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A POSSIBLE CENTRAL MECHANISM IN AUTISM SPECTRUM DISORDERS, PART 3: THE ROLE OF EXCITOTOXIN FOOD ADDITIVES AND THE SYNERGISTIC EFFECTS OF OTHER ENVIRONMENTAL TOXINS Russell L. Blaylock,
There is compelling evidence from a multitude of studies of various design indicating that foodborne excitotoxin additives can elevate blood and brain glutamate to levels known to cause neurodegeneration and in the developing brain, abnormal connectivity. Excitotoxins are also secreted by microglial activation when they are in an activated state. Recent studies, discussed in part 1 of this article, indicate that chronic microglial activation is common in the autistic brain. The interac-
tion between excitotoxins, free radicals, lipid peroxidation products, inﬂammatory cytokines, and disruption of neuronal calcium homeostasis can result in brain changes suggestive of the pathological ﬁndings in cases of autism spectrum disorders. In addition, a number of environmental neurotoxins, such as ﬂuoride, lead, cadmium, and aluminum, can result in these pathological and biochemical changes. (Altern Ther Health Med. 2009;15(2):56-60.)
Russell L. Blaylock, MD, is a retired neurosurgeon and visiting professor of biology at Belhaven College, Jackson, Mississippi.
Editor’s note: The following is part 3 of a 3-part series. Parts 1 and 2 appeared in the Nov/Dec 2008 and Jan/Feb 2009 issues of Alternative Therapies in Health and Medicine, respectively.
number of those working with children having one of the autism spectrum disorders have noted a connection between the child’s diet and symptomatology. Explanations for these effects have been focused on either immunological effects or the release of opioid-like substances. A third and more likely mechanism involves excitotoxicity secondary to elevated levels of glutamate, aspartate, and quinolinic acid in the autistic brain. Though food-based cross-reactivity with brain proteins has been demonstrated, as we have seen, bystander damage from inﬂammatory cytokine interactions may play a more important role. In this section, I will review the scientiﬁc literature concerning food-based excitotoxins and their effects on the developing brain. A discussion of the correlation between inﬂammatory cytokines, oxidative stress, and excitotoxicity on the developing brain will demonstrate the connection between these various factors. FOOD ADDITIVES We should be concerned with the diets of autistic children, as many commercial foods contain substances and additives that
have been shown to be neurotoxic, such as glutamate, aspartate, aluminum, and ﬂuoride. Of particular concern are glutamate and aspartate additives. Orally ingested glutamate, as monosodium glutamate (MSG), has been shown to signiﬁcantly increase blood levels of glutamate in animals and humans. Blood levels in humans can increase from 20- to 45-fold1 and even more in certain neurodegenerative diseases.2 It also has been shown that glutamate from ingested or injected MSG can pass through the placenta and accumulate in the fetal brain.3 In fact, the glutamate level was 2-fold higher in the fetal brain than the maternal brain level in this study. A great number of studies has shown that elevated levels of glutamate in the blood can produce numerous lesions in the brain, particularly in the hypothalamic, hippocampal, and entorhinal areas, and can disrupt neuroendocrine function.4-7 Olney et al have shown that the immature brain is approximately 4 times more sensitive to glutamate excitotoxicity than the adult brain.8 Hypoglycemia, hypoxia, and ischemia, which commonly occur during development, greatly aggravate excitotoxicity.311 And inﬂammatory cytokines, in particular interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, also magnify excitotoxicity. Recent studies have shown that ingestion of MSG early in life can lead to prolonged free radical and lipid peroxidation generation in the brain that can last until adulthood.10,11 MSG and other forms of free glutamate and aspartate are frequently used as food additives; therefore, this would put the child’s brain at risk throughout most of the period of rapid brain growth and maturation, which extends well into the first 2 years of life. Many foods, including toddler foods, contain several forms of
ALTERNATIVE THERAPIES, mar/apr 2009, VOL. 15, NO. 2
A Possible Central Mechanism in ASD, Part 3
