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The potential role of brain proinflammatory cytokines in the brain in the pathogenesis of psychiatric diseases was discussed almost 10 years ago. Increasing evidence implicates brain inflammation in neuropsychiatric diseases, including depression, bipolar disease, and autism spectrum disorders (ASD). Genome analysis of brains from deceased patients with bipolar disorder, depression, and schizophrenia showed increased expression of inflammatory genes and decreased expression of mitochondrial function. Other studies have also implicated mitochondrial dysfunction and neuroinflammation in Alzheimer disease, as well as in ASD, in which it was shown that extracellular mitochondrial components were increased in the serum of patients with ASD and could trigger autoinflammatory responses. In fact, nonsteroidal anti-inflammatory drugs have been considered in schizophrenia. However, nonsteroidal anti-inflammatory drugs reduce the antidepressant action of specific serotonin receptor antagonists. Moreover, corticosteroids that have strong anti-inflammatory effects can induce or exacerbate depression. In this void, certain natural flavonoids with anti-inflammatory actions have been used for neuropsychiatric diseases, and their intake was associated with decreased incidence of dementia in a 23-country study. Moreover, the use of polyphenolic compounds that contain flavonoids in psychiatric and cognitive disorders has been reviewed recently. Quercetin is a flavonol, and luteolin is a structurally related flavone, with 1 less hydroxyl group in the center ring. Both are rich in onions, tea, apples, and broccoli, with luteolin being more plentiful in olive FRUITextract, CHAMOMILE, celery, spinach, and oregano. Luteolin reduces amyloid-beta peptide production in human transgenicbearing neuronlike cells and primary neurons. A number of comprehensive reviews have shown that the flavonol quercetin and its structurally related flavone luteolin are safe. In fact, these flavonoids seem safer than most of the psychotropic drugs prescribed to children. A recent study actually showed that a formulation of luteolin and quercetin was both well tolerated and resulted in significant improvement of children with ASD. The case of luteolin is particularly interesting. Luteolin has been shown to have anti-inflammatory, antiallergic, and neuroprotective properties. It also inhibits mercury-induced activation of human mast cells, T-cell activation, and activation of peripheral blood mononuclear cells derived from patients with multiple sclerosis. In animal models, luteolin inhibited ASD-like symptoms, along with related biochemical changes. Moreover, luteolin increases spatial memory in mice and reduces cognitive decline in rats. It, therefore, came as a surprise that a recent publication reported that luteolin and quercetin have detrimental effects on the hormonal ‘‘system’’ and in ‘‘models’’ of breast and endometrial cancer. In particular, these authors reported that luteolin has estrogenic activity and antagonizes progesterone receptor activation. These results were obtained using transformed cell lines that can hardly qualify as a system or model of any disease. Moreover, other authors using different cell lines have reached opposite conclusions. For instance, 1 study reported that luteolin inhibits estrogen production, whereas another showed that progesterone does not bind to the progesterone receptor. In fact, there are hundreds of publications showing that these flavonoids, and especially luteolin, have potent anticancer actions. Most importantly, recent articles reported that combining luteolin with quercetin, as well as with celcoxib, had more potent anticancer effect than each one individually. Finally, the consumption of luteolin or quercetin at 200 to 400 mg/d found in some GMPmanufactured dietary supplements would never reach the concentrations used in the aforementioned article because oral absorption of these flavonoids is less than 10%. Even if one were to assume that the entire body is 1 compartment, the blood concentrations reached after consuming COMMENTARY

Brain Inflammation, Neuropsychiatric Disorders, and Immunoendocrine Effects of Luteolin