The Experts below are selected from a list of 207 Experts worldwide ranked by ideXlab platform
Cinzia Volonté - One of the best experts on this subject based on the ideXlab platform.
-
Actions of the antihistaminergic Clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression
Journal of Neuroinflammation, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Cinzia VolontéAbstract:Background Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine Clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia. Methods Here, we have chronically treated female SOD1-G93A mice with Clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of Clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells. Results We found that a short treatment with Clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, Clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with Clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that Clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice Clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells. Conclusions By gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.
-
Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1^G93A Mouse Model of Amyotrophic Lateral Sclerosis
Molecular Neurobiology, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Chiara Parisi, Cinzia VolontéAbstract:Mutations in the Cu^2+/Zn^2+ superoxide dismutase 1 (SOD1) gene underlie 14–23 % of familial and 1–7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if Clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1^G93A mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic Clemastine administration in SOD1^G93A mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, Clemastine is able to modify several activation parameters of SOD1^G93A microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being Clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.
Mikael Hedeland - One of the best experts on this subject based on the ideXlab platform.
-
structural elucidation of n oxidized Clemastine metabolites by liquid chromatography tandem mass spectrometry and the use of cunninghamella elegans to facilitate drug metabolite identification
Rapid Communications in Mass Spectrometry, 2010Co-Authors: Annica Tevell Åberg, Ulf Bondesson, Mikael Hedeland, Helena LöfgrenAbstract:Cunninghamella elegans is a filamentous fungus that has been shown to biotransform drugs into the same metabolites as mammals. In this paper we describe the use of C. elegans to aid the identification of Clemastine metabolites since high concentrations of the metabolites were produced and MS(n) experiments were facilitated. The combination of liquid chromatography and tandem mass spectrometry with two different ionization techniques and hydrogen/deuterium exchange were used for structural elucidation of the Clemastine metabolites. NorClemastine, four isomers of hydroxylated Clemastine, and two N-oxide metabolites were described for the first time in C. elegans incubations. The N-oxidations were confirmed by hydrogen/deuterium exchange and deoxygenation (-16 Da) upon atmospheric pressure chemical ionization mass spectrometry. By MS(n) fragmentation it was concluded that two of the hydroxylated metabolites were oxidized on the methylpyrridyl moiety, one on the aromatic ring with the chloro substituent, and one on the aromatic ring without the chlorine.
-
Structural elucidation of N-oxidized Clemastine metabolites by liquid chromatography/tandem mass spectrometry and the use of Cunninghamella elegans to facilitate drug metabolite identification.
Rapid communications in mass spectrometry : RCM, 2010Co-Authors: Annica Tevell Åberg, Ulf Bondesson, Helena Löfgren, Mikael HedelandAbstract:Cunninghamella elegans is a filamentous fungus that has been shown to biotransform drugs into the same metabolites as mammals. In this paper we describe the use of C. elegans to aid the identification of Clemastine metabolites since high concentrations of the metabolites were produced and MS(n) experiments were facilitated. The combination of liquid chromatography and tandem mass spectrometry with two different ionization techniques and hydrogen/deuterium exchange were used for structural elucidation of the Clemastine metabolites. NorClemastine, four isomers of hydroxylated Clemastine, and two N-oxide metabolites were described for the first time in C. elegans incubations. The N-oxidations were confirmed by hydrogen/deuterium exchange and deoxygenation (-16 Da) upon atmospheric pressure chemical ionization mass spectrometry. By MS(n) fragmentation it was concluded that two of the hydroxylated metabolites were oxidized on the methylpyrridyl moiety, one on the aromatic ring with the chloro substituent, and one on the aromatic ring without the chlorine.
-
Clinical pharmacology of Clemastine in healthy dogs.
Veterinary dermatology, 2004Co-Authors: H Hansson, Kerstin Bergvall, Ulf Bondesson, Mikael Hedeland, K. TörnekeAbstract:The pharmacokinetic properties of Clemastine were investigated in six healthy dogs and compared with the effect of the drug recorded as inhibition of wheal formation induced by intradermal injections of histamine. Clemastine clearance was high (median: 2.1 L h(-1) kg(-1)) and the volume of distribution large (13.4 L kg(-1)). The half-life after intravenous administration was 3.8 h and the plasma protein binding level in vitro was 98%. After oral administration, the bioavailability was only 3%. Given intravenously, Clemastine (0.1 mg kg(-1)) inhibited wheal formation completely for 7 h, whereas the effect after oral administration (0.5 mg kg(-1)) was minor. The data show that most dosage regimens suggested in the literature for the oral administration of Clemastine to dogs are likely to give too low a systemic exposure of the drug to allow effective therapy.
Savina Apolloni - One of the best experts on this subject based on the ideXlab platform.
-
Actions of the antihistaminergic Clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression
Journal of Neuroinflammation, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Cinzia VolontéAbstract:Background Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine Clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia. Methods Here, we have chronically treated female SOD1-G93A mice with Clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of Clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells. Results We found that a short treatment with Clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, Clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with Clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that Clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice Clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells. Conclusions By gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.