22 Using radiolabeled [3H] glutamate. Using reverse PCR methods.19 The animals also failed to maintain or consolidate LTP. Ironically. elevated brain levels of glutamate would trigger intense inflammatory cytokine and chemokine release. NO. this follows the increasing toxicity of mercury in the cerebral cortex and hippocampus of rats. such as hydrolyzed protein and sodium or calcium caseinate in concentrations known to produce brain lesions in the rat and mouse.27. 15. Sanabria et al demonstrated a dramatic decrement of the long-term potentiation (LTP) ﬁeld excitatory postsynaptic potential in adult rats at 60 days after they were exposed to MSG during the ﬁrst 10 days of postnatal life. This confirms other reports showing long-term damage after neonatal exposure to MSG. A study by Mitani et al showed that NMDA neurotoxicity was most prominent at PND 15 and not at birth. with maturation they play a predominantly inhibitory role. González-Burgos et al exposed male rats to 4 mg/g MSG subcutaneously at postnatal days (PND) 1. extensive microglial activation was present. which is insensitive to magnesium blockade of voltage-gated receptors.23-25 In addition. a major memory mechanism.10.31 Babies and small children are exposed to concentrations of MSG.30 This may be due to an increase in the NR2C NMDA glutamate receptor subunit expression at a later time postnatally.20 Damage following neonatal exposure to MSG is not limited to the hippocampus.41 It is known that GABA neurons possess A Possible Central Mechanism in ASD. Yu et al demonstrated penetration of the placental barrier by glutamate and its distribution in the fetal brain. lipid peroxidation was increased 56% in these brain areas.26 Exposure to MSG is also known to lower reduced glutathione levels. areas very sensitive to MSG neurotoxicity. again emphasizing the importance of priming. mar/apr 2009. aspartame. Even though during early embryogenesis GABAnergic neurons are excitatory. and occasionally cysteine that have been shown to be excitotoxic in experimental studies. Importantly. hydrolyzed proteins.5 mg/g or 4 mg/g) during later pregnancy decreased the threshold for seizures at 10 days postnatal and signiﬁcantly impaired Y-maze discrimination learning in their offspring when studied at day 60. Studies have also shown advanced oxidative stress and lipid peroxidation in autism. Another biochemical change commonly found in autistic cases is low reduced glutathione levels. This indicates that signiﬁcant impairment of learning and behavior can occur at doses of MSG below that which produces obvious neuron death.1 In addition.12 Humans are 5 times more sensitive to the excitotoxic effects of oral MSG than are mice and 20 times more sensitive than monkeys. These studies indicate that exposure to dietary MSG during neonatal periods can produce prolonged reactive oxygen species/reactive nitrogen species and lipid peroxidation generation. 5. and 7 and found fewer neurons and shorter. less ramiﬁed dendritic processes in the third-layer pyramidal neurons of the prefrontal cortex. exogenously applied glutamate has been shown to prime microglia.21 The cerebellar cortex and Purkinje cells are also sensitive to systemically administered MSG.17. Part 3 ALTERNATIVE THERAPIES. as well as neurodegeneration.18 These neurotransmitter levels were not altered in the hippocampus.3 They also found that MSG given to maternal mice (2. They also found extensive microglial activation with MSG exposure.18. indicating a chronic impairment of CA1 synaptic plasticity. these behavioral changes occurred without damage being detected by light microscope in the hypothalamus or periventricular organs. lasting as long as PND 90. demonstrating that sensitivity to glutamate can be induced by the actions of glutamate on speciﬁc genes controlling subunit expression. as well as the release of excitotoxins from both microglia and astrocytes. In addition. a number of studies have shown that MSG given systemically can lower seizure threshold and prolong seizures. NR2A.36-39 Related to the child’s brain and excitotoxin-induced seizures.34. The presence of a brain insult (ischemia) produced an even greater elevation in brain TNF-α levels in the MSG-treated animals. Beas-Zárate et al demonstrated that gene expression for NMDA receptor subunits NR1. Frieder and Grimm demonstrated that oral feeding of MSG to pregnant rats produced profound defects in learning that affected only the male offspring. and NR2B in the striatum and hippocampus increased in rats exposed neonatally to MSG. VOL.33 Inflammation in both tissues increased as a result of MSGinduced nuclear factor kappa B (NFκB) activation. one sees elevations in superoxide dismutase activity and decreased catalase activity in autism. which peaks at PND 14 and in the cerebellum at PND 35. 