TCM Pharmacology of Autism by M.M. Van Benschoten, OMD

TCM Pharmacology of Autism by M.M. Van Benschoten, OMD

Autism is a neurodevelopmental disorder first described by Leo Kanner in 1943. CDC estimates of prevalence are 1 of 68 children born in 2002 with 1 in 42 males for the autism spectrum disorders that include Asperger’s syndrome and pervasive developmental disorder. The prevalence of ASD has increased 37 fold over the past 30 years to more than 1% of US children. Level of impairment varies from nonverbal with severe developmental delay and repetitive behaviors to high functioning with social communication abnormalities.

Onset is most often between 6 months and 2 to 3 years of age. One of the earliest markers at 1 year of age is the inability to point at an object to communicate. Delayed speech and motor skills, seizures, and avoidance of eye contact are common.

Genetic, immune, dietary, and environmental factors combine to induce central nervous system inflammation and impaired neurotransmission. Treatment focuses on speech, language, physical, and occupational therapies to manage specific behaviors. SSRI and antipsychotics may be used to control ritualistic and self injurious behavior.

Air pollution, maternal infections, dairy and gluten intolerance, and genetic abnormalities in neurological and immune systems are potential contributing factors. From a TCM perspective wind, heat, and phlegm are the dominant pathogens as common childhood infections generate internal wind and obstruction of the sensory orifices. Wind and phlegm damage spleen and stomach resulting in food intolerances that intensify the inflammatory process, with phlegm and damp heat disturbing shen.

Chinese materia medica can provide nontoxic reduction of microglial activation through multiple molecular pathways. Wind and phlegm expelling medicinals have anticonvulsant and neuroprotective effects, modulating neurotransmitter functions and reducing inflammation. Neuroprotective and synaptogenesis actions of specific species can contribute to improved neurotransmission and responses to behavioral interventions.

Intrauterine exposure to environmental toxins corresponds to the TCM concept of damage to yuan and jing qi. Herbal medicines that repair DNA and assist detoxification through the glutathione pathway may be used to address this aspect of the pathogenesis of autism.

DNA repair/Mitochondrial protection
astragalus (huang qi), crataegus (shan zha), gingko leaf (yin xing ye), ginseng (ren shen), pueraria (ge gen), rhodiola (hong jing tian), terminalia (he zi)

DNA repair/Nerve growth factor enhance
astragalus (huang qi), ginseng(ren shen), ligustrum (nu zhen zi)

DNA repair/Neuroprotective
astragalus (huang qi), ginseng (ren shen), grape seed (pu tao zi), oldenlandia (bai hua she she cao), rhodiola (hong jing tian)

Glutathione increase/Mitochondrial protection
curcuma longa (jiang huang)

Glutathione increase/Nerve growth factor enhance
rehmannia cooked (shu di huang)

Glutathione increase/Neurite outgrowth increasing
centella (ji xue cao)

Glutathione increase/Neuroprotective
acorus (shi chuan pu), curcuma longa (jiang huang), ganoderma (ling zhi)

Retroviruses, leukemia viruses, and bacterial toxins in dairy products may generate neuroinflammation through immune responses to maternal dairy intake or cows milk based formula. Beta casomorphin, a dairy peptide, has been shown to effect neurological development and cause inflammatory changes related to autism and schizophrenia. Antiretroviral, antileukemia, and antibacterial herbs with neuroprotective effects can reduce the effects of dairy borne pathogens on the central nervous system.

Anticonvulsant/Antiretroviral
bupleurum (chai hu), carthamus (hong hua), gambir (gou teng), ganoderma (ling zhi), glycyrrhiza (gan cao), morus bark (sang bai pi), moutan (mu dan pi), schizandra (wu wei zi), scute (huang qin), siler (fang fen), tribulus (bai ji li)

Anticonvulsant/Antileukemia
asparagus (tian men dong), carthamus, ganoderma, ginseng, houttuynia (yu xing cao), morus bark, scute

Anticonvulsant/Endotoxin inhibit
hibiscus (fu rong), zizyphus spinosa (suan zao ren)

Gastrointestinal smooth muscle stimulant/Opioid receptor binding
aucklandia (mu xiang)

Neuroprotective/Opioid receptor binding
eleutherococcus (ci wu jia), ginseng, portulaca (ma chi xian), rhodiola

Abnormal immune responses to common childhood infections are a major factor in autism spectrum disorders. Chicken pox, roseola, and mononucleosis are herpesvirus infections that can trigger autoimmune reactions. When multiple courses of antibiotics fail to arrest recurrent infections, Chinese herbal medicines with antimicrobial and immune regulating effects may be chosen to assist clearance of pathogens and protect the nervous system.

