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.”
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 pro-inflammatory genes was increased in the brains of deceased patients with neuropsychiatric diseases (Theoharides et al., 2011b).
It is still not clear what triggers brain inflammation. Mounting evidence suggests that stress (Theoharides et al., 2011b) and exposure to mold (Crago et al., 2003; Shoemaker and House, 2006; Reinhard et al., 2007; Shenassa et al., 2007; Empting, 2009), especially airborne mycotoxins (Rea et al., 2003; Gordon et al., 2004; Kilburn, 2009; Brewer et al., 2013), may be involved. It is interesting that mold can potentiate histamine release from MCs (Larsen et al., 1996).
In fact, cross-talk between MCs and microglia is being considered critical in the pathogenesis of neurodegenerative diseases (Skaper et al., 2012, 2013) (Figure (Figure1).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 corticotropin-releasing hormone (CRH) could contribute to the pathogenesis of mental disorders (Kritas et al., 2014b).
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”
Luteolin (5,7-3′5′-tetrahydroxyflavone) has potent antioxidant, anti-inflammatory (Middleton et al., 2000) and MC inhibitory activities (Kimata et al., 2000; Kempuraj et al., 2005; Asadi et al., 2010) and also inhibits auto-immune T cell activation (Verbeek et al., 2004; Kempuraj et al., 2008) (Table (Table2).2). Luteolin also inhibits microglial IL-6 release (Jang et al., 2008), microglial activation and proliferation (Chen et al., 2008; Dirscherl et al., 2010; Kao et al., 2011), as well as microglia-induced neuron apoptosis (Zhu et al., 2011).
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.
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.
