Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin

Brain “fog” is a constellation of symptoms that include reduced cognition, inability to concentrate and multitask, as well as loss of short and long term memory. Brain “fog” characterizes patients with autism spectrum disorders (ASDs), celiac disease, chronic fatigue syndrome, fibromyalgia, mastocytosis, and postural tachycardia syndrome (POTS), as well as “minimal cognitive impairment,” an early clinical presentation of Alzheimer's disease (AD), and other neuropsychiatric disorders. Brain “fog” may be due to inflammatory molecules, including adipocytokines and histamine released from mast cells (MCs) further stimulating microglia activation, and causing focal brain inflammation. Recent reviews have described the potential use of natural flavonoids for the treatment of neuropsychiatric and neurodegenerative diseases. The flavone luteolin has numerous useful actions that include: anti-oxidant, anti-inflammatory, microglia inhibition, neuroprotection, and memory increase. A liposomal luteolin formulation in olive fruit extract improved attention in children with ASDs and brain “fog” in mastocytosis patients. Methylated luteolin analogs with increased activity and better bioavailability could be developed into effective treatments for neuropsychiatric disorders and brain “fog.”


Introduction
Brain "fog" is a constellation of symptoms that include reduced mental acuity and cognition, inability to concentrate and multitask, as well as loss of short and long-term memory. Brain "fog" characterizes patients with many neuroimmune diseases (Theoharides, 2013a) with celiac disease (Lebwohl and Ludvigsson, 2014;Lichtwark et al., 2014) chronic fatigue syndrome (Ocon, 2013), fibromyalgia and tachycardia postural syndrome (POTS) (Ross et al., 2013), as well as those with autism spectrum disorders (ASDs) and "minimal cognitive impairment, " which is now considered the early clinical presentation of Alzheimer's disease (AD) (Drzezga et al., 2011). Moreover, patients on chemotherapy often experience brain "fog" (Raffa, 2011).
Brain "fog" is particularly common in patients with systemic mastocytosis (SM) (Theoharides et al., 2015c) or disorders of mast cell (MC) activation (Valent et al., 2012;Petra et al., 2014). A recent survey of the symptoms experienced by patients with MC disorders reported that >90% of them experienced moderate to severe brain "fog" almost daily (Moura et al., 2012) and cognitive impairment was confirmed using a validated instrument (Moura et al., 2012). Patients with MC disorders also experience other related neurologic (Smith et al., 2011) and psychiatric (Moura et al., 2014) symptoms. It is interesting that children with mastocytosis were reported to have increased risk of developing ASDs compared to the general population (Theoharides, 2009). Children with ASDs are also characterized by brain "fog" (Rossignol and Frye, 2012) and focal brain inflammation  with MC activation being implicated in their pathogenesis Theoharides, 2013b).

