BDNF and Other Neutrophic Factors May Prevent Seizures and Assoc. Inflammation!

Bovolenta, R. et al. Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures. Journal of neuroinflammation 7, 81+ (2010). URL http://dx.doi.org/10.1186/1742-2094-7-81.

Neuroinflammation and Microglia: Considerations and approaches for neurotoxicity assessment

"Recent work, however, has clearly demonstrated that the cellular activities are, for the most part, beneficial. It is when the strict regulatory control normally imposed on them is altered that these cells may begin to show detrimental effects. One could speculate that such functions could be related to senescence and the inability to perform normal activities or the production of pro-inflammatory cytokines exceeding the down-regulatory capacity of the system with either an acute or chronic induction"

Harry, G. J. J. and Kraft, A. D. (2008). Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment. Expert opinion on drug metabolism & toxicology, 4(10):1265-1277. http://www.citeulike.org/user/HEIRS/article/7943439

Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation

Seems to me that the findings from this author are pretty important....:)

"up-regulation of HO-1 in astrocytes is associated with down-regulation of iNOS expression and thereby NO production, an effect that involves the p38 MAPK signaling pathway, which suggests that this glial cell response could play an important protective role against oxidative stress in the brain."

"Sheng, W., Hu, S., Nettles, A., Lokensgard, J., Vercellotti, G., and Rock, R. (2010). Hemin inhibits no production by il-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 mapk activation. Journal of Neuroinflammation, 7(1):51+."

Read more: CiteULike: Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation:

Gut Inflammation and Changes in Intestinal Function From Loss of NO Neurons~!

In a recent study the author writes "enteric neurons are supported by glial cells, the ENS counterparts of astrocytes of the CNS, that can modulate enteric neuron function. Enteric neurons are known to control virtually all GI functions, including motility, secretion, blood flow, mucosal growth and aspects of the local immune system. Consequently, permanent or even transient structural alterations in the ENS, as occur in IBD, disrupt normal GI function. Structural changes in the ENS are predictive of disease evolution suggesting that neuroprotection would decrease disease severity and may play a role in recurrence in CD." Further he continues that under conditions of experimental trichinosis infection in the murine "that in this animal model of colitis, there was a significant loss of nitric oxide synthase- (NOS-) immunoreactive neurons in the myenteric plexus of infected rats. Moreover, the selective loss of NOS-positive neurons appears to underlie changes in motility." (Lakhan) Recent reports also suggest that hormones such as serotonin influences gut regulation and may activate inflammatory cytokines in the intestine leading to alterations in gut function. (Khan) Inflammatory activity such as Tnf-a in the periphery such as the gut may influence production of cytokines and changes in gene expression in the brain that change behavior and have other unexpected health effects.




Khan, W. I. and Ghia, J. E. (2010). Gut hormones: emerging role in immune activation and inflammation. Clinical and experimental immunology, 161(1):19-27.
http://www.citeulike.org/user/HEIRS/article/7323747

Lakhan, S. E. and Kirchgessner, A. (2010). Neuroinflammation in inflammatory bowel disease. Journal of neuroinflammation, 7:37+.
http://www.citeulike.org/user/HEIRS/article/7471133

Estrogen's Influence on Neuroinflammation May Explain Sex Differences in Environmental Illness.

Previously we noted that the estrogen signalling may influence expression of Nrf2 enzymes. A new study provides support that estrogen may provide some protection against LPS exposure effects. It has been noted by a number of researchers the sexual dimorphism that occurs with environmental conditions including CFS, FM and MCS and this relationship could provide a mechanism for the significantly higher prevalence of some EI conditions in women especially as they get older.

"these studies identify a dramatic cytokine- and chemokine-mediated neuroinflammatory response that is regulated through ERalpha- and ERbeta-mediated ligand-dependent and ligand-independent mechanisms"

Read more: CiteULike: Production of Proinflammatory Cytokines and Chemokines During Neuroinflammation: Novel Roles for Estrogen Receptors alpha and beta:

Supplemental Resource: Yao, Y., Brodie, A. M., Davidson, N. E., Kensler, T. W., and Zhou, Q. (2010). Inhibition of estrogen signaling activates the nrf2 pathway in breast cancer. Breast cancer research and treatment. http://www.citeulike.org/user/HEIRS/article/7493023?show_msg=already_posted

GSK-3 Knock-down Allows for Endotoxin Tolerance in Astrocytes~!

"GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance"

Link: CiteULike: Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes.:

Curcumin Exerts Neuroprotective Effects Against Homocysteine Intracerebroventricular Injection-Induced Cognitive Impairment and Oxidative Stress in Rat Brain

Curcumin Exerts Neuroprotective Effects Against Homocysteine Intracerebroventricular Injection-Induced Cognitive Impairment and Oxidative Stress in Rat Brain

Chronic Elevated Ammonia Contributes to Neuroinflammation, Cognitive and Motor Dysfunction.

