Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others. Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)
- EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
- Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
- Aging influences increased expression of GSK-3b. (Mercado-Gomez)
- GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
- Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness
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