2 57 .14-16 For example.17 In a follow-up study.28 N-methyl-D-aspartate (NMDA) receptors are known to be fully functional in early rat embryogenesis.29 In the cerebral cortex the NR2B subunit was increased.35 Likewise.13 A number of studies have shown that MSG can alter behavior and learning when given to animals postnatally.11 Giving MSG on PND 1-10 has been shown to increased lipid peroxidation and alter antioxidant defenses in the midbrain and frontal cortex of rats. is the finding of reduced GABA function. 3. Both clinical and subclinical seizures are known to occur in relatively high rates in autism spectrum disorders.23 Reduced catalase in the presence of normal or elevated glutathione peroxidase activity can increase free radical damage because of the elevation in hydrogen peroxide. aggravating any preexisting oxidative stress.glutamate additives. soy protein isolates. and in previously primed microglia. with the immature brain being signiﬁcantly more susceptible. they demonstrated a 25% decrease in brain choline acetyltransferase (ChAT) activity during early development and a reduction in norepinephrine to 25% of normal levels in the frontal lobes.40.11 In a study by Bawari et al. Administering MSG systemically to animals has been shown to increase oxidative stress and lipid peroxidation in peripheral tissues and the brain. which subsequently breaks down into hydroxyl radicals.32 Xu et al found that MSG given intraperitoneally increased both brain and intestinal TNF-α levels 3-fold. Examination of the animals’ hippocampi demonstrated decreased neuron numbers and abnormalities of dendrite arborizations and spine density in the CA1 zone as compared to controls.
Primarily involved are abnormalities in calcium homeostasis caused by stimulation of various receptors via inﬂammatory cytokines. including microglial activation.45 They found a major decline in [3H]-GABA release under baseline conditions in the cerebral cortex at days 30 and 60. alpha-lipoic acid. neurodegeneration. Central in this process is dysfunction of mitochondria. who studied a large number of autistic subjects and found a strong linkage between the GluR6 gene and autism. Beas-Zárate et al exposed rats to MSG at PND 1. In one study. by inhibiting antioxidant enzymes and glutathione. resulting in a loss of excitotoxic protection postnatally.50 Mundy et al found that aluminum potentiated glutamate excitotoxicity and increased ROS formation by increasing iron entry into neurons. Finally. and contaminated foods. which converts glutamate into gamma amino butyric acid. there is an intimate interrelationship between excitotoxicity. processed cheeses. Stimulated GABA release was suppressed in the cerebral cortex on days 14 and 21 and signiﬁcantly increased on day 60. free radical generation. and 7 and assessed GABA release on days 14. and mitochondrial dysfunction. abnormal pathway development. and ﬂuoride. especially processed meats and teas. Of particular interest is the study by Jamain et al.and dose-dependent behavior abnormalities in rats exposed to ﬂuoride in drinking water. fluoride drops. cadmium. which has been shown to accumulate in the brain and trigger reactive oxygen species and lipid peroxidation accumulation. lipid peroxidation. In an earlier study. free radical and lipid peroxidation damage.64 Abnormalities in the 58 ALTERNATIVE THERAPIES.46 Recent studies have shown very high levels in a number of commonly used feeding and intravenous parenteral solutions used in pediatrics. and that was time.48 Aluminum not only accumulates in the brain but produces inﬂammation. and androgen excess. Increasing energy production. aluminum. Likewise. Neurotoxic metals. The doses were comparable to those seen in humans.metabotropic receptors. and abnormalities in calcium homeostasis. inflammatory cytokine release.58 cholinergic. all of which regulate either glutamatergic receptors or GABA receptors. recent studies have identiﬁed a number of common genetic abnormalities in autism spectrum disorders. lead.63 The GABA receptors normally play a role in controlling glutamate receptor overactivity. Part 3 . and other metabolic precursors and substrates can signiﬁcantly reduce glutamate excitotoxic damage. dendritic outgrowth. and 60 and on all days in the striatum. VOL. there are a number of natural products that inhibit glutamate receptors and reduce excitotoxicity. a loss of calcium oscillation caused by excitotoxic and androgeninduced calcium excess impairs progenitor cell migration and differentiation. L-carnitine. 