9/14/15 Solving the Mystery of
Chronic Pain and Depression
Nutritional Supplements for the Treatment
of Central Sensitization Syndrome
Gary Kaplan, DO, DABFP, DABPM, FAAMA
Medical Director, Kaplan Center for Integrative Medicine
Clinical Associate Professor, Georgetown University School of Medicine
Disclosures
•  Nothing to disclose
Central Sensitization Syndrome
CSS = Chronic Pain + Neuropsychiatric Condition
•  Neuroinflammatory
•  Neurodysregulatory
•  Neurodegenerative
1 9/14/15 Chronic pain and depression are
symptoms of inflammation in
the brain.
Inflammation is a result of
cumulative assaults on
the brain.
17, 50, 51
2 9/14/15 17, 50
18, 21, 23, 39, 43
3 9/14/15 50, 51
Brain Aging and Neurodegeneration
•  Microglia from aging or degenerated brains:
− Exaggerated inflammatory response to secondary and
sub threshold challenges
− Higher percentage are “stuck” in the inflammatory
phenotype
− Produce significantly more pro-inflammatory cytokines
(IL-1,IL-6, TNF)
− Produce significantly less anti-inflammatory mediators
(IL-10,BNDF,inhibitor of NF-kB)
PMC 4186766, PMID: 18026097, 25445485
Brain Aging and Neurodegeneration
“There is a strong correlation between brain aging
and neurodegeneration and redox imbalance, as
well as chronic low grade inflammation”
(Rojo et al., 2014)
PMC 4186766
4 9/14/15 Brain Aging and Neurodegeneration
•  Neurodegenerative diseases are characterized by
chronic microglial over-activation and oxidative stress. It
is now beginning to be recognized that reactive oxygen
species (ROS) produced by either microglia or the
surrounding environment not only impact neurons but
also modulate microglial activity
•  Despite its high dependence on oxidative metabolism,
the brain has low levels of antioxidants and is vulnerable
to oxidative stress
PMID: 24597893
Redox Imbalance
•  Oxidative stress:
ROS + RNS > Available antioxidants
•  ROS and RNS predominately originate from activated
inflammatory and immune cells:
− Microglia
− Mitochondria
Glutathione (GSH)
•  GSH is the main antioxidant in the CNS and it has a
crucial role in maintaining redox balance, particularly in
astrocytes and microglia
•  GSH is essential for mitochondrial survival
•  GSH level decrease with aging
PMC4186766, PMID: 24752591 PMID: 22532869 PMID: 25405315
5 9/14/15 Glutathione (GSH)
• 
• 
• 
• 
• 
• 
Crucial role in cellular signaling and antioxidant defenses
Most abundant of the endogenous antioxidants
Detoxification of ROS and RNS
Detoxification of electrophiles produced by Xenobiotic
Optimal functioning of the immune system
CNS antioxidant, neuromodulator, neurotransmitter
PMID: 24752591 PMID: 26233704 PMID: 24145751 PMID: 11111154
GSH
•  GSH depletion has marked consequences for the
homeostatic control of the immune system, oxidative
and nitrosative stress (O&NS) pathways, regulation of
energy production, and mitochondrial survival
PMID: 24752591 PMID: 22532869 PMID: 25405315
GSH Clinical Applications
•  Depletion/dysfunction plays an important role during the
onset and progression of neuropsychiatric and
neurodegenerative diseases.
•  Neuroimmune disorders:
− Depression
− Parkinson’s
− ME/CFS
− Fibromyalgia
PMID: 25405315,, 24752591 PMID: 22532869 PMID: 25405315
6 9/14/15 Oral GSH Supplementation
•  Generally poorly absorbed and poor bioavailability
•  Effects of oral glutathione supplementation on systemic
oxidative stress biomarkers in human volunteers in 2010
showed no effect
PMC 3162377
Oral GSH Dosage
•  Oral GSH at 250mg/day x 6 months
− 30-35% increase in erthrocytes, plasma and lymphocytes
− 260% increase in buccal cells
•  Oral GSH at 1000mg a day > 2X increase in natural
killer cytotoxicity
•  Baseline levels re-established 1 month after stopping the
supplement
PMID: 24791752
Liposomal GSH Supplementation
•  “Liposomal glutathione supplementation restores Th1
cytokine response to Mycobacterium tuberculosis
infection in HIV-infected individuals” (Ly et al., 2015).
