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Restorative Medicine Approach Multiple Sclerosis

Michaёl Friedman, NDFinancial Disclosure: Co- owner Restorative Formulations

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PATHOPHYSIOLOGY OF MS

• Chronic Autoimmune,

inflammatory

neurological disease

of the CNS.

• Destroys myelin and

axons to varying

degree.

2

Calabresi PA . Diagnosis and management of multiple

sclerosis. Am Fam Physician. 2004 Nov 15; 70(10):1935-

44.

Demyelination

• Demyelination leading

to impaired saltatory

conduction of action

potentials.

3

Podbielska, Maria et al. “Myelin Recovery in Multiple Sclerosis:

The Challenge of Remyelination.” Brain Sciences 3.3 (2013):

1282–1324. PMC. Web. 4 Sept.2017.

SYMPTOMS OF MS

4

Goldenberg MM. Multiple Sclerosis Review. Pharmacy and Therapeutics. 2012;37(3):175-184.

MS LESIONS (MRI)

5

A

B

C

D

Poor prognosis predictors

• > 40 years of age at

onset

• Male sex

• Non-Caucasian origin

• Motor or polyregional

symptoms in first year of

attack.

• Brain stem lesion.

6

Hunter SF. Overview and diagnosis of multiple sclerosis. Am J Manag Care. 2016 Jun; 22(6 Suppl):s141-50.

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8

9

Cervical Lesion

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11

12

13

14

15

16

17

18

19

20

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Neurologist

• what can account for

your success as drug

therapy alone can not

explain your results of

your MRI?

22

Gut Bacteria Changes the

Brain

• Hepatic Encephalophy

– Lactose & Lactulose

protective

Campollo O, Sprengers D, McIntyre N. The BCAA/AAA ratio of plasma amino acids in three different groups of cirrhotics. Rev Invest

Clin. 1992 Oct-Dec;44(4):513-8.

Gut Bacteria Produces

Neurotransmitters• Gut microbes like Bacillus

spp. Account for almost half

of the of body's DA

production.1

• Gut bacteria & Brain –

Bidirectional signaling

involving multiple

neuroendocrine mechanisms.

Eisenhofer, G., Aneman, A., Friberg, P., Hooper, D., Fandriks, L., Lonroth, H., Hunyady, B., and Mezey, E. Substantial production of

dopamine in the human gastrointestinal tract. J. Clin. Endocrinol. Metabolism. 1997; 82: 3864–3871

25

Microbiome and inflammatory

demyelinating disease

Ochoa-Repáraz J, Mielcarz DW, Haque-Begum S, Kasper LH. Induction of a regulatory B cell population in experimental allergic

encephalomyelitis by alteration of the gut commensal microflora. Gut Microbes. 2010;1:103–8.

Autoimmune

Encephalomyelitis (EAE) is

the most commonly used

animal model for the human

inflammatory demyelinating

disease, multiple sclerosis

(MS).

LPS & Intestinal Inflammation

27LPS Inflamed intestines

Intestinal barrier and MS

•Changes in intestinal tight junction

permeability associated with industrial food

additives explain the rising incidence of

autoimmune disease.

•Glucose, salt, emulsifiers, organic solvents,

gluten, microbial transglutaminase, and

nanoparticles are the culprits involved in the

pathogenesis.

28

Autoimmunity ReviewsVolume 14, Issue 6, June 2015, Pages 479-489

Review

Fasano, Alessio. “Zonulin, Regulation of Tight Junctions, and Autoimmune Diseases.” Annals of the New York Academy of

Sciences 1258.1 (2012): 25–33. PMC. Web. 4 Sept. 2017.

Nuro-Endotoxins Up-Regulate

Inflammation

29

http://medical-dictionary.thefreedictionary.com/endotoxin

Lee, Jae Woong et al. “Neuro-Inflammation Induced by Lipopolysaccharide Causes Cognitive Impairment through Enhancement of

Beta-Amyloid Generation.” Journal of Neuroinflammation 5 (2008): 37. PMC. Web. 4 Sept. 2017.

All seven patients with MS

had elevated Candida tests

Good News

• Dysbiois can be

changed and alter

progression and

symptomology of MS

with Fecal Microbial

Transplant (FMT).