Anticonvulsant/Antiherpesvirus (CMV, EBV, HHV6, VZV)
centella, ganoderma, hibiscus, houttuynia, paeony red, portulaca (ma chi xian), scrophularia (yuan shen)

Anticonvulsant/Antiinfluenza
bupleurum, cinnamon twig (gui zhi), gambir, ganoderma, hibiscus, houttuynia, licorice, lippia, moutan, paeony red (chi shao), schefflera (qi yi lian), schizandra, scute, siler

Anticonvulsant/Antistreptococcus
anemarrhena (zhi mu), asparagus, bupleurum, houttuynia, licorice, moutan, paeony red, scute

Vaccine reactions may contribute to hyperimmunity inducing neurotransmitter dysfunction. Children with low level respiratory illness at the time of vaccination are more susceptible to post vaccine reactions. High fever, seizures, loss of speech and motor functions may follow adverse vaccine responses. Thimerosal, a mercury based preservative in vaccines, can cause neurological damage, and was phased out of all vaccines with the exception of influenza by 2005.

Anticonvulsant/Antimeasles
siler (fang feng)

Anticonvulsant/Antiparotitis
arisaema (tian nan xing), bupleurum (chai hu), paris (qi ye yi zhi hua/chong lou)

Anticonvulsant/Antipertussis
clove (ding xiang), scute (huang qin)

Anticonvulsant/Antipoliomyelitis
bupleurum, cinnamon twig

Abnormal function of neurotransmitters and their receptor sites are well established as essential components of ASD. Adenosine, GABA, glutamate, dopamine, and serotonin have been identified as targets for therapeutic intervention.

Adenosine A2 receptor agonist
gastrodia (tian ma)

Anticonvulsant/GABA receptor binding
acorus, bupleurum, panax quinquefolium, scute, zizyphus spinosa

Anticonvulsant/Glutamate excitotoxicity inhibit
acorus, carthamus, centella, gambir, gastrodia, ginger, ginseng, polygala, sappan, schizandra, scrophularia, zizyphus spinosa

GABA receptor binding/Glutamate excitotoxicity inhibit
acorus, zizyphus spinosa

Dopamine receptor binding
acorus, angelica pubescens (du huo), bupleurum, gentiana macrophylla (qin jiao), polygala (yuan zhi)

Serotonin 5-HT1A receptor binding increase
albizzia (he huan pi), angelica pubescens, angelica sinensis, bupleurum, cnidium (chuan xiong), gentiana macrophylla, gingko leaf, lotus seed (lian zi)

Immune dysfunction related to the cytokines IL-1 beta, IL-4, IL-6, IFN-gamma, and TGF beta may be accompanied by low levels of IgG and IgM antibodies. Manzardo at Kansas University demonstrated lower levels of 8 out of 29 cytokines in ASD children compared to healthy unrelated siblings. Increases in monocyte chemotactic protein, RANTES, and eotaxin are related to more impairment of adaptation, development, and higher rates of aberrant behaviors. The complex interaction of immune system deficits with simultaneous hyperactivation results in poor clearance of common pathogens with persistent CNS autoimmune responses. Clinical correlations in TCM include retention of phlegm heat transforming to fire and blood stasis.