Pathogenesis/Focal Inflammation
Inflammatory molecules, secreted in the brain could contribute to the pathogenesis of such diseases (Theoharides et al., 2004b) possibly including brain "fog." Brain expression of proinflammatory genes was increased in the brains of deceased patients with neuropsychiatric diseases (Theoharides et al., 2011b).
In fact, cross-talk between MCs and microglia is being considered critical in the pathogenesis of neurodegenerative diseases (Skaper et al., 2012(Skaper et al., , 2013 (Figure 1). Microglia activation is a common finding in brains of children with ASDs (Pardo et al., 2005;Sandoval-Cruz et al., 2011;Gupta et al., 2014), as well as in other psychiatric diseases (Beumer et al., 2012). Activation of microglia directly or indirectly by corticotropinreleasing hormone (CRH) could contribute to the pathogenesis of mental disorders (Kritas et al., 2014b).
Maternal administration of the viral substitute poly (I:C) produced autism-like behavior in mice that was dependent on IL-6 (Hsiao et al., 2012) and was absent in IL-6 knock-out mice (Smith et al., 2007). We had shown that acute immobilization stress significantly increased serum IL-6 and this was absent in MC deficient mice (Huang et al., 2003). It was recently reported that plasma IL-6 was significantly increased after social stress, especially in mice that developed a phenotype susceptible to stress, while IL-6 −/− mice were resilient to social stress (Hodes et al., 2014).
It appears that some histamine is necessary for alertness, learning and motivation, but too much histamine shuts the system down, in MCs and histaminergic neurons, by activating H3 autoinhibitory receptors leading to brain "fog" ( Table 1).
Brain histamine can be increased by triggers of brain MCs, by histamine-containing foods (Bodmer et al., 1999;Maintz and Novak, 2007;Schwelberger, 2010;Prester, 2011), histamine produced by bacteria (Landete et al., 2008), or overuse of H1 receptor antagonists that would shift histamine binding from H1 to H3 receptors leading to autoinhibition of histamine synthesis and release (Table 1). In fact, we had shown that in rats at least only brain MCs express functional H3 receptors (Rozniecki et al., 1999b), as evidenced by the fact that an H3 receptor agonist inhibited while at H3 receptor antagonist augmented histamine and serotonin release only from brain, but not peritoneal MCs.
Flavonoids (Figure 2) are naturally occurring compounds mostly found in green plants and seeds (Middleton et al., 2000). Unfortunately, our modern life diet contains progressively fewer flavonoids and under these conditions, the average person cannot consume enough to make a positive impact on health. Moreover, less than 10% of orally ingested flavonoids are absorbed (Passamonti et al., 2009;Thilakarathna and Rupasinghe, 2013) and are extensively metabolized to inactive ingredients in the liver .
Flavonoids have been proposed as possible therapeutic agents for CAD Perez-Vizcaino and Duarte, 2010;Yap et al., 2010). A meta analysis of epidemiological studies showed an inverse relationship between flavonol/flavone intake and CAD (Perez-Vizcaino and Duarte, 2010). A review of publications from European and US population cohorts reported that consumption of flavonoids was strongly associated with lower CAD mortality (Peterson et al., 2012). A double-blind, placebo-controlled, randomized clinical study using the polyhenolic compound Pycnogenol showed improved endothelial function in patients with CAD (Enseleit et al., 2012) and a study of 2-week consumption of a polyphenolic drink lowered urinary biomarkers of CAD (Mullen et al., 2011).
Flavonoids can also inhibit acetylcholinesterase (Tsai et al., 2007;Boudouda et al., 2015), which will increase acetylcholine and improve memory ( Table 1). It is of interest that luteolin further inhibits release of the excitatory neurotransmitter glutamate , while it activates receptors for the inhibitory neurotransmitter γ-amino butyric acid (GABA) independent of GABA, suggesting it may also have a calming effect (Hanrahan et al., 2011). In fact, benzodiazepines that act by activating GABA receptors were shown to bind to MCs (Miller et al., 1988).

Conclusion
Presently, 1 in 20 individuals over the age of 65 has dementia, while just the European population over 65 will rise from 17.4% in 2010 to 24% in 2030 or about 200 million people (United Nations Department of Economic and Social Affairs Population Division, 2015). The cost of caring for AD patients in the US is estimated to be $220 billion per year (Alzheimers Association, 2015). These numbers do not include brain "fog" present in the others disorders discussed. For instance, the cost of ASDs to the US economy is estimated at $ 180 billion per year. It is therefore obvious that any effective treatment will make a significant difference both to the health of the patients and to the economy. However, in spite of intensive research, clinical trials targeting Aβ have failed (Corbett et al., 2012) necessitating new therapeutic targets and there are no effective treatments for the other neuropsychiatric disorders discussed.
Flavonoids are generally considered safe (Kawanishi et al., 2005;Harwood et al., 2007;Seelinger et al., 2008;Corcoran et al., 2012;Theoharides et al., 2014). Unfortunately, some of the cheaper sources of flavonoids found in dietary supplements are from peanut shells and fava beans and may lead to anaphylactic reactions or hemolytic anemia to allergic and G 6 PD-deficient individuals, respectively. Flavonoids are extensively metabolized  primarily through glucoronidation, methylation, and sulphation (Hollman et al., 1995;Hollman and Katan, 1997). Therefore, flavonoids must be used with caution when administered with other natural polyphenolic molecules (e.g., curcumin, resveratrol) or drugs metabolized by the liver as they may affect the blood levels of themselves or of other drugs (Theoharides and Asadi, 2012). Tetramethoxyluteolin is already methylated and less likely to affect liver metabolism, is more stable (Walle, 2007), and has better bioavailability (Wei et al., 2014). Intranasal tetramethoxyluteolin preparations would offer the additional advantage of delivering the flavonoid directly to the brain through the cribriform plexus as was shown for some other compounds (Zhuang et al., 2011).

Disclosures
TT is on the Scientific Advisory Board of the Mastocytosis Society (http://www.tmsforacure.org/) and on the Board of Directors of two nonprofit foundations (http://www.braingate. org; www.autismfreebrain.org). JS is the TMS regional patient support leader for Michigan. TT is the recipient of US Patent No. 8,268,365 for the treatment of brain inflammation, US Patent No. 7,906,153 for the treatment of multiple sclerosis, and US Patent No. 13/009.282 for the diagnosis and treatment of ASDs.