Precept: Brain disorder stems from treatable physical illness. Oxidative Stress in Disordered Behavior and Cognition. Profusion of clues

Transcription

1 Oxidative Stress in Disordered Behavior and Cognition MD Melbourne 7 March 2009 woody.mcginnis@gmail.com Precept: Brain disorder stems from treatable physical illness Autism ADHD Schizophrenia Profusion of clues Bernard Rimland Associated abnormalities Symptom modulators Individual variability Abnormalities and modulators in autism A core mechanism? Gut Brain ATP Cholinergic Sulfurs B6, GAD Toxins Infections Nutrients... Bethanecol DMSA GSH, NAC Many nutrients Low oxalate Hyperbaria [Casein/gluten] [Copper] [Excitotoxins] Accomodate diverse abnormalities and modulators Allow variability Refine treatment and focus genetic and environmental research 1

2 Wood burning Fruit browning Rancid oil Cellular damage Toxins Suboptimal nutrition Emotional stress Genes Pollution Chemicals Heavy metals Insecticides Herbicides Halothane Chlorine MSG Aspartame Cu and Fe Food color Infections Allergies Stress Mercury blocks energy production Lead and tin over-excite via calcium influx Free radicals from unbound copper and iron Superoxide O 2 Hydroxyl OH Nitric oxide NO Peroxynitrite ONOO Singlet oxygen 1 O 2 Hydrogen peroxide H 2 O 2 Vitamin C Vitamin E Vitamin A B vitamins Selenium Magnesium Zinc Carnosine Carnitine CoQ10 DHA Vanilla 2

3 Oxidative Stress in Disordered Behaviour and Cognition Glutathione family: GSH, GSHPx, GST Metallothionein (MT) Superoxide dismutase (SOD) Catalase Melatonin Estrogen Oxidative stress is the state in which oxidants overwhelm the antioxidant defense. It results in excess physical damage and functional impairment. Lipids Proteins Sugars Nucleic acids 3

4 Microbes and food Glutathione import needs If low zinc, rapid MT depression Low ileal GSH and GST High oxygen consumption Oxidizable catecholamines Fragile blood-brain barrier Modest catalase and GSH High glutamate, Fe and fat Low energy Excitotoxicity Higher toxins Lower nutrients Lower endogenous defenses Emotional stress Oxidative stress Emotional stress Oxidative stress Tension-anxiety scores correlate with oxidized DNA in blood Meditation lowers blood lipid peroxides 4

5 Immobilization-stress Increases free radicals and oxidized lipid, protein and DNA Brain peroxidation prevented by antioxidants Nutrition Toxins Energy Endogenous protection Response to antioxidants Response to chelation Elevated peripheral BDNF Depressed cholinergic, GAD and ATP in brain Hypoperfusion and ERG s Language loss correlates with protective enzymes Response to antioxidants and hyperbaric Evidence of oxidative stress in autism NO (x2)* and XO (x3) GSH, GSHPx*, catalase ceruloplasmin, transferrin LPO (x2)* and isoprostanes Nitrotyrosine, correlates with mercury Axonal CEP, isolevuglandin and hemoxygenase Lipofuscin, associated with neuronal loss 5

6 Oxidative Stress in Disordered Behaviour and Cognition Autism nutritional profile Published: lower red-cell P5P, selenium, fatty acids; plasma zinc and serum carnitine By abstract: lower red-cell magnesium, zinc; plasma A, C, E, B3, B12 and folate ADHD nutritional profile Oxidative stress in ADHD Red-cell lipid peroxides (PubMed ) Low zinc: hair/red-cell/serum 78/59/34% ( ) Tx: ZnSO4 150 mg/d X 3 m. ( ) Lower magnesium: plasma/red-cell/urine ( ) Tx: Mg 200 mg/d X 6 m ( ) Expired breath ethane ( ) 6