CiteULike: Hyperammonemia Induces Neuroinflammation that Contributes to Cognitive Impairment in Rats with Hepatic Encephalopathy.: "Chronic moderate hyperammonemia or BDL activated the microglia, especially in cerebellum; increased iNOS, IL-1beta, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls"

Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses

Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.


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)

Notes:

• 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)

For Further Reading:

• 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

Original article and citations located here.

Inhibition of Glycogen Synthase Kinase 3beta (GSK3beta) Decreases Inflammatory Responses in Brain Endothelial Cells.

CiteULike: Inhibition of Glycogen Synthase Kinase 3beta (GSK3beta) Decreases Inflammatory Responses in Brain Endothelial Cells.: "Ramirez, S. H., Fan, S., Zhang, M., Papugani, A., Reichenbach, N., Dykstra, H., Mercer, A. J., Tuma, R. F., and Persidsky, Y. (2010). Inhibition of glycogen synthase kinase 3beta (gsk3beta) decreases inflammatory responses in brain endothelial cells. The American journal of pathology."

MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.

MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.: "URL: MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats.

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HEIRS LIbrary: Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease

CiteULike: Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease: "Rojo, A. I., Innamorato, N. G., Martín-Moreno, A. M., De Ceballos, M. L., Yamamoto, M., and Cuadrado, A. (2009). Nrf2 regulates microglial dynamics and neuroinflammation in experimental parkinson's disease. Glia, 9999(9999):NA+."

Study: Potentiation of methamphetamine neurotoxicity by intrastriatal lipopolysaccharide administration

Title: Potentiation of methamphetamine neurotoxicity by intrastriatal lipopolysaccharide administration.

Summary: "neuroinflammation, oxidative stress, and pro-apoptotic changes in the striatum were more accentuated with combined treatment of LPS and MA compared to either treatment alone. In addition, it is important that cytoplasmic accumulation of alpha-synuclein was observed in the substantia nigra of mice treated with LPS plus MA, and that L-Dopa treatment significantly attenuated behavioral changes and dopaminergic deficits induced by LPS plus MA."

Jung, B. D. D., Shin, E.-J. J., Nguyen, X.-K. T. K., Jin, C.-H. H., Bach, J.-H. H., Park, S. J. J., Nah, S.-Y. Y., Wie, M.-B. B., Bing, G., and Kim, H.-C. C. (2009). Potentiation of methamphetamine neurotoxicity by intrastriatal lipopolysaccharide administration. Neurochemistry international. http://www.citeulike.org/user/HEIRS/article/6003313

Manipulating brain inflammation may help clear brain of amyloid plaques, Mayo Clinic researchers say

"In a surprising reversal of long-standing scientific belief, researchers at the Mayo Clinic campus in Florida have discovered that inflammation in the brain is not the trigger that leads to buildup of amyloid deposits and development of Alzheimer's disease."


Manipulating brain inflammation may help clear brain of amyloid plaques, Mayo Clinic researchers say

Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat.

Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat.

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

Activation of MCP-1/CCl2/CCR2 by TNF-a to cause microglial neuroinflammation and alterations in neurotransmission require the presence of the TNFR1. (D' Mello) The Nrf2 pathway has been shown to modulate inflammatory mediators including Tnf-a and the glutamate antiporter system. (Lewerenz) The TNFR1 receptor is important for preconditioning in ischemia to reduce injury from subsequent ischemia through interaction with the EAAT3. The EAAT3 transporter regulates glutamate and also is involved with glutathione synthesis and is present in cortical and striatal neurons. (Suchak) It works cooperatively with xCT to prevent depletion of glutathione caused by high glutamate levels and may be useful in eventual therapy for Parkinson's. (Lewerenz)

D'Mello, C., Le, T., and Swain, M. G. (2009). Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J. Neurosci., 29(7):2089-2102. http://www.citeulike.org/user/HEIRS/article/4079736
Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. http://www.citeulike.org/user/HEIRS/article/5699931
Pradillo, J., Hurtado, O., Romera, C., Cardenas, A., Fernandeztome, P., Alonsoescolano, D., Lorenzo, P., Moro, M., and Lizasoain, I. (2006). Tnfr1 mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 138(4):1171-1178. http://www.citeulike.org/user/HEIRS/article/5699676
Lewerenz, J., Klein, M., and Methner, A. (2006). Cooperative action of glutamate transporters and cystine/glutamate antiporter system xc- protects from oxidative glutamate toxicity. Journal of neurochemistry, 98(3):916-925. http://www.citeulike.org/user/HEIRS/article/762845
Lewerenz, J., Albrecht, P., Tien, M.-L. T. L., Henke, N., Karumbayaram, S., Kornblum, H. I., Wiedau-Pazos, M., Schubert, D., Maher, P., and Methner, A. (2009). Induction of nrf2 and xct are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5627214
Maher, P., Lewerenz, J., Lozano, C., and Torres, J. L. L. (2008). A novel approach to enhancing cellular glutathione levels. Journal of neurochemistry, 107(3):690-700.
http://www.citeulike.org/user/HEIRS/article/3401858