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7. mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy: Preclinical and human genetics data

Author

Celli, R., Striano, P., Citraro, R., Di Menna, L., Cannella, M., Imbriglio, T., Koko, M., De Sarro, G., Monn, J. A., Battaglia, G., van Luijtelaar, G., Nicoletti, F., Russo, E., Leo, A., Palotie, A., Folkhalsan, A. -E. L., Ruppert, A. -K., Lal, D., Thiele, H., Altmuller, J., Jabbari, K., Nurnberg, P., Sander, T., Siren, A., Becker, F., Lerche, H., Weber, Y., Koeleman, B., Caglayan, H., Hjalgrim, H., Moller, R., Muhle, H., Helbig, I., Everett, K., May, P., Krause, R., Balling, R., Nabbout, R., Zara, F., Scala, M., Iacomino, M., Scudieri, P., Bocciardi, R., Balagura, G., Minetti, C., Riva, A., Vari, M. S., Amadori, E., Perinelli, M., Verrotti, A., Baulac, S., and Kunz, W.

Subjects
gaba, Pharmacology, cortico-thalamo-cortical network, Action, intention, and motor control, human genetics, glutamate, General Medicine, absence epilepsy, eeg, mglu3 receptors, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical)
Abstract

Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for the treatment of absence epilepsy. However, no information is available on mGlu3 receptors. Objective: To examine whether (i) abnormalities changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; real-time PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other IGE/GGE Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusions: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

Published
2023

16. Pharmacokinetic interactions between esketamine and different classes of antidepressants in patients with treatment-resistant depression

Author

Alborghetti, M., primary, Lionetto, L., additional, Lombardozzi, G., additional, Matrone, M., additional, Trovini, G., additional, Donato, D., additional, Catapano, F., additional, Pagano, I., additional, Surano, M., additional, Montaguti, L., additional, Di Lorenzo, G., additional, Simmaco, M., additional, Martinotti, G., additional, Nicoletti, F., additional, and De Filippis, S., additional

Published
2023
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18. Natural products in drug discovery: advances and opportunities

Author

Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., Orhan, I. E., Banach, M., Rollinger, J. M., Barreca, D., Weckwerth, W., Bauer, R., Bayer, E. A., Majeed, M., Bishayee, A., Bochkov, V., Bonn, G. K., Braidy, N., Bucar, F., Cifuentes, A., D'Onofrio, G., Bodkin, M., Diederich, M., Dinkova-Kostova, A. T., Efferth, T., El Bairi, K., Arkells, N., Fan, T. -P., Fiebich, B. L., Freissmuth, M., Georgiev, M. I., Gibbons, S., Godfrey, K. M., Gruber, C. W., Heer, J., Huber, L. A., Ibanez, E., Kijjoa, A., Kiss, A. K., Lu, A., Macias, F. A., Miller, M. J. S., Mocan, A., Muller, R., Nicoletti, F., Perry, G., Pittala, V., Rastrelli, L., Ristow, M., Russo, G. L., Silva, A. S., Schuster, D., Sheridan, H., Skalicka-Wozniak, K., Skaltsounis, L., Sobarzo-Sanchez, E., Bredt, D. S., Stuppner, H., Sureda, A., Tzvetkov, N. T., Vacca, R. A., Aggarwal, B. B., Battino, M., Giampieri, F., Wink, M., Wolfender, J. -L., Xiao, J., Yeung, A. W. K., Lizard, G., Popp, M. A., Heinrich, M., Berindan-Neagoe, I., Stadler, M., Daglia, M., Verpoorte, R., Supuran, C. T., Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., Orhan, I. E., Banach, M., Rollinger, J. M., Barreca, D., Weckwerth, W., Bauer, R., Bayer, E. A., Majeed, M., Bishayee, A., Bochkov, V., Bonn, G. K., Braidy, N., Bucar, F., Cifuentes, A., D'Onofrio, G., Bodkin, M., Diederich, M., Dinkova-Kostova, A. T., Efferth, T., El Bairi, K., Arkells, N., Fan, T. -P., Fiebich, B. L., Freissmuth, M., Georgiev, M. I., Gibbons, S., Godfrey, K. M., Gruber, C. W., Heer, J., Huber, L. A., Ibanez, E., Kijjoa, A., Kiss, A. K., Lu, A., Macias, F. A., Miller, M. J. S., Mocan, A., Muller, R., Nicoletti, F., Perry, G., Pittala, V., Rastrelli, L., Ristow, M., Russo, G. L., Silva, A. S., Schuster, D., Sheridan, H., Skalicka-Wozniak, K., Skaltsounis, L., Sobarzo-Sanchez, E., Bredt, D. S., Stuppner, H., Sureda, A., Tzvetkov, N. T., Vacca, R. A., Aggarwal, B. B., Battino, M., Giampieri, F., Wink, M., Wolfender, J. -L., Xiao, J., Yeung, A. W. K., Lizard, G., Popp, M. A., Heinrich, M., Berindan-Neagoe, I., Stadler, M., Daglia, M., Verpoorte, R., and Supuran, C. T.

