By Teresa Conrick
In Part 1, I discussed some connections between melanin, autism and cancer. I started on this research road as my red-haired, teen daughter, who regressed after vaccines, is brutally affected with health issues, behaviors of autism and now with extraordinary estrogen dominance and seizures. Those factors kept me challenged into pursuing causation and treatments. I kept coming across more research that connected so many of her health issues -- for example -- (HERE)
"The presence of GluRs in the follicles and the corpus luteum in the ovary of rats and monkeys suggests a possible female sex steroid-GluRs interaction. It is possible that the glutaminergic excitation system may play a role in the up- or down-regulation of estrogen and progesterone."
So I had to keep looking and saw that the metabotropic glutamate receptors are not only involved in autism but also cancer. Looking deeper into their mechanism of action brings us to a closer, more magnified look. What seems to be a pattern is something called protein kinase and phosphorylation. A cell's ability to respond to its extracellular environment involves a complex and highly organized series of events referred to as cellular signalling. "Signalling processes regulate fundamental cellular responses and abrogation of these processes can lead to the development of various human diseases. Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer." Tyrosine kinase – Role and significance in Cancer (HERE)
Now lets take a look at Riluzole at this new magnification. We saw from Part 1 that it is being used for ALS and also now in Clinical Trials via NIH and NCI for breast cancer: David H. Gorski, Barbara Ann Karmanos Cancer Institute/Wayne State University, Detroit MI(HERE) :
Ten years ago, this study was done about Riluzole and its effect on tyrosine phosphorylation which seems very pertinent in this exploration. 2001 Jun - "Effects of riluzole on N-methyl-D-aspartate-induced tyrosine phosphorylation in the rat hippocampus".
"Since increased tyrosine phosphorylation has been observed in response to brain ischemia, we investigated whether riluzole (an inhibitor of glutamate neurotransmission with neuroprotective properties) affects tyrosine phosphorylation stimulated by N-methyl-D-aspartate (NMDA) in rat hippocampal slices. Riluzole produced an extremely potent concentration-related inhibition of NMDA (1 mM)-stimulated protein tyrosine phosphorylation....These results suggest that inhibition of tyrosine phosphorylation may contribute to the neuroprotective effects of riluzole against excitotoxic injury."
This could then be a key into more observations. First a closer look at how mercury is involved in this cellular signaling:
"Low and Nontoxic Inorganic Mercury Burdens Attenuate BCR-Mediated Signal Transduction" HERE 2007 Department of Immunology and Microbiology, Wayne State University, Detroit, MI Department of Pharmacology, Wayne State University, Detroit, MI
"The ubiquitous environmental heavy metal contaminant mercury (Hg) is a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease. However, the mechanism(s) whereby Hg initiates or perpetuates autoimmune responses, especially at the biochemical/molecular level, remain poorly understood. inorganic mercury (Hg+2) interfered with BCR-mediated growth control, suggesting that BCR signal strength was impaired by Hg+2. Extracellular signal-regulated kinase (ERK) 1,2 mitogen-activated protein kinase (MAPK) is responsible for the activation of several transcription factors in B cells. Phosphorylation of ERK serves as an essential node of signal integration Hg+2 does not seem to act directly on ERK-MAPK but rather on an upstream element or elements of the BCR signal transduction pathway, above the level of the key protein tyrosine kinase Syk. Our data suggest that the site of action of Hg+2 may very well be localized on the plasma membrane. These findings support a connection between Hg+2 and attenuated BCR signal strength in the etiology of autoimmune disease."
In 1999, another related study: "Low and nontoxic levels of ionic mercury interfere with the regulation of cell growth in the WEHI-231 B-cell lymphoma" - Institute of Chemical Toxicology, Wayne State University, Detroit, USA "These data suggest that low levels of mercury, which are not toxic, may still contribute to immune dysfunction by interfering with antigen-receptor-mediated and protein-kinase-dependent signal transduction in lymphocytes"
and more evidence:
"Mercuric chloride activates the Src-family protein tyrosine kinase, Hck in myelomonocytic cells" 2000 HERE
Hck is a member of the Src-family of protein tyrosine kinases that appears to function in mature leukocytes to communicate a number of extracellular signals including various cytokines. In this study we show that the thiolreactive heavy metal, mercuric chloride (HgCl2) induces rapid and robust activation of tyrosine phosphorylation within human myelomonocytic cells. ... The ability of HgCl2 to activate Src-family kinases such as Hck in hematopoietic cells may help explain why exposure to the heavy metal is associated with immune system dysfunction in rodents as well as humans. Keywords: autoimmune disease; Src-family kinases; Syk; tyrosine phosphorylation
"Differential effects of methylmercury on the phosphorylation of protein species in the brain of acutely intoxicated rats" HERE received Oct 1993 - available online Nov 2002
"The in vivo effect of methylmercury (MeHg) on the phosphorylation in vitro of the brain cytosol fraction was examined in acutely poisoned rats. Two-dimensional electrophoretic analysis of the phosphorylated cytosol fractions from control and MeHg-treated rats revealed that (1) the extents of phosphorylation of the 24 major protein species in the control rats differed greatly from each other, (2) the effect of MeHg on the phosphorylation was not uniform regarding the individual 24 proteins or the period of intoxication, and (3) in the symptomatic period, many protein species including tubulin subunits showed elevated phosphorylation, while a few protein species showed decreased phosphorylation. These results suggest that the neurotoxic action of MeHg could be mediated through, at least in part, the modification of functional protein species due to excess phosphorylation that leads to impairment of the normal cellular processes."