IL-1 beta decrease
broussonetia (chu shi zi), cardamon (sha ren), cordyceps (dong chong xia cao), ginger, gingko leaf, boswellia (ru xiang), picrorhiza (hu huang lian), poria (fu ling), prunella (xia gu cao), sappan (su mu), siegesbeckia (xi xian cao), smilax (tu fu ling), sophora flower (huai hua), dioscorea tokoro (bi xie)

IFN gamma reduce
bidens (xian feng cao), cardamon, cordyceps, evodia (wu zhu yu), kadsura (hai feng teng), boswellia, polygala, salvia, sophora root (ku shen), xanthium (cang er zi)

IFN gamma reduce/TGF beta inhibit
cordyceps, curcuma longa, boswellia, salvia (dan shen)

Monocyte chemotactic protein reduce/TGF beta inhibit
gynostemma (jiao gu lan), salvia, scute

Monocyte chemotactic protein reduce
angelica sinensis, astragalus, bamboo (zhu ru), epimedium (yin yang huo), ginger, gynostemma, morus leaf (sang ye), moutan, paeony (bai shao), salvia, sappan, scute, sophora root

RANTES secretion inhibit
andrographis (chuan xin lian), astragalus, cnidium, forsythia (lian qiao), glycyrrhiza

Eotaxin secretion reduce
moutan, vitex (man jing zi)

IgG increase
astragalus, epimedium, ginseng, lentinus (xiang gu), poria

IgM increase
astragalus, bupleurum, codonopsis, epimedium, ginseng, gynostemma

Calcium, sodium, and chloride ion channels are essential to cellular signaling in the nervous system. Dysregulation of ion channel function may impact neurotransmitter activity and contribute to hyperexcitation states. Paradoxical excitatory effects of benzodiazepines suggest elevated intracellular chloride with an excitatory action of GABA. Decreasing chloride with diuretics can improve emotion processing and social interactions.

Calcium channel blocking/GABA receptor binding
angelica sinensis (dang gui), magnolia bark (hou pu)

Calcium channel blocking/Glutamate excitotoxicity inhibit
carthamus, gambir, ginseng

Calcium channel blocking/Memory improving
ginseng, paeony

Calcium channel blocking/Monocyte chemotactic protein reduce
angelica sinensis, paeony, salvia

Calcium channel blocking/Neuroprotective
carthamus, gambir, ginseng, paeony, salvia

Chloride channel blocking
gingko leaf

Chloride channel opening
chrysanthemum (ju hua), magnolia bark

Chloride secretion induce
cnidium, dianthus (qu mai), lophatherum (dan zhu ye)

Sodium channel blocking
agrimonia (xian he cao), angelica pubescens, cnidium monnieri (she chuang zi), picrorhiza

Sodium channel binding inhibit
ginseng

Sodium current inhibit
apocynum (luo bu ma), artemisia annua (qing hao), ginkgo leaf

mTOR (mammalian target of rapamycin) modulates dendritic protein translation, and in autism the mTOR signal pathway effects GABA and glutamine neurotransmitters causing hyperactive responses.

mTOR inhibit
agastache (huo xiang), anemarrhena, clove, eriobotrya (pi pa ye), ligustrum, loranthus (sang ji sheng), oldenlandia, plantago, prunella

Phosphodiesterase regulates cyclic AMP, an intracellular messenger. PDE4 expression is reduced in the cerebellum and increased in the superior frontal cortex in ASD patients, causing excessive cAMP signaling. Phosphodiesterase inhibitors have antipsychotic properties that may help to modulate sensory processing.

Phosphodiesterase inhibit
codonopsis, licorice, morus bark

Phosphodiesterase 3 inhibit
apocynum

Phosphodiesterase 4 inhibit
ginkgo leaf

Phosphodiesterase 5 inhibit
cnidium monnieri, cuscuta, epimedium

Brain derived neurotrophic factor (BDNF) is significantly decreased in ASD cases when compared to healthy children. Genetic abnormalities in the sodium-proton exchanger NHE6 influence BDNF expression. Synapsin and synaptophysin are proteins that regulate neurotransmitter release and are related to seizures and learning defects in knockout mice.