Wei, Yanling et al. “Successful Treatment with Fecal Microbiota Transplantation in Patients with Multiple Organ Dysfunction

Syndrome and Diarrhea Following Severe Sepsis.” Critical Care 20 (2016): 332. PMC. Web. 4 Sept. 2017.

Fecal Microbiota

transplantation

Fecal Microbiota

transplantation• What is it?• Administration of fecal material containing distal gut microbiota

from a healthy person to a patient with a disease or condition related to dysbiosis.

• Why do it?• Restore phylogenetic diversity and therefore microbiome

physiological functions.

• Replace and or inhibit pathogenic species.

• Does it work?• For recurrent C. difficile infections the efficacy of FMT is now

undisputed, with cure rates of 85-90% in case series.

1. Van Nood et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile NEJM 368;5

2. Kelly et al. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms and Outlook.

Gastroenterology 2015; 149: 223-237

FMT and MS

• Reported three wheelchair-bound patients with MS treated with FMT for constipation.

• Bowel symptoms resolved following FMT.

• Two of the patients with prior indwelling urinary catheters experienced restoration of urinary function.

Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS). Am J

Gastroenterol 2011; 106:S352ssion and ‘no evidence of active disease

• all three patients regaining the ability to

walk unassisted.

• In one patient of the three, follow-up MRI

15 years after FMT showed a halting of

disease progression

34Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS) [abstract].Am J

Gastroenterol 2011; 106:S352ssion and ‘no evidence of active disease.

Carlos walks after FMT

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Microbial diversity

• How to Grow Your Microbiome

37

CNS Lymphatics

38

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J.

Corrigendum: Structural and functional features of central nervous system lymphatic vessels. Nature. 2016 May 12;533(7602):278.

Vitamin-D in MS

• High-dose vitamin D (∼10,000 IU/day) in

multiple sclerosis is safe, with evidence of

immunomodulatory effects.

• Patients had fewer relapses.

• Low Vit-D levels – Risk for MS development.

39

•J.M. Burton, MD, MSc, FRCPC, S. Kimball, MSc, MLT, R. Vieth, PhD, A. Bar-Or, MD, MSc, FRCPC, H.-M. Dosch, MD, PhD, R.

Cheung, MSc, D. Gagne, C. D'Souza, PhD, M. Ursell, MS, MSc, FRCPC, and P. O'Connor, MS, MSc, FRCPC. A phase I/II dose-

escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010 Jun 8; 74(23): 1852–1859.

•Alharbi, Fatimah M. “Update in Vitamin D and Multiple Sclerosis.” Neurosciences 20.4 (2015): 329–335.

Vit B12

❖Easily passes Blood Brain Barrier.

❖Neuroprotective & anti-oxidant agent

involved in the synthesis of

phospholipids and myelin.

40Moosavirad, Saeedeh Alsadat et al. “Protective Effect of Vitamin C, Vitamin B12 and Omega-3 on Lead-Induced Memory Impairment

in Rat.” Research in Pharmaceutical Sciences 11.5 (2016): 390–396. PMC. Web. 3 Feb. 2017.

Testosterone

41Pakpoor J, Wotton CJ, Schmierer K, Giovannoni G, Goldacre MJ. Gender identity disorders and multiple sclerosis risk: A

national record-linkage study. Mult Scler. 2016 Nov;22(13):1759-1762. Epub 2016 Feb 8.

➢ Low testosterone in males –

Increased risk of MS.

➢Testosterone – converted to

estrogen (estradiol) in brain.

➢Anti-inflammatory,

neuroprotective.

Modafinil and Neuroprotection

• Modafinil (50 and 100 mg/kg) - Prevented against

decrease of DA, 5-HT, and NA in the striatum and

GSH, GABA in the SN induced by MPTP in PD

models.

• This was due to antioxidant effects

42

Xiao YL, Fu JM, Dong Z, Yang JQ, Zeng FX, Zhu LX, He BC. Neuroprotective mechanism of modafinil on Parkinson disease

induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Acta Pharmacol Sin. 2004 Mar;25(3):301-5.

Polyphenols

• Polyphenols - potential to block neural inflammation

and damage by modulation of inflammatory

cytokines.