7 OS in Schizophrenia Plasma antioxidant capacity ( ) Plasma uric acid ( ) Plasma NO and XO ( ) Red-cell GSH, GSHPx ( ) Plasma lipid peroxides ( ) X2-3 ( ) ( ) Red-cell MDA p <.001 ( ) OS in Schizophrenia Lipid peroxides in CSF ( ) Lipid peroxides in rat-brain exposed to serum or CSF of schizophrenics ( ) ( ) GABA plasma and brain ( ) Brain mitochondria ( ) Brain complex IV activity ( ) Nutrients in schizophrenia Anti-oxidant neuroleptics Plasma and urine vitamin C ( ) Vitamin E / cholesterol ratio ( ) Response to C + E ( ) ( ) Plasma magnesium ( ) RBC membrane DHA and AA (four studies) Thorazine a strong free-radical quencher, X100 C or E in vitro Chlorpromazine reduced serum MDA in schizophrenics Risperidone normalized SOD; this correlated with symptom improvement in schizophrenia Constituent of SOD Blocks lipid peroxidation Shields -SH groups Induces and protects MT Maintains vitamin A level If low, intestinal NO 7

8 Treat oxidative stress Optimize nutrition Address allergies Stem overgrowths Eliminate toxins Reduce stress Laboratory testing for oxidative stress Isoprostanes Lipid peroxides Oxidized DNA, RNA Nitrotyrosine Neopterin HPL (Mauve) Pre- and post-chelation oxidized nucleic acids Mauve History nmol/gcr OHdG 8OHG Discovery in urine 1958 Lilac-colored appearance on paper chromatograms Labile and elusive Abram Hoffer is the father of Mauve 8

9 Mauve is hydroxyhemopyrrolin- 2-one (HPL), not kryptopyrrole CH 3 CH 3 HO Mauve (HPL) N H C 2 H 5 C 2 H 5 O CH 3 Kryptopyrrole N H CH 3 H Down syndrome 71% Schizophrenia 40-80% Autism 46-48% ADHD 40-47% ETOH 20-84% Elevated Mauve Mauve Associations Poor dream recall Poor breakfast appetite Nail spots Stretch marks Pale skin / poor tanning Lighter hair Acne, allergy, obesity Mauve Associations Course eyebrows Knee and joint pain Cold hands or feet Abdominal tenderness Constipation Eosinophilia Mauve Associations Light / sound / odor intolerance Tremor / shaking / spasms Hypoglycemia / glucose intolerance Delayed Puberty / Impotence Amenorrhea / irregular periods B6-responsive anemia Mauve Associations Stress intolerance Emotional lability Explosive anger Anxiety / Withdrawal Pessimism Depression 9

10 Mauve Associations Familial Paranoia / Hallucinations Perceptual disorganization Crime and deliquency Substance abuse Attention deficit Red-cell zinc in mg / liter Red-cell Zinc HPL and RBC Zinc HPL in micrograms / deciliter Leukodynia in Zinc Deficiency 0.84 HPL B6 Activity HPL and B6 Activity 0.82 r neg 0.77; p< EGOT activity ratio HPL in micrograms per deciliter 10

11 HPL and Heme Require Heme Graham 1979: HPL injection acutely depresses hepatic microsomal heme and p450 Ames 2002: Experimental heme depression lowers intracellular zinc, induces NOS and increases oxidative stress Cystathionine synthase Catalase Heme-hemopexin for MT translation Guanylate cyclase Cytochromes Sulfite reductase NOS Pyrrolase Catalase units / min / mg of hemoglobin HPL Red-cell HPL and RBC Catalase r neg 0.92; p< HPL micrograms / deciliter Plasma GSH in micromoles / liter and Plasma Reduced Glutathione HPL and Plasma GSH 6 r neg 0.88; p< HPL in micrograms / deciliter 200 and Plasma Nitric Oxide HPL and Plasma NO Oxidative Stress Nitric Oxide in micromoles / liter r=0.97; p> if exclude outlier Emotional Stress Gut Permeability Low Zinc p450 HPL Regulatory Heme HPL in micrograms / deciliter 11

12 Utility of HPL Testing Economical yardstick for zinc deficiency, B6 deficiency, and oxidative stress The extent of HPL elevation helps prioritize zinc, B6 and stress reduction in management 12