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Trends in Pharmacological Sciences
This journal offers authors two options (open access or subscription) to publish research

Aug 01, 2022

Volume 43Issue 8p609-702, e1-e2
Special issue: Advances in neuroimmunology based therapeutic opportunities
The August special issue calls attention to both current and emerging neuroimmune cell and molecular pharmacological targets and therapies for diseases of the central nervous system (CNS) such as neurodegenerative disorders and glioblastoma. It also presents discussions on insightful therapeutic approaches that could have significant impact on future clinical and translational neuroimmunology research. The cover is an illustration of microglia, the resident immune cells of the CNS, highlighting some typical and novel drug targets including surface receptors: purinergic (blue), TREM2 (green), CSF1 (brown), fractalkine (dark blue), cannabinoid (orange), cytokine (purple), and complement (green), involved in a wide range of physiological and pathological events in the CNS. Featured in the background are other CNS cell types and structures such as neurons, oligodendrocytes and astrocytes, blood vessels, as well as amyloid beta plaques, misfolded proteins and degenerating myelin sheats, hallmarks associated with some CNS pathologies. The cover image is conceptualized and designed by Eva Šimončičová and Elisa Gonçalves de Andrade using Biorender and Adobe Illustrator....
The August special issue calls attention to both current and emerging neuroimmune cell and molecular pharmacological targets and therapies for diseases of the central nervous system (CNS) such as neurodegenerative disorders and glioblastoma. It also presents discussions on insightful therapeutic approaches that could have significant impact on future clinical and translational neuroimmunology research. The cover is an illustration of microglia, the resident immune cells of the CNS, highlighting some typical and novel drug targets including surface receptors: purinergic (blue), TREM2 (green), CSF1 (brown), fractalkine (dark blue), cannabinoid (orange), cytokine (purple), and complement (green), involved in a wide range of physiological and pathological events in the CNS. Featured in the background are other CNS cell types and structures such as neurons, oligodendrocytes and astrocytes, blood vessels, as well as amyloid beta plaques, misfolded proteins and degenerating myelin sheats, hallmarks associated with some CNS pathologies. The cover image is conceptualized and designed by Eva Šimončičová and Elisa Gonçalves de Andrade using Biorender and Adobe Illustrator.

Editorial

  • Promising neuroimmune targets and drugs for CNS diseases

    • Jerry Madukwe
    The global health and economic burden of central nervous system (CNS) diseases continues to rise. Current treatment measures focus on relieving symptoms rather than curing the diseases, and have both use and efficacy limitations. However, the past 5 years have seen tremendous increases in our understanding of the role of neuroinflammation and neuroimmune interactions in neuropathology and neuroprotection of the CNS. Better understanding of the cellular and molecular details of neurodegenerative disorders (Alzheimer’s and Parkinson diseases, etc.) and glioblastoma (GBM), and elucidation of the pharmacology of small-molecule drug candidates and biologics present promising pharmacological targets and approaches for the treatment of diseases of the CNS.

TrendsTalk

  • The future of neuroimmunology research for CNS disease therapeutics

    • John D. Lambris,
    • Arnon Rosenthal,
    • Pablo Pelegrín,
    • Marie-Ève Tremblay,
    • Peiwen Chen
    It is an exciting time to be in neuroimmunology research. Promising pharmacological targets and drug approaches for the treatment of diseases of the central nervous system (CNS) are emerging. Jerry Madukwe, the Editor-in-Chief of Trends in Pharmacological Sciences asked authors of the August 2022 special issue to reflect on the global challenges in the field and what they see as the future of neuroimmunology research for CNS disease therapy.