-
Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1^G93A Mouse Model of Amyotrophic Lateral Sclerosis
Molecular Neurobiology, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Chiara Parisi, Cinzia VolontéAbstract:Mutations in the Cu^2+/Zn^2+ superoxide dismutase 1 (SOD1) gene underlie 14–23 % of familial and 1–7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if Clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1^G93A mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic Clemastine administration in SOD1^G93A mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, Clemastine is able to modify several activation parameters of SOD1^G93A microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being Clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.
Emily R. Derbyshire - One of the best experts on this subject based on the ideXlab platform.
-
plasmodium chaperonin tric cct identified as a target of the antihistamine Clemastine using parallel chemoproteomic strategy
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Baiyi Quan, Kayla Sylvester, Tamanna Srivastava, Michael C. Fitzgerald, Emily R. DerbyshireAbstract:The antihistamine Clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of Clemastine and identify that Clemastine binds to the Plasmodium falciparum TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight P. falciparum TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a Clemastine-induced thermodynamic stabilization of the Plasmodium TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that Clemastine reduces levels of the major TRiC substrate tubulin in P. falciparum parasites. In addition, Clemastine treatment leads to disorientation of Plasmodium mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This Clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively target Plasmodium TRiC-mediated protein folding for malaria intervention.
-
Plasmodium chaperonin TRiC/CCT identified as a target of the antihistamine Clemastine using parallel chemoproteomic strategy
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Baiyi Quan, Kayla Sylvester, Tamanna Srivastava, Michael C. Fitzgerald, Emily R. DerbyshireAbstract:The antihistamine Clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of Clemastine and identify that Clemastine binds to the Plasmodium falciparum TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight P. falciparum TRiC subunits based on thermal proteome profiling (TPP). Further analysis using stability of proteins from rates of oxidation (SPROX) revealed a Clemastine-induced thermodynamic stabilization of the Plasmodium TRiC delta subunit, suggesting an interaction with this protein subunit. We demonstrate that Clemastine reduces levels of the major TRiC substrate tubulin in P. falciparum parasites. In addition, Clemastine treatment leads to disorientation of Plasmodium mitotic spindles during the asexual reproduction and results in aberrant tubulin morphology suggesting protein aggregation. This Clemastine-induced disruption of TRiC function is not observed in human host cells, demonstrating a species selectivity required for targeting an intracellular human pathogen. Our findings encourage larger efforts to apply chemoproteomic methods to assist in target identification of antimalarial drugs and highlight the potential to selectively target Plasmodium TRiC-mediated protein folding for malaria intervention.
Paola Fabbrizio - One of the best experts on this subject based on the ideXlab platform.
-
Actions of the antihistaminergic Clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression
Journal of Neuroinflammation, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Cinzia VolontéAbstract:Background Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine Clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia. Methods Here, we have chronically treated female SOD1-G93A mice with Clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of Clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells. Results We found that a short treatment with Clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, Clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with Clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that Clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice Clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells. Conclusions By gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.
-
Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1^G93A Mouse Model of Amyotrophic Lateral Sclerosis
Molecular Neurobiology, 2016Co-Authors: Savina Apolloni, Paola Fabbrizio, Susanna Amadio, Chiara Parisi, Cinzia VolontéAbstract:Mutations in the Cu^2+/Zn^2+ superoxide dismutase 1 (SOD1) gene underlie 14–23 % of familial and 1–7 % of sporadic cases of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by a specific loss of motor neurons in the brain and spinal cord. Neuroinflammation and oxidative stress are emerging as key players in the pathogenesis of ALS, thus justifying the interest in glial cells and particularly microglia, in addition to motor neurons, as novel therapeutic approaches against ALS. Recently, histamine was proven to participate in the pathogenesis of neuroinflammatory and neurodegenerative diseases, and particularly, microglia was shown to be sensitive to the histamine challenge mainly through histamine H1 receptors. Clemastine is a first-generation and CNS-penetrant H1 receptor antagonist considered as a safe antihistamine compound that was shown to possess immune suppressive properties. In order to investigate if Clemastine might find promising application in the treatment of ALS, in this work, we tested its action in the SOD1^G93A mouse model which is extensively used in ALS preclinical studies. We demonstrated that chronic Clemastine administration in SOD1^G93A mice reduces microgliosis, modulates microglia-related inflammatory genes, and enhances motor neuron survival. Moreover, in vitro, Clemastine is able to modify several activation parameters of SOD1^G93A microglia, and particularly CD68 and arginase-1 expression, as well as phospho-ERK1/2 and NADPH oxidase 2 levels. Being Clemastine a drug already employed in clinical practice, our results strongly encourage its further exploitation as a candidate for preclinical trials and a new modulator of neuroinflammation in ALS.