Melbourne 2009 Second talk Oxidative Stress, brain

Oxidative Stress in Disordered Behaviour and Cognition

Woody McGinnis

Integrative Solutions - Melbourne, 2009

www.mindd.org 1

Oxidative Stress in

Disordered Behavior and

Cognition

Woody McGinnis MD

Melbourne

7 March 2009

[email protected]

Precept: Brain disorder

stems from treatable

physical illness

Autism

ADHD

Schizophrenia

Bernard

Rimland

1928-2006

Profusion of clues

Associated

abnormalities

Symptom modulators

Individual variability

Abnormalities and

modulators in autismGut

Brain

↓ ATP

↓ Cholinergic

↓ Sulfurs

↓ B6, GAD

↑ Toxins

↑ Infections

↓ Nutrients...

Bethanecol

DMSA

GSH, NAC

Many nutrients

Low oxalate

Hyperbaria

[Casein/gluten]

[Copper]

[Excitotoxins]

A core mechanism?

Accomodate diverse abnormalities and modulators

Allow variability

Refine treatment and focus genetic and environmental research


Woody McGinnis


www.mindd.org 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 O2 ¯˙

Hydroxyl OH˙

Nitric oxide NO˙

Peroxynitrite ONOO¯

Singlet oxygen 1O2

Hydrogen peroxide H2O2

Vitamin C Zinc

Vitamin E Carnosine

Vitamin A Carnitine

B vitamins CoQ10

Selenium DHA

Magnesium Vanilla


Woody McGinnis


www.mindd.org 3

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


Woody McGinnis


www.mindd.org 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


Woody McGinnis


www.mindd.org 5

Increases free radicals and

oxidized lipid,

protein and DNA

Brain peroxidationprevented by antioxidants

Immobilization-stress↓ 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


Woody McGinnis


www.mindd.org 6

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

Autism nutritional profile

ADHD nutritional profile

Low zinc: hair/red-cell/serum 78/59/34% (9368235)

Tx: ZnSO4 150 mg/d X 3 m. (14687872)

Lower magnesium: plasma/red-cell/urine (8078966)

Tx: Mg 200 mg/d X 6 m (9368236)

Oxidative stress in ADHD

↑ Red-cell lipid peroxides

(PubMed 10533254)

↑ Expired breath ethane

(14609313)


Woody McGinnis


www.mindd.org 7

OS in Schizophrenia

↓Plasma antioxidant capacity (9690328)

↓Plasma uric acid (9727961)

↑Plasma NO˙ and XO (12369276)

↓Red-cell GSH, GSHPx (11205693)

↑Plasma lipid peroxides (9583001)

X2-3 (1684458) (9583001)

↑ Red-cell MDA p <.001 (11205693)

OS in Schizophrenia

↑ Lipid peroxides in CSF (8888122)

↑ Lipid peroxides in rat-brain exposed to serum or CSF of schizophrenics (6547798) (3618046)

↓GABA plasma and brain (9645548)

↓Brain mitochondria (10025685)

↓Brain complex IV activity (8530074)

Nutrients in schizophrenia

↓Plasma and urine vitamin C (2275953)

↓Vitamin E / cholesterol ratio (8564316)

Response to C + E (9072891) (9784725)

↓Plasma magnesium (2077436)

↓RBC membrane DHA and AA (four studies)

Anti-oxidant neuroleptics

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˙


Woody McGinnis


www.mindd.org 8

Treat oxidative stress

Optimize nutrition

Address allergies

Stem overgrowths

Eliminate toxins

Reduce stress

Laboratory testing for

oxidative stressIsoprostanes

Lipid peroxides

Oxidized DNA, RNA

Nitrotyrosine

Neopterin

HPL (Mauve)

Pre- and post-chelation oxidized

nucleic acids

0

10

20

30

40

50

60

70

80

8OHdG 8OHG

nm

ol/

gC

r

Mauve History

Discovery in urine 1958

Lilac-colored appearance on paper chromatograms

Labile and elusive

Abram Hoffer is the father of Mauve


Woody McGinnis


www.mindd.org 9

Mauve is hydroxyhemopyrrolin-

2-one (HPL), not kryptopyrrole

OHOCH3

CH3

CH3N

CH3

NH H

C2H5 C2H5

H

Mauve (HPL) Kryptopyrrole

Elevated Mauve

Down syndrome 71%

Schizophrenia 40-80%

Autism 46-48%

ADHD 40-47%

ETOH 20-84%

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


Woody McGinnis


www.mindd.org 10

Mauve Associations

Familial

Paranoia / Hallucinations

Perceptual disorganization

Crime and deliquency

Substance abuse

Attention deficit

HPL and Red-cell Zinc

0

2

4

6

8

10

12

14

16

18

1 10 100 1000

HPL in micrograms / deciliter

Red-c

ell z

inc in m

g / liter

HPL and RBC Zinc

Leukodynia in Zinc Deficiency

HPL and B6 Activity

0.72

0.74

0.76

0.78

0.8

0.82

0.84

0 50 100 150 200

HPL in micrograms per deciliter

EG

OT a

ctivity ratio

r neg 0.77; p<0.0001

HPL and B6 Activity


Woody McGinnis


www.mindd.org 11

HPL and 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

Require Heme

Cystathioninesynthase

Catalase

Heme-hemopexin

for MT translation

Guanylate cyclase

Cytochromes

Sulfite reductase

NOS

Pyrrolase

HPL and Red-cell Catalase

0

50

100

150

200

250

300

350

400

0 50 100 150 200 250

HPL micrograms / deciliter

Cata

lase u

nits / m

in / m

g o

f hem

oglo

bin

HPL and RBC Catalase

r neg 0.92; p<0.0001

HPL and Plasma Reduced Glutathione

0

1

2

3

4

5

6

0 50 100 150 200 250


Pla

sm

a G

SH in m

icro

mole

s / liter

HPL and Plasma GSH

r neg 0.88; p<0.0001

HPL and Plasma Nitric Oxide

0

20

40

60

80

100

120

140

160

180

200

0 50 100 150 200 250


Nitric O

xid

e in m

icro

mole

s / liter

HPL and Plasma NO˙

r=0.97; p>0.0001 if

exclude outlier

Oxidative Stress

Emotional Stress

↑ Gut Permeability Low Zinc

↑ HPL↓ Regulatory Heme

↓ p450


Woody McGinnis


www.mindd.org 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

Documents

Melbourne 2009 Second talk Oxidative Stress, brain