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Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Reduces Microglial and Astroglial Inflammatory Responses¹

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612

Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology of several neurodegenerative disorders. This study explores the anti-inflammatory property of cinnamon metabolite sodium benzoate (NaB) in microglia and astrocytes. NaB, but not sodium formate, was found to inhibit LPS-induced expression of inducible NO synthase (iNOS), proinflammatory cytokines (TNF- and IL-1β) and surface markers (CD11b, CD11c, and CD68) in mouse microglia. Similarly, NaB also inhibited fibrillar amyloid β (Aβ)-, prion peptide-, double-stranded RNA (polyinosinic-polycytidylic acid)-, HIV-1 Tat-, 1-methyl-4-phenylpyridinium⁺-, IL-1β-, and IL-12 p40₂-induced microglial expression of iNOS. In addition to microglia, NaB also suppressed the expression of iNOS in mouse peritoneal macrophages and primary human astrocytes. Inhibition of NF-B activation by NaB suggests that NaB exerts its anti-inflammatory effect through the inhibition of NF-B. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on iNOS expression, and NF-B activation by hydroxymethylglutaryl-CoA, mevalonate, and farnesyl pyrophosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the anti-inflammatory effect of NaB. Furthermore, we demonstrate that an inhibitor of p21^ras farnesyl protein transferase suppressed the expression of iNOS, that activation of p21^ras alone was sufficient to induce the expression of iNOS, and that NaB suppressed the activation of p21^ras in microglia. These results highlight a novel anti-inflammatory role of NaB via modulation of the mevalonate pathway and p21^ras.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the National Institutes of Health (NS39940), Alzheimer’s Association (IIRG-07-58684), and Michael J. Fox Foundation for Parkinson’s Research.

² Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. E-mail address: kpahan{at}rush.edu

³ Abbreviations used in this paper: AD, Alzheimer’s disease; HAD, HIV-associated dementia; MS, multiple sclerosis; NaB, sodium benzoate; FDA, Food and Drug Administration; iNOS, inducible NO synthase; HMG, CoA, hydroxymethylglutaryl-CoA; NaFO, sodium formate; poly(IC), polyinosinic-polycytidylic acid; MPP, 1-methyl-4-phenylpyridinium; p40₂, p40 homodimer; GFAP, glial fibrillary acidic protein; PBST, PBS-Tween 20; Aβ, amyloid β; PrP, prion peptide; wtNBD, wild-type IKK NEMO-binding domain peptide; FPT inhibitor II, inhibitor of p21^ras farnesyl protein transferase; FPP, farnesyl pyrophosphate; IKK-, IB kinase-.