We read with interest the comments by Drs Manev and Manev (2006) concerning upregulation in two S100 genes, namely S100A8 and S100A9 in the frontal cortex of rats treated chronically by olanzapine (Fatemi et al, 2006).
The S100 proteins consist of a superfamily of EF-hand calcium binding proteins, which contribute to various cell signaling pathways by modulating Ca levels and regulating cellular growth, transcription and differentiation, and cell-cycle progression (Heizmann et al, 2002). Several members of S100 family like S100A8/A9 and S100B can be secreted from cells and exhibit cytokine-like extracellular functions related to inflammation (Heizmann et al, 2002). S100A8 is involved in inflammatory response and associated with oxidative defense (Hsu et al, 2005). Glucocorticoids increase constitutive levels of both A8 and A9 forms of S100 mRNA in human monocytes (Hsu et al, 2005). Moreover, increases in S100A8 have been associated with several acute and chronic inflammatory conditions and involved in inflammatory demyelination (Chen et al, 2002). More recently, significant elevations in levels of several S100 genes (S100A6, A8, A9, A11, A12, S100P, and S100Z) were observed in lymphocytes of patients with Kawasaki disease (Ebihara et al, 2005). A recent study implicates S100A9 and S100A12 as being involved in brain plaques observed in Alzheimer's cases (Shepherd et al, 2005) alluding to the inflammatory nature of these proteins.
Additionally, a recent report by Svenningsson et al (2006) indicated an increase in levels of S100A10 protein (p11) in mouse brains in response to administration of antidepressants. It was also suggested that S100A10 levels were reduced in brains of subjects with depression (Svenningsson et al, 2006) and that deficiency in S100A10 protein may be the cause for lack of availability of 5-HT1B receptors in the brain. As to whether elevations in S100A8 and A9 genes are owing to antidepressant effects of olanzapine, or are simply markers of inflammation and oxidative response by brain, will remain to be determined in future studies. Finally, as noted cogently by Drs Manev and Manev, involvement of several members of S100 proteins as markers of brain response to psychotropic agents like fluoxetine (Manev et al, 2001), olanzapine (Fatemi et al, 2006), imipramine, tranylcypromine, and ECT (Svenningsson et al, 2006) may bode well for potential beneficial effects of these proteins in the treatment of several mental disorders.
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We acknowledge the generous grant support by Stanley Medical Research Institute to SH Fatemi and the clerical assistance by Ms L Iversen.
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Fatemi, S., Reutiman, T. & Folsom, T. Olanzapine Upregulates Genes for S100A8 and S100A9 in the Frontal Cortex of Rats. Neuropsychopharmacol 31, 2568–2569 (2006). https://doi.org/10.1038/sj.npp.1301187