There is much more but let's instead take a look at Thimerosal, the mercury used in vaccines:
"Effects of Thimerosal on NGF Signal Transduction and Cell Death in Neuroblastoma Cells" 2005 HERE
"Ethylmercury and its decomposition product, Hg2+, rapidly accumulate in the tissues (Magos, 2001), preferentially in the kidneys and brain (Blair et al., 1975). Following in vivo administration, ethylmercury passes through cellular membranes and concentrates in cells of vital organs, including the brain, where it releases inorganic mercury, raising its concentrations higher than equimolar doses of its close and highly toxic relative methylmercury (Magos et al., 1985). ..........the unique dependence of the developing nervous system on growth factors suggests that the neurotrophins and their receptors represent a possible target for thimerosal. There are a several studies suggesting that thimerosal may alter neurotrophin signaling, including binding of secondary messengers (Vanlingen et al., 2001), microtubule assembly (Alexandre et al., 2003), and intracellular calcium concentrations (Ueha-Ishibashi et al., 2004a). Concentrations of thimerosal showing an effect on the development and viability of undifferentiated human neuroblastoma cells and neurotrophin cell signaling in terms of protein phosphorylation and cell viability are of interest. ------(neurotrophins are usually tyrosine kinase receptors)
To summarize : "Mercury salts have been shown to affect cytokine production by triggering Ca2+ signals and activating protein kinase C" HERE
And yet still, a closer look at Riluzole as we magnify that view:
"Riluzole has several actions: Sodium channel blockade High-voltage calcium channel blockade N-methyl-D-aspartate (NMDA)/glutamate receptor antagonism Glutamate transporter activation. Inhibition of protein kinase C. Riluzole preferentially blocks TTX sensitive sodium channels, which are associated with damaged neurons. This reduces influx of calcium ions and indirectly prevents stimulation of glutamate receptors. Together with direct glutamate receptor blockade, the effect of the neurotransmitter glutamate on motor neurons is greatly reduced. However, the action of Riluzole on Glutamate receptors has been controversial, as no binding of the molecule has been shown on any known receptor. In addition as its antiglutamate action is still detectable in the presence of sodium channel blockers, it is also uncertain whether or not it acts via this way."
Riluzole MSDS HERE
Interestingly, this was an abstract from IMFAR, International Meeting For Autism Research, just this past month, May, 2011 - "Brain Region-Specific Decrease In the Activity of Protein Kinase C, and Increase In Activated MAP Kinases In Regressive Autism" HERE
"The aim of this study was to compare the activity of PKC and the levels of activated MAP-kinases, namely c-jun N-terminal kinase (JNK), MAPK/extracellular signal-regulated kinase-1 (MEK 1) and P38 kinase in postmortem brain tissue samples from individuals with regressive autism, autistic subjects without clinical history of regression, and age-matched control subjects. Results: The activity of PKC was significantly decreased in the frontal cortex of individuals with regressive autism compared to developmentally normal subjects and autistic individuals without regression. Conclusions: These results suggest that regression in autism may in part, be associated with oxidative stress and altered PKC-mediated phosphorylation of proteins involved in cell signaling."