Subjects
0301 basic medicine, Engineering, Drug Industry, Review Article, Communicable Diseases, Natural (archaeology), 03 medical and health sciences, 0302 clinical medicine, Transferases, Neoplasms, Drug Discovery, Humans, Pharmaceutical industry, Pharmacology, Biological Products, Natural products, Genome, business.industry, Drug discovery, General Medicine, Chemical biology, 030104 developmental biology, Risk analysis (engineering), 030220 oncology & carcinogenesis, Genome mining, business
Abstract

The International Natural Product Sciences Taskforce: et al., Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities., A.C. and E.I. thank the Ministerio de Ciencia, Innovación y Universidades, Spain (Project AGL2017-89417-R) for support. F.A.M. acknowledges the support by Ministerio de Economia y Competitividad, Spain (project AGL2017-88083-R).

Published
2021
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21. Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

Author

di Nuzzo L, Orlando R, Nasca C, and Nicoletti F

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Luigi di Nuzzo,1 Rosamaria Orlando,2 Carla Nasca,1 Ferdinando Nicoletti1,31Department of Physiology and Pharmacology, Sapienza University of Rome, 2IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, 3IRCCS Neuromed, Pozzilli, ItalyAbstract: New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood–brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.Keywords: demyelinating diseases, pharmacotherapy, fingolimod, dimethyl fumarate, laquinimod, teriflunomide

Published
2014

26. Profile of gantenerumab and its potential in the treatment of Alzheimer's disease

Author

Novakovic D, Feligioni M, Scaccianoce S, Caruso A, Piccinin S, Schepisi C, Errico F, Mercuri NB, Nicoletti F, and Nisticò R

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Dijana Novakovic,1 Marco Feligioni,2 Sergio Scaccianoce,1 Alessandra Caruso,1 Sonia Piccinin,2 Chiara Schepisi,1,2 Francesco Errico,3 Nicola B Mercuri,4 Ferdinando Nicoletti,1,5 Robert Nisticò1,41Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy; 2European Brain Research Institute, Rome, Italy; 3Ceinge Biotecnologie Avanzate, Naples, Italy; 4Laboratory of Experimental Neurology, Istituto di Ricerca e Cura a Carattere Scientifico, Santa Lucia Foundation, Rome, Italy; 5Istituto di Ricerca e Cura a Carattere Scientifico, Neuromed, Pozzilli, ItalyAbstract: Alzheimer's disease, which is characterized by gradual cognitive decline associated with deterioration of daily living activities and behavioral disturbances throughout the course of the disease, is estimated to affect 27 million people around the world. It is expected that the illness will affect about 63 million people by 2030, and 114 million by 2050, worldwide. Current Alzheimer's disease medications may ease symptoms for a time but are not capable of slowing down disease progression. Indeed, all currently available therapies, such as cholinesterase inhibitors (donepezil, galantamine, rivastigmine), are primarily considered symptomatic therapies, although recent data also suggest possible disease-modifying effects. Gantenerumab is an investigational fully human anti-amyloid beta monoclonal antibody with a high capacity to bind and remove beta-amyloid plaques in the brain. This compound, currently undergoing Phase II and III clinical trials represents a promising agent with a disease-modifying potential in Alzheimer's disease. Here, we present an overview of gantenerumab ranging from preclinical studies to human clinical trials.Keywords: Alzheimer's disease, gantenerumab, monoclonal antibody, amyloid-β, clinical trialsCorrigendum for this paper has been published