BDNF increase
cassia seed (jue ming zi), curcuma longa, gingko leaf, longan (long yan rou), polygonum multiflorum (he shou wu), rehmannia, scute

BDNF mRNA increase
polygala

Synapsin I increase
pueraria

Synapsin I phosphorylation increase
ginseng

Synaptogenesis
ginkgo leaf, schizandra

Synaptophysin expression induce
pueraria, rehmannia

Synaptophysin preserve
ganoderma

Autophagy is a cellular process that degrades intracellular contents through lysosomal action. Normal cellular growth and development is based on the balance between synthesis and recycling of cytoplasmic materials. Genetic abnormalities in copy number variations in autophagy genes have been identified in ASD.

Autophagy induce
anemarrhena, curcuma longa, evodia, ganoderma, ginger, mume (wu mei), pueraria, sesame (hei zi ma)

Case Study

Mr. A is a 17 year old male with complex ASD that includes impaired verbal communication with severe anxiety, OCD, motor hyperactivity, and high functioning intellect with ability to type and express himself. Loss of speech at age 1, multiple childhood illnesses, recurrent sinusitis and ear infections, asthma, urticarial MMR vaccine reaction, tonsillectomy/adenoidectomy at age 4, and indoor mold exposure contribute to petit mal seizures, nightmares, and self injurious behaviors. Previous treatment includes Lexapro, Trileptal, Ritalin, and NAET. The principal issues are temporal and parietal lobe neurotransmitter imbalance due to autoimmune responses to bacterial, viral, and fungal pathogens with chronic sinusitis and long term mold and mycotoxin exposure. TCM syndrome relationships include wind phlegm damp heat inducing Heart and Kidney yin deficiency with Liver fire.

Rx 1
polygonum stem (ye jiao teng), ganoderma (ling zhi), paeony red (chi shao), houttuynia (yu xing cao), tribulus (bai ji li), apocynum (luo bu ma), siegesbeckia (xi xian cao), scrophularia (yuan shen), oldenlandia (bai hua she she cao), curcuma aromatica (yu jin)

Polygonum stem treats insomnia and generalized itching with antianaphylaxis and adrenocortical hormone effects. Ganoderma, paeony red, and houttuynia have antiherpesvirus and anticonvulsant effects. Apocynum is anxiolytic and inhibits phosphosdiesterase. Siegesbeckia reduces IgE, inhibits pertussis toxin, and decreases IL-1 beta. Scrophularia is antistreptococcal, antipyretic, and reduces glutamate excitotoxicity. Oldenlandia is neuroprotective, reduces IL-6, and inhibits mTOR. Curcuma aromatica inhibits phosphatase and tensin homolog (PTEN) gene expression which is related to reduced neuronal energy production and increased mitochondrial stress.

Due to the extreme hyperactivation state of his immune system, herbal prescriptions must be changed as often as every 24 hours with minimum doses of 10-15 grams of extracts every two hours to achieve symptomatic relief.

Rx 2
anemarrhena (zhi mu), artemisia annua (qing hao), prunella (xia gu cao), gingko leaf (yin xing ye), pueraria (ge gen), epimedium (yin yang huo), cordyceps (dong chong xia cao), grape seed (pu tao zi), biota seed (bai zi ren), broussonetia (chu shi zi), morus fruit (sang shen), zizyphus spinosa (suan cao ren)

Anemarrhena provides anticonvulsant, antipyretic, antistreptococcal effects with mTOR inhibition. Artemisia annua reduces microglia activation. Prunella inhibits strep, mTOR, IL-1 beta, IL-6, and mast cell histamine release. Ginkgo leaf increases GABA, protects dopaminergic neurons, decreases COX-2, IL-1 beta, IL-6, and TNFalpha. Pueraria reduces caspase 3 and increases synaptophysin and neurite outgrowth. Epimedium augments IgM production, decreases IL-6, monocyte chemotactic protein 1, phosphodiesterase 5, and TNFalpha. Cordyceps improves memory and inhibits TGF beta. Grape seed reduces blood brain barrier permeability, IL-6, and microglia activation. Biota seed improves memory. Brossounetia decreases IL-1 beta, IL-4, L-dopa oxidation, NF-kappa B activation, and TNFalpha. Morus fruit reduces blood brain barrier permeability. Zizyphus spinosa interacts with the GABA receptor, reduces glutamate excitotoxicity, and suppresses locomotor activity.