Reviews

  • Targeting complement in neurodegeneration: challenges, risks, and strategies

    • Wioleta M. Zelek,
    • B. Paul Morgan
    Open Access
    Evidence implicating complement in neuroinflammatory and neurodegenerative diseases (NDDs) has accumulated over the past decade, revealing complement as a driver of pathology across these diverse diseases. Over the same period, there has been an explosion of interest in the development of complement-modulating drugs, first for a few rare complement dysregulation diseases but recently also for more common diseases where complement contributes to the disease process. To date, there has been little attention paid to the potential role of anticomplement drugs in neurodegeneration and the current landscape does not feature drugs that can enter the central nervous system (CNS), a prerequisite in most NDDs.
  • Compstatins: the dawn of clinical C3-targeted complement inhibition

    • Christina Lamers,
    • Dimitrios C. Mastellos,
    • Daniel Ricklin,
    • John D. Lambris
    Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted therapy. However, it became apparent that inhibition of late-stage effector generation might not be sufficient in multifactorial complement disorders. Upstream intervention at the level of C3 activation has therefore been considered promising. The approval of pegcetacoplan, a C3 inhibitor of the compstatin family, in 2021 served as critical validation of C3-targeted treatment.
  • Progranulin as a therapeutic target in neurodegenerative diseases

    • Herve Rhinn,
    • Nadine Tatton,
    • Stella McCaughey,
    • Michael Kurnellas,
    • Arnon Rosenthal
    Open Access
    Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer’s disease, Parkinson’s disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene.
  • NLRP3 and pyroptosis blockers for treating inflammatory diseases

    • Rebecca C. Coll,
    • Kate Schroder,
    • Pablo Pelegrín
    Open Access
    The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases and is an exciting drug target. Here, we review the molecular basis of NLRP3 inhibition by drug-like small molecules under development as novel therapeutics. We also summarize recent strategies to block pyroptosis as a novel approach to suppress chronic inflammation. Major recent developments in this area include the elucidation of mechanisms of action (MoAs) by which small molecules block NLRP3 inflammasome assembly and gasdermin D (GSDMD)-induced pyroptosis.
  • Present and future of microglial pharmacology

    • Eva Šimončičová,
    • Elisa Gonçalves de Andrade,
    • Haley A. Vecchiarelli,
    • Ifeoluwa O. Awogbindin,
    • Charlotte I. Delage,
    • Marie-Ève Tremblay
    Microglia, brain resident immune cells, modulate development, activity, and plasticity of the central nervous system. Mechanistically implicated in numerous neurological pathologies, microglia emerge as strong contenders for novel neurotherapies. Shifting away from merely an attenuation of excessive microglial inflammatory and phagocytic activities, current therapies aim toward targeting the complex context-dependent microglial heterogeneity, unveiled by large-scale genetic studies and emerging single-cell analyses.
  • Pharmacological targeting of the tumor–immune symbiosis in glioblastoma

    • Lizhi Pang,
    • Fatima Khan,
    • Madeline Dunterman,
    • Peiwen Chen
    Glioblastoma (GBM) is the most common and highly lethal form of primary brain tumor in adults. The median survival of GBM patients is approximately 14–16 months despite multimodal therapies. Emerging evidence has substantiated the critical role of symbiotic interactions between GBM cells and noncancerous immune cells (e.g., myeloid cells and T cells) in regulating tumor progression and therapy resistance. Approaches to target the tumor–immune symbiosis have emerged as a promising therapeutic strategy for GBM.

Drug of the Month

  • Atogepant (Qulipta®) for migraine prevention

    • Debbie L. Hay,
    • Christopher S. Walker,
    • Paul W.R. Harris
    STRUCTURE: Atogepant (MK-8031/AGN-241689) is a heavily polycyclic molecule, containing four chiral centers, three aromatic and three aliphatic rings. An intriguing feature is the 2-azaspiro [4.4]nonan-1-one (spiroazaindane) motif in an S configuration, which is also present in earlier preclinical leads from Merck. The azospiro bispyridine unit is linked via an amide bond to a piperidine-2-one ring; the amide linkage is reversed to that seen in earlier leads to avoid potential release of a toxic aniline.
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