This also shows a possible clue for autism then: "Seizure-induced protein tyrosine phosphorylation in rat brain regions" 1991
"Phosphorylation of protein tyrosines is an important modulatory process for cell signaling and other cellular functions. Rat brain regions were examined for altered protein phosphotyrosines, using Western blot analysis and microwave irradiation to limit postmortem alterations, after administration of two convulsants: lithium plus pilocarpine or kainic acid (KA). Most phosphotyrosine proteins were unaltered by these treatments, but there was a large, specific increase in the tyrosine phosphorylation of a 40-Kd protein. This increase was evident in all three regions examined: cerebral cortex, hippocampus, and striatum; it occurred abruptly with onset of generalized status epilepticus (SE) and remained elevated for at least 90 min. Most of the tyrosine phosphorylated 40-Kd protein was in the cytosolic fraction. These results demonstrate a large, specific effect of chemically induced seizures on a single phosphotyrosine protein in rat brain."
This process of protein kinase - phosphorylation extends to other diseases:
"Scientists shed light on what causes neuron death in Parkinson patients" January 7, 2011 HERE
"Study finds blocking tyrosine kinase c-Abl activation preserves parkin function, spares neurons. Just 5% of Parkinson disease cases can be explained by genetic mutation, while the rest have no known cause. But a new discovery by researchers at The University of Texas Health Science Center may begin to explain why the vast majority of Parkinson patients develop the progressive neurodegenerative disease....After analyzing cells and postmortem brain tissue from animals and humans, researchers noted that oxidative stress—a known culprit in neuron death—activated the protein tyrosine kinase c-Abl in the nigra-striatum area of the brain. Neurons in this part of the brain are particularly vulnerable to Parkinson disease injury...
“When we blocked tyrosine kinase c-Abl activation, parkin function was preserved and neurons were spared,” Dr Imam said. “We believe these studies provide sound rationale for moving forward with a preclinical trial of tyrosine kinase c-Abl inhibitors, with the goal of developing a potent therapeutic drug for slowing the progression of Parkinson’s.” If preclinical trials in animal models of Parkinson disease yield positive results, the next step would be clinical trials in human patients, Dr Imam said. Tyrosine kinase c-Abl inhibitors are approved by the FDA for treating myeloid leukemia and gastrointestinal tumors."
"Altered protein tyrosine phosphorylation in Alzheimer's disease" 1991 HERE
The activity of protein tyrosine kinase was determined in extracts from Alzheimer's disease brains and age- and postmortem time-matched control brains at autopsy using the synthetic peptide substrate poly(Glu4Tyr1). These results suggest that altered protein tyrosine kinases and protein tyrosine phosphorylation are involved in the pathology of Alzheimer's disease.
"Protein tyrosine kinases in malignant melanoma" Oct 2000
"Protein tyrosyl phosphorylation is an essential component in intracellular signalling, with diverse and crucial functions including mediation of cell proliferation, survival, death, differentiation, migration and attachment. It is regulated by the balance between the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases. ..... PTKs expressed in significant amounts in both benign and malignant melanocytes, such as insulin-like growth factor-1 receptor (IGF1-R), FGF-R1, HER2/NEU and FAK, are likely to play a role in melanoma genesis and progression."
"The Association Between Parkinson's Disease and Melanoma" March 2011 HERE
"Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of melanin-positive, dopaminergic neurons in the substantia nigra. Although there is convincing epidemiologic evidence of a negative association between PD and most cancers, a notable exception to this is that melanoma, a malignant tumor of melanin-producing cells in skin, occurs with higher-than-expected frequency among subjects with PD and that melanoma patients are more likely to have PD. A clear biological explanation for this epidemiological observation is lacking. Here, we present a comprehensive review of published literature exploring the association between PD and melanoma. On the basis of published findings, we conclude that (i) changes in pigmentation including melanin synthesis and/or melanin synthesis enzymes, such as tyrosinase and tyrosine hydroxylase, play important roles in altered vulnerability for both PD and melanoma"
"US Parkinson's Rates Highest in Whites, Hispanics, and Midwest, Northeast"
ScienceDaily (Feb. 3, 2010) — The largest epidemiological study of Parkinson's disease in the United States has found that the disease is more common in the Midwest and the Northeast and is twice as likely to strike whites and Hispanics as blacks and Asians.
"The study, based on data from 36 million Medicare recipients, is both the first to produce any significant information on patterns of Parkinson's disease in minorities and to show geographic clusters for the condition. "Finding clusters in the Midwest and the Northeast is particularly exciting," says lead author Allison Wright Willis, M.D., assistant professor of neurology at Washington University School of Medicine in St. Louis. "These are the two regions of the country most involved in metal processing and agriculture, and chemicals used in these fields are the strongest potential environmental risk factors for Parkinson's disease that we've identified so far."
Please stay tuned for Part 3 as we explore more connections. Autism and many of these environmental illnesses appear man-made. We are all canaries in the coal mine and we must take back our God-given health.
Teresa Conrick is Contributing Editor for Age of Autism