•  “Glutathione supplementation improves macrophage
functions in HIV” (Morris et al., 2013).
PMID: 23409922, PMID: 26133750
7 9/14/15 Sublingual GSH Supplementation
•  A 2015 study entitled “Effects of N-acetylcysteine, oral
glutathione (GSH) and a novel sublingual form of GSH
on oxidative stress markers: A comparative crossover
study” found that:
“Overall, our results demonstrate the significant superiority
of a new sublingual form of GSH over the oral form, both in
terms of bioavailability and positive effects on oxidative
stress. Compared to NAC, better effects of the sublingual
form of GSH were also observed.”
PMID: 26262996
IV GSH Supplementation
•  “Intravenous glutathione prevents renal oxidative stress
after coronary angiography more effectively than oral Nacetylcysteine” (Saitoh et al., 2011).
•  “Randomized, double-blind, pilot evaluation of
intravenous glutathione in Parkinson's disease” (Hauser
et al., 2009).
•  “Effect of glutathione infusion on leg arterial circulation,
cutaneous microcirculation, and pain-free walking
distance in patients with peripheral obstructive arterial
disease: a randomized, double-blind, placebo-controlled
trial” (Arosio et al., 2002).
PMID: 21127883, PMID: 19230029, PMID: 12173710
GSH Supplementation Dosage
• 
• 
• 
• 
Oral 250mg QD-500mg BID
Liposomal 450mg a day
Sublingual 450mg a day
IV 1400mg QD-BID
PMID: 2479175223409922, 26133750,26262996,21127883, 19230029, 12173710
8 9/14/15 N-acetylcysteine (NAC)
• 
• 
• 
• 
Antioxidant
Precursor of L-cysteine and reduced GSH
Source of sulfhydryl group in cells
Scavenger of free radicals
PMID: 2546864
NAC and GSH
•  Glutathione = glutamate + glycine + cysteine
•  Cysteine has the lowest intracellular concentration and
therefore is the rate limiting molecule in glutathione
production
PMID: 185009594,PMC396752, PMID: 22634224
NAC and GSH
•  Questionable if glutathione can cross the BBB
•  NAC does contribute cysteine to the CNS across the
BBB
•  NAC can minimize the oxidative effect of ROS through
correcting or preventing GSH depletion
PMID: 185009594,PMC396752
9 9/14/15 NAC Clinical Applications
• 
• 
• 
• 
Major Depressive Disorder
Bipolar disorder
Addiction
Neurodegenerative Diseases
PMC3497002, PMID: 21118657
NAC Dosage
•  Oral 200-400mg
•  Anecdotal 500mg-6gms
NOTE: At very high dosages potential for toxicity
reaction
PMC3967529
Melatonin (N-acetyl-5mthoxytryptamine)
•  Hormone (Pineal gland)
•  Macrophages/Astrocyte/Microglia
•  GI melatonin from serotonin-rich enterochromaffin cells
of the GI mucosa
•  Circadian Rhythm
•  Antioxidant (ROS/RNS)
•  Immunologic functions/ Anti-inflammatory
•  Antinocioceptive
PMID:25908646 PMID: 25012620 PMC3091156
10 9/14/15 Melatonin Clinical Applications
• 
• 
• 
• 
• 
• 
Circadian sleep disorders
Psychiatric disease
Migraines
Fibromyalgia
Neuropathic pain
Neurodegenerative disease
PMC3593297 . PMID 25012620 PMC3354573 PMC4119581 PMC3949259, PMID: 25052847
Melatonin Impact on the Microglia
•  It is suggested that melatonin attenuates the release of
pro-inflammatory cytokines from microglia and the
development of neuropathic pain through the inhibition
of Ca2+ influx-mediated microglial activation
•  This results in reduction of neuroinflammatory factors
and is neuroprotective.
