Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

Nuzzo, Luigi di; Orlando, Rosamaria; Nasca, Carla; Nicoletti, Ferdinando

doi:10.2147/dddt.s52428

“…These studies in conjunction with this study indicate that clozapine may help promote CNS repair and inflammatory damage. Moreover, orally-administered compounds that can cross the blood brain barrier such as clozapine may offer better access to the central nervous system than currently available protein or antibody-based treatments (di Nuzzo, Orlando, Nasca, & Nicoletti, 2014). The data presented in this thesis supports the possibility that clozapine is neuroprotective in ways that are also independent of the immune response.…”

Section: Discussionsupporting

confidence: 55%

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

Zareie¹

0

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<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

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“…These studies in conjunction with this study indicate that clozapine may help promote CNS repair and inflammatory damage. Moreover, orally-administered compounds that can cross the blood brain barrier such as clozapine may offer better access to the central nervous system than currently available protein or antibody-based treatments (di Nuzzo, Orlando, Nasca, & Nicoletti, 2014). The data presented in this thesis supports the possibility that clozapine is neuroprotective in ways that are also independent of the immune response.…”

Section: Discussionsupporting

confidence: 55%

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

Zareie¹

0

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<p>Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by damage to the myelin sheaths that surround nerve axons. Inflammatory damage to the myelin sheath leads to severe physical disability in patients. Whereas approved disease modifying treatments are available for relapsing-remitting forms of MS, there are no approved treatments for the progressive stages, leaving approximately 50% of MS sufferers without treatment. Therefore, there is an urgent need for development of effective alternatives. Atypical antipsychotic agents used for treating schizophrenia have recently been recognized for their immune-modifying properties and our laboratory has shown previously that treating mice with risperidone or clozapine reduces the severity of disease in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Although atypical antipsychotic agents like clozapine have been used in the clinic for almost 60 years, there is very little experimental data that describes the mechanism by which atypical antipsychotic agents like clozapine are able to modify the immune response. This thesis aimed to describe the immunological mechanisms by which clozapine is able to reduce EAE disease and to determine the underlying cellular signalling alterations that occur during treatment to facilitate immune modifying properties. In vitro experiments showed that clozapine can impair induction of Th1 and Th17 cells while promoting the differentiation of iTreg and increasing Foxp3 expression. However, although clozapine effectively delayed disease onset and reduced the severity of EAE, the therapeutic effect of clozapine was not associated with impaired capacity to induce antigen specific Th1 or Th17 responses in the periphery. Moreover, Treg function was dispensable for disease protection by clozapine. Instead, disease protection by clozapine was associated with a suppressed state of activation in CNS resident microglia and infiltrating monocytes assessed by flow cytometric measurement of activation associated receptor expression. In vitro experiments using primary macrophage cell culture revealed that clozapine can alter the activation of activated macrophages towards a less inflammatory state directly. Interestingly, the altered state of activation in primary macrophages was not associated with detectable changes in cell signalling pathways known to mediate activation. This thesis demonstrated that clozapine treatment protects from EAE by a multi-faceted immunological mechanism that likely involves modifying multiple pathways and cell types during EAE and may be of therapeutic benefit to MS patients in the progressive stages of disease. Finally, this thesis also has relevance to psychiatry as it demonstrates that clozapine has potential to alter cellular immune responses.</p>

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“…Underlying mechanisms how Teriflunomide inhibited aggregation and decreased aggregate size of polyQ aggregates in this study are not clear, but the authors suggested that Teriflunomide prevented the incorporation of new polyQ into existing aggregates rather than disintegrating already formed aggregates. There have been multiple potential additional effects of Leflunomide/Teriflunomide, such as an inhibition of protein tyrosine kinases [ 78 , 79 ] resulting in decreased IgG1 secretion of stimulated B cells via a reduction of JAK3 and STAT6, or an inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways [ 80 , 81 ], an inhibition of cyclooxygenase-2 [ 82 ], interference with the kynurenine pathway [ 83 ], and decreased T cell receptor (TCR)/CD3-mediated calcium mobilization during formation of the immunological synapse [ 84 ]. However, all these effects were observed in vitro at much higher concentrations than those required to block DHODH.…”

Section: Mode Of Actionmentioning

confidence: 99%

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis

Aly

¹

,

Hemmer

²

,

Korn

³

2017

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Background: Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS).Methods: Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide.Results: Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy.Conclusion: Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS.

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Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

Cited by 20 publications

References 116 publications

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

Investigating the mechanism by which the atypical antipsychotic clozapine reduces disease in experimental autoimmune encephalomyelitis

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis

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