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The Journal of Neuroscience, January 14, 2004, 24(2):479-487; doi:10.1523/JNEUROSCI.4288-03.2004

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Cellular/Molecular
5-Aminoimidazole-4-Carboxamide-1--4-Ribofuranoside Inhibits Proinflammatory Response in Glial Cells: A Possible Role of AMP-Activated Protein Kinase

Shailendra Giri,¹ Narendra Nath,¹ Brian Smith,¹ Benoit Viollet,³ Avtar K. Singh,^2,4 and Inderjit Singh¹

¹Department of Pediatrics and ²Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, ³Department of Genetic, Development, and Molecular Pathology, Institut Cochin, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, René Descartes University, 24 Rue du Faubourg Saint Jacques, 75014 Paris, France, and ⁴Department of Pathology and Laboratory Medicine, Ralph Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis and metabolic stress. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR) inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines (tumor necrosis factor , interleukin-1, and interleukin-6) and inducible nitric oxide synthase in primary rat astrocytes, microglia, and peritoneal macrophages. AICAR attenuates the LPS-induced activation of nuclear factor B via downregulation of IB kinase / activity. It also inhibits nuclear translocation of CCAAT/enhancer-binding protein (C/EBP) transcription factor by inhibiting the expression of C/EBP- in brain glial cells. The dominant negative form of AMPK₂ (D157A) and its antisense documents a possible role of AMPK in the regulation of the cellular proinflammatory process. AICAR also inhibited the production of inflammatory mediators in serum and their expression in CNS of rats injected with a sublethal dose of LPS by intraperitoneal injection. These observations in cultured cells as well as in the animal model suggest that AICAR may be of therapeutic value in treating inflammatory diseases.

Key words: glia; AICAR; NF-B; inflammation; C/EBP; AMPK

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Received Sep 20, 2003; revised November 4, 2003; accepted November 4, 2003.

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