Published
2013

29. mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy: Preclinical and human genetics data

Author

Celli, R., Striano, P., Citraro, R., Di Menna, L., Cannella, M., Imbriglio, T., Koko, M., De Sarro, G., Monn, A.J., Battaglia, G., Luijtelaar, E.L.J.M. van, Nicoletti, F., Russo, E., Leo, A., Celli, R., Striano, P., Citraro, R., Di Menna, L., Cannella, M., Imbriglio, T., Koko, M., De Sarro, G., Monn, A.J., Battaglia, G., Luijtelaar, E.L.J.M. van, Nicoletti, F., Russo, E., and Leo, A.

Abstract

09 mei 2022, Item does not contain fulltext, Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for the treatment of absence epilepsy. However, no information is available on mGlu3 receptors. Objective To examine whether (i) abnormalities changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; real-time PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other IGE/GGE Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusions: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

Published
2022

34. Control of the of the final stage of immune-mediated diabetes by ISO-1, an antagonist of macrophage migration inhibitory factor

Author

Stojanović Ivana, Maksimović-Ivanić Danijela, Al-Abed Y., Nicoletti F., and Stošić-Grujičić Stanislava

Subjects
Macrophage migration inhibitory factor (MIF), autoimmunity, diabetes, (S,R)-3-(4-hydroxyphenil)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), nitric oxide (NO), IL-18 - IL-1β, Biology (General), QH301-705.5
Abstract

We recently showed that attenuation of inflammatory cytokine MIF with pharmacological inhibitor ISO-1 down-regulates the immune-mediated diabetes in mice. Here we explore the effects of MIF neutralization by ISO-1 on the local inflammatory pathway of the disease. In vivo treatment of mice with ISO-1 inhibited the expression of pro-inflammatory cytokines and iNOS in the pancreatic islets. Moreover, ISO-1 affected in vitro cytokine-induced NO pro­duction by fibroblasts, endothelial cells, insulinoma cells, and pancreatic islets, and rescued β cells from NO-dependent damage. These results suggest regulatory potential of ISO-1 at the level of the pancreas which can preserve the target tissue from autoimmune attack.

Published
2008
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42. Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats

Author

Verhaeghe, R. (Remy), Gao, V. (Vance), MORLEY-FLETCHER, S. (Sara), Bouwalerh, H. (Hammou), Van Camp, G. (Gilles), Cisani, F. (Francesca), Nicoletti, F. (Ferdinando), Maccari, S. (Stefania), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], and Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Subjects
Early life stress, Sex differences, Brain aging, Behaviors, Hormones
Abstract

Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taking behavior, spatial memory, exploratory behavior, and fine motor behavior in male aged rats. In contrast, female aged PRS rats displayed only increased risk-taking behavior and reduced exploratory behavior. PRS induced large reductions in the expression of glutamate receptors in the ventral and dorsal hippocampus and prefrontal cortex only in male rats. PRS also reduced the expression of synaptic vesicle-associated proteins, glucocorticoid receptors (GR), and mineralocorticoid receptors (MR) in the ventral hippocampus of aged male rats. In contrast, in female aged rats, PRS enhanced the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus and the expression of glial fibrillary acidic protein (GFAP) and BDNF in the prefrontal cortex. A common PRS effect in both sexes was a reduction in exploratory behavior and metabotropic glutamate (mGlu2/3) receptors in the ventral hippocampus and prefrontal cortex. A multidimensional analysis revealed that PRS induced a demasculinization profile in glutamate-related proteins in the ventral and dorsal hippocampus and prefrontal cortex, as well as a demasculinization profile of stress markers only in the dorsal hippocampus. In contrast, defeminization was observed only in the ventral hippocampus. Measurements of testosterone and 17-β-estradiol in the plasma and aromatase in the dorsal hippocampus were consistent with a demasculinizing action of PRS. These findings confirm that the brains of males and females differentially respond to PRS and aging suggesting that females might be more protected against early stress and age-related inflammation and neurodegeneration. Taken together, these results may contribute to understanding how early environmental factors shape vulnerability to brain aging in both sexes and may lay the groundwork for future studies aimed at identifying new treatment strategies to improve the quality of life of older individuals, which is of particular interest given that there is a high growth of aging in populations around the world.

