compounds incorporated antioxidant fragments to counteract oxidative stress. Compound 12a showed an affinity profile compatible with antipsychotic activity, while compound 9b had an affinity profile consistent with ASD studies. Both compounds also had antioxidant properties.
Article
Chemistry, Medicinal
Claudia Cristiano, Floriana Volpicelli, Marianna Crispino, Enza Lacivita, Roberto Russo, Marcello Leopoldo, Antonio Calignano, Carla Perrone-Capano
Summary: Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions characterized by social deficits, repetitive behaviors, and altered inflammatory responses. This study found that ASD children have decreased levels of lipoxin A4 (LXA4), a mediator involved in inflammation resolution. Activation of the receptor FPR2 by a compound called MR-39 had positive effects on inflammation markers, LXA4 expression, and social behavior in validated animal models of ASD. These findings suggest that FPR2 could be a potential target for therapeutic approaches in ASD.
Article
Chemistry, Medicinal
Robert W. Garvey, Enza Lacivita, Mauro Niso, Beata Duszynska, Paul E. Harris, Marcello Leopoldo
Summary: This study reports the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. One of the probes has the ability to selectively label the 5-HT1A receptor in pancreatic islet cells and shows useful properties for further characterization of this receptor's role.
Article
Chemistry, Medicinal
Margherita Mastromarino, Maria Favia, Igor A. Schepetkin, Lylia N. Kirpotina, Ewa Trojan, Mauro Niso, Antonio Carrieri, Monika Leskiewicz, Magdalena Regulska, Massimiliano Darida, Francesco Rossignolo, Stefano Fontana, Mark T. Quinn, Agnieszka Basta-Kaim, Marcello Leopoldo, Enza Lacivita
Summary: Formyl peptide receptor 2 (FPR2) agonists, including the newly identified ureidopropanamide derivatives, show promising potential in resolving inflammation and treating neurodegenerative disorders with underlying chronic neuroinflammation. Computational studies provide insights into the interactions between these compounds and FPR2. In vitro and in vivo experiments demonstrate the anti-inflammatory effects and improved mitochondrial function of selected compounds.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Neurosciences
Antonella Comitato, Enza Lacivita, Marcello Leopoldo, Rita Bardoni
Summary: The 5-HT7 receptors play an important role in synaptic modulation, particularly in synaptic inhibition, in the dorsal horn of the spinal cord. The stronger impact on synaptic inhibition suggests that these receptors may have an anti-nociceptive role in the spinal cord of naive animals.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Review
Neurosciences
Giulia Leonardi, Rosella Ciurleo, Francesca Cucinotta, Bartolo Fonti, Daniele Borzelli, Lara Costa, Adriana Tisano, Simona Portaro, Angelo Alito
Summary: This review examined randomized controlled trials on brain oscillations in stroke patients and explored the role of brain oscillations in modulating cortical excitability. Neuromodulation approaches are considered effective tools for improving stroke rehabilitation outcomes, but further high-quality research is needed to determine their specific effects.
FRONTIERS IN SYSTEMS NEUROSCIENCE
(2022)
Editorial Material
Neurosciences
Ewa Trojan, Monika Leskiewicz, Enza Lacivita, Marcello Leopoldo, Agnieszka Basta-Kaim
CURRENT NEUROPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kinga Tylek, Ewa Trojan, Monika Leskiewicz, Fabio Francavilla, Enza Lacivita, Marcello Leopoldo, Agnieszka Basta-Kaim
Summary: A substantial body of evidence shows a link between dysfunctional acute inflammation resolution and the development of chronic inflammation. The importance of formyl peptide receptor 2 (FPR2) has been highlighted in this context. The activity of FPR2 is regulated by a range of endogenous ligands, including specialized pro-resolving mediators (SPMs) and synthetic ligands. A new potent FPR2 agonist, compound CMC23, has been found to have protective and anti-inflammatory effects.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Cell Biology
Kinga Tylek, Ewa Trojan, Monika Leskiewicz, Imane Ghafir El Idrissi, Enza Lacivita, Marcello Leopoldo, Agnieszka Basta-Kaim
Summary: Microglial cells play a significant role in maintaining homeostasis and resolving inflammation. The study found that a new ureidopropanamide agonist, AMS21, has protective and anti-inflammatory effects in LPS-stimulated hippocampal cells. These effects are mediated through the FPR2 receptor specifically located on microglial cells.