• limiting demyelination in MS

43Bhullar KS, Rupasinghe HPV. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases. Oxidative

Medicine and Cellular Longevity. 2013;2013:891748.

Neurotrophins

44

Neurotrophins -

Neural survival,

development,

function, plasticity

BDNF

Considerably low in

Alzheimer’s &

cognitive impairment

Administration of S.

miltiorrhiza reduced

Aβ-induced

reductions in BDNF

in pre-clinical

models

Rosmarinic acid –

Increased BDNF

and restored

hippocampal BDNF

- Protective against

memory deficits

Lopresti, Adrian L. “Salvia (Sage): A Review of Its Potential Cognitive-Enhancing and Protective Effects.” Drugs in R&D 17.1 (2017):

53–64. PMC. Web. 7 Sept. 2017.

Fulgenzi A.et al A case of multiple sclerosis improvement following removal of heavy metal intoxication: lessons learnt from Matteo's

case. Biometals 2012 Jun;25(3):569-76.

• The Clinical data correlated with the

reduction of heavy metal levels in the urine to

normal range values.

• Case reports suggest that levels of toxic

metals can be tested in patients affected by

neurodegenerative diseases as MS.

Heavy Metals

MS

Dietary considerations

• The human brain is nearly 60 percent fat.

• Omega-3 fatty acids reduces the level of matrix

metalloproteinase (MMP) which plays an

important role in the migration of inflammatory

cells in the CNS fluid, which breaks down blood–

brain barriers.

46Jahromi SR, Toghae M, Jahromi MJR, Aloosh M. Dietary pattern and risk of multiple sclerosis. Iranian Journal of Neurology.

2012;11(2):47-53.

Dietary considerations

• Omega-3 fatty acids as immune system

regulators which act by reducing the levels

of inflammatory cytokines such as TNF-α,

IL-1, IL-2, and vascular cell adhesion

molecule (VCAM1).

• Shinto L, Marracci G, Baldauf-Wagner S, et al. Omega-3 fatty acid supplementation decreases matrix

metalloproteinase-9 production in relapsing-remitting multiple sclerosis. Prostaglandins, leukotrienes, and essential

fatty acids. 2009;80(2-3):131-136.47

❖n-3 PUFAs possibly have a role in promotion of

remyelination after toxic injury to CNS

oligodendrocytes via modulation of the immune

system or a direct effect on oligodendrocytes through

EPA-derived lipid metabolites as demonstrated in pre-

clinical studies.

n-3 PUFAs and Remyelination

Siegert E, Paul F, Rothe M, Weylandt KH. The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice.

BMC Neuroscience. 2017;18:19. doi:10.1186/s12868-016-0312-5.

Brain needs oxygen

49

• Lipopolyscharide induced

demylination prevents and

decreases with oxygen and

thymoquinone found in Black

Cumin Seed Extracts.

•Noor NA, Fahmy HM, Mohammed FF, Elsayed AA, Radwan NM. Nigella sativa amliorates inflammation and demyelination in the

experimental autoimmune encephalomyelitis-induced Wistar rats. International Journal of Clinical and Experimental Pathology.

2015;8(6):6269-6286.

•Desai RA, Davies AL, Tachrount M, Kasti M, Laulund F, Golay X, Smith KJ.Cause and prevention of demyelination in a model

multiple sclerosis lesion. Ann Neurol. 2016 Apr;79(4):591-604.

Chronic Cerebrospinal Venous

Insufficiency (CCSVI) & MS

• Veins in the head and neck are narrowed resulting

in inefficient blood drain from the CNS.

• Reflux of blood back to the CNS due to pressure

caused by build-up of blood.

• Compensatory blood vessels developed lack the

same structural integrity and are leaky.

• Leaked blood with iron deposits in the CNS

triggering immune response and MS.

50Costello F et al. Validity of the diagnostic criteria for chronic cerebrospinal venous insufficiency and association with

multiple sclerosis. Canadian Medical Association Journal 2014 June 2

Exercise/ Physical activity

✓ Exercise - Shown to increase synaptic density and growth in

the hippocampus in the animal model of MS.

✓ Physical activity Increases levels of neurotrophic factors,

elevates expression of anti-inflammatory cytokines, and

reduces levels of pro-inflammatory cytokines and activates

microglia and is thus neuroprotective.

