Development of a platelet-activating factor antagonist for HIV-1 associated neurocognitive disorders

• Published in: Journal of neuroimmunology 2009-08, Vol.213 (1), p.47-59
• Main Authors: Eggert, Dawn, Dash, Prasanta K, Serradji, Nawal, Dong, Chang-Zhi, Clayette, Pascal, Heymans, Francoise, Dou, Huanyu, Gorantla, Santhi, Gelbard, Harris A, Poluektova, Larisa, Gendelman, Howard E
• Format: Article
• Language: English
• Subjects: AIDS Dementia Complex - drug therapy; AIDS Dementia Complex - immunology; AIDS Dementia Complex - metabolism; Allergy and Immunology; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Cell Death - drug effects; Cell Death - immunology; Cells, Cultured; Cognition Disorders - drug therapy; Cognition Disorders - immunology; Cognition Disorders - metabolism; Disease Models, Animal; Focal Adhesion Kinase 2 - drug effects; Focal Adhesion Kinase 2 - metabolism; Giant Cells - drug effects; Giant Cells - immunology; Giant Cells - metabolism; Gliosis - drug therapy; Gliosis - immunology; Gliosis - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunologic Factors - pharmacology; Immunologic Factors - therapeutic use; Inflammation Mediators - agonists; Inflammation Mediators - metabolism; Male; Mice; Mice, SCID; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Multinucleated giant cell; Neurology; NF-kappa B - drug effects; NF-kappa B - metabolism; Nuclear factor kappa beta; Piperazines - pharmacology; Piperazines - therapeutic use; Platelet activating factor; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - metabolism; PMS-601; Proline-rich tyrosine kinase 2
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2009.06.002

Abstract The neuroregulatory activities of PMS-601, a platelet activating factor antagonist, were investigated in laboratory and animal models of HIV-1 encephalitis (HIVE). For the former, PMS-601 reduced monocyte-derived macrophage pro-inflammatory secretions, multinucleated giant cell (MGC) formation, and neuronal loss independent of antiretroviral responses. PMS-601 treatment of HIVE severe combined immunodeficient mice showed reduced microgliosis, MGCs and neurodegeneration. These observations support the further development of PMS-601 as an adjunctive therapy for HIV-1 associated neurocognitive disorders.