Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Neuroprotective Parkinson Disease Protein DJ-1 in Astrocytes and Neurons

Abstract

DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21ras farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21ras alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21ras in DJ-1 expression. However, an inhibitor of geranyl geranyl transferase (GGTI) and a dominant-negative mutant of p21rac had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21ras, but not p21rac, is involved in the regulation of DJ-1.

Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

“…Immunostaining of Cells-Immunocytochemistry was performed as described earlier (29). Briefly, mouse primary astrocytes or neurons cultured to 70 -80% confluence in 8-well chamber slides were fixed with chilled methanol (Fisher Scientific, Waltham, MA) overnight, followed by two brief rinses with filtered PBS.…”

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…Immunostaining of Cells-Immunocytochemistry was performed as described earlier (25). Briefly, 8-well chamber slides containing mouse primary astrocytes, mouse neurons, human primary astrocytes, or SH-SY5Y cells cultured to 70 -80% confluence were fixed with chilled methanol (Fisher) overnight, followed by two brief rinses with filtered PBS.…”

Benzoate and Sorbate Salts: A Systematic Review of the Potential Hazards of These Invaluable Preservatives and the Expanding Spectrum of Clinical Uses for Sodium Benzoate

“…As indicated above, there are a number of situations where SB appears to be anti-inflammatory (Brahmachari and others 2009;Maier and others 2010), or exerts more of an antioxidant than a prooxidant action (Khasnavis and Pahan 2012;Modi and others 2015). Furthermore, prolonged oral administration of SB to UCD patients is clearly a very effective therapeutic intervention, with no reports to date of major adverse effects (Husson and others 2016).…”

“…Treatment with SB leads to an upregulation of DJ-1, a protein that is protective against oxidative stress in primary mouse and human astrocytes, as well as human neurons (Khasnavis and Pahan 2012). DJ-1 is also thought to be neuroprotective, since loss-offunction mutations in this protein have been linked to a familial form of early onset Parkinson's disease.…”

“…Furthermore, prolonged oral administration of SB to UCD patients is clearly a very effective therapeutic intervention, with no reports to date of major adverse effects (Husson and others 2016). As described above, SB is now attracting increased interest as a potentially promising agent for use in conjunctive therapy during the treatment of liver failure (De Las Heras and others 2017), MS (Kundu and others 2016), schizophrenia (Lane and others 2013;Matsuura and others 2015), early-stage AD (Lin and others 2014), and Parkinson's disease (Khasnavis and Pahan 2012).…”