• Rossi S., Furlan R., De Chiara V., Musella A., Lo Guidice T., Mataluni G. (2009) Exercise attenuates the clinical, synaptic

and dendritic abnormalities of EAE. Neurobiol Dis 36: 51–59.

• Svensson M, Lexell J, Deierborg T.Neurorehabil Neural Repair. Effects of Physical Exercise on Neuroinflammation,

Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings. 2015

Jul;29(6):577-89. 51

Seasonality of MS – Role of

Melatonin

52

Seasonal

changes (length

of day and night)

Melatonin levels

Negatively

correlate

with MS

Melatonin

treatment

ameliorates MS

Induces expression

of transcription factor

Nfil3, promotes

generation of

protective Tr1 cells

Influence

differentiation

of T cells

Farez, Mauricio F. et al. “Melatonin Contributes To The Seasonality Of Multiple Sclerosis Relapses.” Cell 162.6 (2015):

1338–1352. PMC. Web. 7 Sept. 2017.

Variation in

Serum Glutamate and MS

• Neurotransmitter Glutamate –

Implicated in autoimmune

demyelination in MS.

MS Control

Serum

Glutnmol/ml

1.318 ±

0.543

0.873 ±

0.341 

53

The mean

serum glutamate levels

determmined by ELISA

Al Gawwam G, Sharquie IK. Serum Glutamate Is a

Predictor for the Diagnosis of Multiple Sclerosis.

ScientificWorldJournal. 2017;2017:9320802.

Cholinergic signaling in

remyelination

54Fields RD, Dutta DJ, Belgrad J, Robnett M. Cholinergic signaling in myelination. Glia. 2017 May;65(5):687-698.

• Cholinesterase inhibitors - Shown to

improve remyelination in animal models

of MS.

• Cholinergic signalling in oligodendroglial

development and myelination seems

possible

Progesterone and

Remyelination• Progesterone and synthetic progestins

• modulate inflammatory responses and partially

reverse the age-dependent decline

in remyelination.

• Progesterone and Nestorone promoted repair of

severe chronic demyelinating lesions induced by

feeding cuprizone to female mice for up to 12

weeks,

55

El-Etr M, Rame M, Boucher C, Ghoumari AM, Kumar N, Liere P, Pianos A, Schumacher M, Sitruk-Ware R. Progesterone and

nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia. 2015

Jan;63(1):104-17.

T3 and Remyelination

• Thyroid hormone (T3) promotes remyelination.

• T3 promotes Kruppel-like factor 9 (KLF9)

transcription factor a novel integral component of

signaling cascade that promotes the regeneration

of lost myelin.

56Dugas, Jason C., Adiljan Ibrahim, and Ben A. Barres. “The T3-Induced Gene KLF9 Regulates Oligodendrocyte Differentiation and

Myelin Regeneration.” Molecular and cellular neurosciences 50.1 (2012): 45–57. PMC. Web. 7 Sept. 2017.

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Treating the Terrain

Healthy

Microbiome

Acetylcholine

Epinephrine

GABA

Serotonin

Dopamine

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Treating the Terrain

Sick

MicrobiomeBlood Brain

PermeabilityNeuroinflammation

Gut Permeability

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Treating the Apparent Mechanism

Neuroinflamation

Polyphenols

Exercise

Omega 3

Microbiome

Diterpenes

Cortisol

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Treating the Apparent Mechanism

Oxidation

Microbiome

Melatonin

Glutathione

Detoxification

Monoclonal Antibodies

Modafinil

Dimethyl fumarate

Antioxidants

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Treating the Apparent Mechanism

GlutamateKava

Neurosteroids

GABA

Green Tea

(Theanine)

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Treating the Apparent Mechanism

Demylination

Oxygen Omega 3

Neuroprotecants

63

Treating the Apparent Mechanism

Monoclonal

Antibodies

Phytollaca

(Poke)

Dimethyl

Fumarate

Interferon

Glatiramer

Acetate

Immunomodulation

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Treating the Apparent Mechanism

Remylination

T3

Microbiome

Turmerones

Lion’s Mane

Mushroom

Exercise

Deiodinase