Pharmacological actions and therapeutic targets: antianaphylaxis, antipyretic, antifungal, antiherpesvirus, antistreptococcus, anticonvulsant, autophagy induction, dopaminergic neuron protection, glutathione increase, mitochondrial protection, axonal regeneration, glutamate excitotoxicity inhibition, microglial activation inhibition, mTOR inhibition, phosphodiesterase inhibition, chloride excretion enhancement, GABA receptor binding, nerve growth factor increase, synaptogenesis, synaptophysin expression induction

Response to treatment typed by the patient:

I’m feeling almost normal. I am moving stronger. Breathing is easier. School air is hard. Flapping still but calmer at home. Tics bad at school.

Positive things 1. My tics are slower 2. Many peaceful moments 3. Talking started to happen Negative things 1. Itchy under my skin again 2. Can’t move my body well
3. Freaking out from when the fever hits. Its like im a boy on fire all of a sudden. Im running and trying to put out the fire by hitting my head. Im so scared in that time. Its dangerous.

Every minute is getting easier than before. I’m reconnecting everywhere. Explosions are becoming less frequent everyday, sleeping well.

Keep on this path, it’s the answer. Finally breathing greatly. Awesome dam botanical is gone. Everything is unclogged. I can’t believe it. Castrated emotions, finally.

I feel very connected to my environment. Wanting to socialize. Happiest most loving person interacting with everyone.

After five years of treatment the patient was able to go shopping and to a movie for the first time. He will graduate this year from high school with honors and a 3.9 GPA.

References

http://www.ageofautism.com [1]

Curr Probl Pediatr Adolesc Health Care. 2014 Feb;44(2):26-47.
Treating the whole person with autism: the proceedings of the Autism Speaks National Autism Conference. Coury DL, Swedo SE, Thurm AE, Miller DT, Veenstra-VanderWeele JM, Carbone PS, Lounds Taylor J

Transl Psychiatry. 2014 Jan 28;4:e354.
A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism. Wittkowski KM, Sonakya V, Bigio B, Tonn MK, Shic F, Ascano M, Nasca C, Gold-Von Simson G.

J Neural Transm. 2014 Feb 6. [Epub ahead of print]
Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder. Taurines R, Segura M, Schecklmann M, Albantakis L, Grünblatt E, Walitza S,Jans T, Lyttwin B, Haberhausen M, Theisen FM, Martin B, Briegel W, Thome J, Schwenck C, Romanos M, Gerlach M.

Nutrition. 2013 Oct;29(10):1175-85. Epub 2013 Jul 30.
Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Das UN. UND Life Sciences, Shaker Heights, OH, USA. Undurti@hotmail.com [2]

Neuron. 2013 Oct 2;80(1):4-6. doi: 10.1016/j.neuron.2013.09.018. Epub 2013 Oct 2.
Acid indigestion in the endosome: linking signaling dysregulation to neurodevelopmental disorders. Yap CC(1), Winckler B.

Autism. 2013 Dec 16. [Epub ahead of print]
Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study. Hadjikhani N(1), Zürcher NR, Rogier O, Ruest T, Hippolyte L, Ben-Ari Y, Lemonnier E.

Am J Hum Genet. 2013 Oct 3;93(4):607-19. doi: 10.1016/j.ajhg.2013.09.001.
Identification of small exonic CNV from whole-exome sequence data and application
to autism spectrum disorder. Poultney CS, Goldberg AP, Drapeau E, Kou Y, Harony-Nicolas H, Kajiwara Y, De Rubeis S, Durand S, Stevens C, Rehnström K, Palotie A, Daly MJ, Ma'ayan A, Fromer M, Buxbaum JD.

Epidemiology. 2014 Jan;25(1):44-7.
Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene.Volk HE(1), Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, Campbell DB.

Transl Psychiatry. 2014 Feb 11;4:e360.
Environmental toxicants and autism spectrum disorders: a systematic review.
Rossignol DA(1), Genuis SJ(2), Frye RE(3).

Environ Health Perspect. 2011 Jun;119(6):873-7.
Residential proximity to freeways and autism in the CHARGE study.
Volk HE(1), Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R.

