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Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide‐induced microglial and astrocytic neuroinflammation by increasing NAD +
Author(s) -
Roboon Jureepon,
Hattori Tsuyoshi,
Ishii Hiroshi,
TakaradaIemata Mika,
Nguyen Dinh Thi,
Heer Collin D.,
O'Meally Denis,
Brenner Charles,
Yamamoto Yasuhiko,
Okamoto Hiroshi,
Higashida Haruhiro,
Hori Osamu
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15367
Subject(s) - neuroinflammation , nad+ kinase , microglia , cd38 , lipopolysaccharide , nicotinamide adenine dinucleotide , nicotinamide , pharmacology , chemistry , biology , biochemistry , immunology , inflammation , microbiology and biotechnology , stem cell , cd34 , enzyme
Abstract Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD + ) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD + , suppressed cuprizone‐induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD + level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD + on lipopolysaccharide (LPS)‐induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS‐induced inflammatory responses and glial activation. Pre‐administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD + precursor, increased NAD + level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS‐induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD + , NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF‐κB signaling pathway in microglia. These results suggest that CD38‐mediated neuroinflammation is linked to NAD + consumption and that boosting NAD + by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain.