Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD.

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.

• Authors: Jureepon Roboon, Tsuyoshi Hattori, Hiroshi Ishii, Mika Takarada-Iemata, Dinh Thi Nguyen, Collin D Heer, Denis O'Meally, Charles Brenner, Yasuhiko Yamamoto, Hiroshi Okamoto, Haruhiro Higashida, Osamu Hori
• Journal: Journal of neurochemistry (J Neurochem) Vol. 158 Issue 2 Pg. 311-327 (07 2021) ISSN: 1471-4159 [Electronic] England
• PMID: 33871064 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 International Society for Neurochemistry.

Chemical References

• Chemokines
• Cytokines
• Lipopolysaccharides
• Membrane Glycoproteins
• NF-kappa B
• Pyridinium Compounds
• nicotinamide-beta-riboside
• NAD
• Niacinamide
• Apigenin
• Cd38 protein, mouse
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase 1 (antagonists & inhibitors)
• Animals
• Apigenin (pharmacology)
• Astrocytes (drug effects, pathology)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Gene Deletion
• Hippocampus (drug effects, metabolism)
• Inflammation (chemically induced, pathology)
• Injections, Intraventricular
• Lipopolysaccharides (administration & dosage)
• Macrophage Activation (drug effects)
• Male
• Membrane Glycoproteins (antagonists & inhibitors)
• Mice
• Mice, Inbred ICR
• Mice, Knockout
• Microglia (drug effects, pathology)
• NAD (metabolism, pharmacology)
• NF-kappa B (genetics)
• Nerve Degeneration
• Niacinamide (analogs & derivatives, pharmacology)
• Pyridinium Compounds (pharmacology)