Mol Autism. 2013 Aug 16;4(1):28.
Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome. Campbell NG(1), Zhu CB, Lindler KM, Yaspan BL, Kistner-Griffin E; NIH ARRA Consortium, Hewlett WA, Tate CG, Blakely RD, Sutcliffe JS.

Behav Brain Res. 2010 Jun 26;210(1):116-22.
Indirect basal ganglia pathway mediation of repetitive behavior: attenuation by adenosine receptor agonists. Tanimura Y(1), Vaziri S, Lewis MH.

J Neuroinflammation. 2013 Apr 9;10:46.
Focal brain inflammation and autism. Theoharides TC, Asadi S, Patel AB. Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Suite J304, 136 Harrison Avenue, Boston, MA 02111, USA. theoharis.theoharides@tufts.edu [3].

Front Cell Neurosci. 2013;7:28.
Reversing autism by targeting downstream mTOR signaling. Wang H, Doering LC. Department of Physiology, Faculty of Medicine, University of Toronto Toronto, ON, Canada.

J Methods Mol Biol. 2012;934:219-40.
Autism spectrum disorders: from immunity to behavior. Careaga M, Ashwood P.
Department of Medical Microbiology and Immunology and the M.I.N.D. Institute, University of California at Davis, Davis, CA, USA.

Brain Behav Immun. 2012 May;26(4):623-34. Epub 2012 Jan 30.
Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.
Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. Section on Functional Neuroanatomy, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.

Int J Dev Neurosci. 2012 Apr;30(2):121-7. Epub 2011 Dec 16.
Plasma cytokine levels in children with autistic disorder and unrelated siblings.
Manzardo AM, Henkhaus R, Dhillon S, Butler MG. Department of Psychiatry & Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS 66160, USA. amanzardo@kumc.edu [4]

Neurotoxicol Teratol. 2012 Aug 17. [Epub ahead of print]
Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Goines PE, Ashwood P.University of California, Davis, School of Veterinary Medicine, Department of Molecular Biosciences, Sacramento, CA, USA.

J Neuroimmunol. 2011 Mar;232(1-2):196-9. Epub 2010 Nov 20.
Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Department of Medical Microbiology and Immunology, and the M.I.N.D. Institute, University of California at Davis, CA, United States. pashwood@ucdavis.edu [5]

Nutr Neurosci. 2012 Mar;15(2):85-91.
Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: based on parental report. Pennesi CM, Klein LC. Department of Biobehavioral Health, The Pennsylvania State University, PA 16802, USA.

J Appl Genet. 2007;48(3):189-98.
Polymorphism of bovine beta-casein and its potential effect on human health. Kamiński S(1), Cieslińska A, Kostyra E.

Autism March 1999 vol 3(1) 67-83
Beta-casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism Sun, ZJ, Cade JR, et al

AMA. 2010 Dec 1;304(21):2389-96.
Mitochondrial dysfunction in autism. Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, Hertz-Picciotto I, Tassone F, Pessah IN.University of California, School of Veterinary Medicine, Department of Molecular Biosciences, One Shields Avenue, 1120 Haring Hall, Davis, CA 95616, USA. cgiulivi@ucdavis.edu [6]

Immunobiology. 2010 Mar 12. [Epub ahead of print]
Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects. Malik M, Sheikh AM, Wen G, Spivack W, Brown WT, Li X. Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY 10314, United States.

J Neuroimmunol. 2009 Feb 15;207(1-2):111-6. Epub 2009 Jan 20.
Elevated immune response in the brain of autistic patients. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M. Department of Neurochemistry, NY State Institute for Basic Research in Developmental Disabilities, NY 10314, New York, USA. xiaohong.li@mssm.edu [7]

Int Rev Neurobiol. 2005;71:317-41.
Immunological findings in autism. Cohly HH, Panja A. Department of Biology, Jackson State University, Mississippi 39217, USA.