Published
2021

50. Third Annual Huntington Disease Clinical Research Symposium: Organized by the Huntington Study Group

Author

Dubinsky, Richard, Roberson, Judy, Battaglia, G., Cannella, M., Riozzi, B., Orobello, S., Maat-Schieman, M. L., Aronica, E., Busceti, C. Letizia, Ciarmiello, A., Alberti, S., Sassone, J., Sipione, S., Bruno, V., Frati, L., Nicoletti, F., Squitieri, F., Rao, A., Gordon, A., Marder, K., Nolta, Jan, Anderson, K., Gruber-Baldini, A., Medalie, J., Reich, S., Fishman, P., Robottom, B., Weiner, W., Shulman, L., Langbehn, D., Paulsen, J., Witten, Celia, Cox, M., Feigin, A., Napolitano, B., Goh, A., Yastrubetskaya, O., Chiu, E., Cloud, L., Helmers, S., Jones, R., Factor, S., Emory, C. Testa, Kegelmeyer, D., Kostyk, S., Fritz, N., Kloos, A., Lessig, S., Goldstein, J., Corey-Bloom, J., Simonelli, M., Martino, T., Colonnese, C., Callaghan, J., Arran, N., Boisse, M. F., Coleman, A., Dar Santos, R., Dumas, E., Hart, E. ’t, Justo, D., Read, J., Say, M., Van Den Bogaard, S., Durr, A., Leavitt, B., Roos, R., Tabrizi, S., Bourdet, C., van Duijn, E., Craufurd, D., Evans, K., Vaccarino, A., Aylward, E., Nopoulos, P., Ross, C., Pierson, R., Mills, J., Magnotta, V., Johnson, H., Mitchell, A., Cortes, J. C., Dahmubed, A., Krakauer, J., Mazzoni, P., Russell, D., Jennings, D., Tamagnan, G., Seibyl, J., Koren, A., Zubal, G., Marek, K., Goodman, L., Carnes, R., Giuliano, J., Vetter, L., MacDonald, M., Lee, J. Min, Seong, I. Sik, Fossale, E., Anderson, M. A., Wheeler, V., Gusella, J., Johnson, J., Yu, T., Jones, D., Chan, A., Richardson, K., McCusker, E., Loy, C., Griffith, J., Paulsen, J. S., Waters, S., Tedroff, J., Kieburtz, K., Krogh, P. Lindskov, Buusman, A., Rembratt, Å., Dorey, J., Lamure, M., Toumi, M., von der Schulenburg, J. -M. Graf, Pettersson, F., Dyhring, T., Sonesson, C., Waters, N., Pontén, H., Erwin, C., Williams, J., Juhl, A., Adams, W., Byars, J., O’Rourke, J., Flynn, A., Fiedorowicz, J., Duff, K., Leserman, A., Beglinger, L., Smith, M., Stout, J., Queller, S., Rao, S., Zimbelman, J., Groves, M., Guttman, M., Wexler, E., Perlman, S., Burgunder, J. -M., Rosenblatt, A., van Kammen, D., PREDICT-HD Investigators of the Huntington Study Group, TRACK-FID Investigators, TRACK-HD Investigators, PREDICT-HD Investigators and Coordinators of the Huntington Study Group, PREDICT-HD Investigators of the Huntington Study Group, Investigators of the Huntington Study Group, Huntington Study Group PHAROS Investigators, and PREDICT-HD Investigators of the Huntington Study Group

Published
2010
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