21. In the hippocampus. 3. food was found to supply 25 times more aluminum systemically than public drinking water. and teas. and synaptic development and consolidation and by triggering neurodegeneration. They found the greatest ﬂuoride accumulation to occur in the hippocampus. generates free radicals.and dose-dependent. and 60 using [3H]-GABA radiolabeling. as well as inhibition of critical antioxidant enzymes. areas signiﬁcantly affected in autism spectrum disorders. and ﬂuoride. which further aggravates disruptions of calcium homeostasis. such as serotonergic.43 Ureña-Guerrero et al found that neonatal MSG treatment in rats reduced GAD activity in the cerebral cortex at PND 21 and 60 due to decreased enzyme afﬁnity.51 Another neurotoxin of concern is ﬂuoride. such as aluminum. 15. and interferes with neuronal tubular function.59 and dopaminergic neurons. inﬂammatory cytokines. secondary suppression of mitochondria occurs as a result of ischemia/hypoxia.49.57 Likewise. mercury aggravates free radical generation and the accumulation of lipid peroxidation products. In the developing brain. such as mercury. This also increases sensitivity to excitotoxicity by reducing cellular energy production. I will conﬁne my remarks to aluminum and ﬂuoride.55 Mullenix et al demonstrated signiﬁcant sex.52-54 It has also been linked to an excitotoxic reaction within the brain. as these are rarely considered. 2 A Possible Central Mechanism in ASD. 5. GABA secretion was suppressed on days 14. 30.62. 21. NO. The glutamate receptors are known to exist on other neuron systems.42 A recent study found that some autistic children have defects in glutamic acid decarboxylase (GAD). As chronic inﬂammatory change takes place in the brain. OTHER ENVIRONMENTAL TOXINS OF CONCERN There are other neurotoxic substances in the environment of autistic children that should be of concern.47. Additive and even synergistic toxicities of these food additives are known to occur. further aggravate the above processes as described. aluminum is found in a number of baked goods (pancakes and biscuits).44 Hippocampal and cerebellar areas demonstrated an upregulation of GAD in response to GABA neuron loss. which occur in an autocrine manner. and females were more sensitive to weaning and adult exposures. mar/apr 2009. Besides vaccines. using coenzyme Q10. resulting in rising levels of extracellular glutamate. glutamate receptors. From these studies it is reasonable to assume that exposure to glutamate and aspartate food additives can significantly worsen the neurotoxic conditions seen in children with autism spectrum disorders.61 thus exercising widespread control of complex neural networks in the prefronto-limbic brain. Mercury is a particularly potent inhibitor of the glutamate transporters. which means they are regulated by glutamate-type receptors. which also increases the generation of free radicals (particularly peroxynitrite) and dramatically increases sensitivity to extracellular glutamate to the extent that even physiological levels of glutamate can be excitotoxic. Sources of ﬂuoride include using ﬂuoridated water used to reconstitute baby formula. CONCLUSION There is compelling evidence that excessive immune stimulation during critical stages of brain development can cause disruption of neurodevelopment by affecting neuronal and glial cell migration.60.56 Males were more sensitive to prenatal exposure on days 17 to 19.
Chauhan V.13(3):171-181.2(4):341-359. Sharpe LG. 24. Prog Brain Res. Grimm VE. should call attention to its being a major mechanism in damage to the autistic brain. Olney JW. and aluminum. Neurosci Lett. De Zeeuw CI. few studies on autism have mentioned this as a major mechanism for the changes seen in the autistic brain.4(3):218-226. The toxic effects of glutamate and related compounds in the retina and the brain. 2000. Yu L. Yu T.75(21):2539-2549. Zhao Y. Anat Histol Embryol. 4. Dolnikoff MS. Priming of the microglia can occur as a result of immune system dysfunction coupled with recurrent immune stimulation secondary to vaccination or recurrent systemic infections or both. While inﬂammatory cytokines can alter behavior acutely or chronically. NO. 19. Chaparro-Huerta V. 2002. Despite the fact that microglia secrete large amounts of two known excitotoxins. 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