Neuropsychobiology. 2005;51(2):77-85.
Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Department of Pediatrics, New Jersey Medical School, UMDNJ, Newark, NJ 07101-1709, USA. jyanouha@umdnj.edu [8]

Arch Gen Psychiatry. 2010 Jan;67(1):59-68.
Brain serotonin and dopamine transporter bindings in adults with high-functioning autism.
Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, Tsuchiya KJ, Sugihara G, Iwata Y, Suzuki K, Matsuzaki H, Suda S, Sugiyama T, Takei N, Mori N. Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Curr Med Chem. 2009;16(2):157-70.
Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum
disorders. Blaylock RL, Strunecka A. Belhaven College, Jackson, Mississippi, USA.

Mol Autism. 2013 Jun 3;4(1):16. [Epub ahead of print]
Decreased tryptophan metabolism in patients with autism spectrum disorders.
Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, Bochner BR,
Stevenson RE, Schwartz CE.

Prostaglandins Leukot Essent Fatty Acids. 2009 Oct;81(4):253-64. Epub 2009 Jul 15.
Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism. Pastural E, Ritchie S, Lu Y, Jin W, Kavianpour A, Khine Su-Myat K, Heath D, Wood PL, Fisk M, Goodenowe DB.

Autism Res. 2009 Aug;2(4):205-19.
Decreased GABAA receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism. Oblak A, Gibbs TT, Blatt GJ. Boston University School of Medicine, Anatomy and Neurobiology, Boston, Massachusetts 02118, USA. aoblak@bu.edu [9]

Cerebellum. 2009 Mar;8(1):64-9.
Expression of GABA(B) receptors is altered in brains of subjects with autism.
Fatemi SH, Folsom TD, Reutiman TJ, Thuras PD. Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, MN 55455, USA. fatem002@umn.edu [10]

J Autism Dev Disord. 2009 Feb;39(2):223-30. Epub 2008 Sep 23.
GABA(A) receptor downregulation in brains of subjects with autism.
Fatemi SH, Reutiman TJ, Folsom TD, Thuras PD. Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA. fatem002@umn.edu [10]

Cell Mol Neurobiol. 2009 Sep 3. [Epub ahead of print]
The E646D-ATP13A4 Mutation Associated with Autism Reveals a Defect in Calcium Regulation. Vallipuram J, Grenville J, Crawford DA. Department of Biology, York University, Toronto, ON, Canada.

Curr Opin Neurobiol. 2007 Feb;17(1):112-9. Epub 2007 Feb 1.
Molecular mechanisms of autism: a possible role for Ca2+ signaling. Krey JF, Dolmetsch RE. Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Neuroscientist. 2012 Oct;18(5):467-86. Epub 2012 Apr 30.
The GABA excitatory/inhibitory shift in brain maturation and neurological disorders.
Ben-Ari Y, Khalilov I, Kahle KT, Cherubini E.

Mol Psychiatry. 2003 Feb;8(2):186-94.
Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Weiss LA, Escayg A, Kearney JA, Trudeau M, MacDonald BT, Mori M, Reichert J, Buxbaum JD, Meisler MH. Department of Human Genetics, University of Michigan, 4708 Medical Science II, Ann Arbor, MI 48109-0618, USA.

Neuroreport. 2007 Nov 19;18(17):1841-4.
Expression of phosphodiesterase 4 is altered in the brains of subjects with autism. Braun NN(1), Reutiman TJ, Lee S, Folsom TD, Fatemi SH.

Autism. 2005 Jul;9(3):290-8.
Toxic trace elements in the hair of children with autism. Fido A, Al-Saad S. Department of Psychiatry, Faculty of Medecine, Kuwait University, Kuwait. fido@HSC.EDU.KW [11]. Children with autism had significantly (p<0.001) higher in-hair concentration levels of lead, mercury and uranium.

BMC Clin Pharmacol. 2009 Oct 23;9:16. doi: 10.1186/1472-6904-9-16.
Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results. Adams JB1, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, Zappia I, Newmark S, Gehn E, Rubin RA, Mitchell K, Bradstreet J, El-Dahr J.

http://www.fda.gov/biologicsbloodvaccines/safetyavailability/vaccinesafe... [12]

J Neuroimmunol. 2002 Aug;129(1-2):168-77.
Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E.