PMC4153058
Melatonin Impact on the Microglia
•  The impact may be indirect:
“Genetic Epigenetic and wider factors that regulate
astrocyte melatonin may then determine the nature of
microglia and wider immune cell responses at sites of
local inflammation” (Huand et al., 2014)
PMC4153058
11 9/14/15 Melatonin Other Mechanisms of
Action
•  Melatonin efficiently protects neuronal cells from Aβmediated toxicity via antioxidant and anti-amyloid
properties.
•  Melatonin not only inhibits Aβ generation, but also
arrests the formation of amyloid fibrils by a structuredependent interaction with Aβ.
PMC3949259
Melatonin Dosage
•  Anywhere from .1-100mg
PMC3949259, 354573, 3587994 PMID: 25052847
Ubiquinone (CoQ10)
•  In vivo 95% is in the reduced form Ubiquinol
•  Located in inner mitochondrial membrane
•  Transfers reducing equivalents from complexes I and II to
complex III
•  Antioxidant
•  Intermembrane CoQ10 are rate limiting in the
production of ATP
PMCID: PMC3262379
12 9/14/15 Ubiquinone (CoQ10) Functions
•  Essential for mitochondrial respiratory chain efficiency;
suggested that levels can be useful as biological marker
of mitochondrial function
•  Deficiency predisposes to apoptosis
•  Anti-inflammatory
•  Neuro-protective
•  Regulates gene expression
PMID: 22342824, 19932599, PMCID: PMC3262379
CoQ10
•  Reduced in patients with myopathy, but all forms of
deficiency show improvements after oral
supplementation
•  Oral supplementation enhanced levels in salivary cells
and blood mononuclear cells
•  Deficiency observed in patients suffering several typical
symptoms found in fibromyalgia patients
PMID: 22342824
CoQ10
•  Deficiencies due to mutations in ubiquinone biosynthetic
genes have excellent responses to oral treatment
•  Respiratory chain dysfunction and oxidative stress
correlate with severity of primary deficiency
•  Treatment restores mitochondrial dysfunction and the
mtDNA copy number, decreases oxidative stress, and
increases mitochondrial biogenesis
PMID: 19932599
13 9/14/15 CoQ10 Deficiencies
• 
• 
• 
• 
Autosomal recessive mutations
Ageing related oxidative stress
Carcinogenesis processes
Statin treatment
PMID: 24389208
CoQ10 Clinical Applications
• 
• 
• 
• 
• 
Neurodegenerative/Neuromuscular disorders
Fibromyalgia
ME/CFS
Migraines
Depression
PMID: 24389208, PMCID: PMC3934515, PMID: 23761046,PMID: 20017723, PMID: 11972582
CoQ10 Dosage
•  300 mg/day, divided in 3 doses (Fibromyalgia patients)
•  300-2,400mg/day in Parkinson’s dx
PMID: 22342824, PMCID: PMC3262379
14 9/14/15 Ginkgo Biloba / EGb761
•  In the United States, EGb761 is one of the most
commonly used over the counter nutraceuticals for
memory enhancement and overall wellbeing.
− 24% ginkgo flavonol glycosides
− 6% terpene lactones
PMCID: PMC3568207
Ginkgo Biloba / EGb761
•  Extract from Gingko biloba tree leaves
•  Main components are quercetin, kaempferol, and
isorhamnetin
•  Antioxidant
•  Immunomodulator
•  Improves vascular flow
PMID 26021285, PMID 23983777
Ginkgo Biloba / EGb761
•  Neuroprotectant with multiple mechanisms of action:
− Downregulates microglia
− Preservation of mitochondrial ATP synthesis
− Inhibition of apoptosis
− Suppression of hypoxia-induced membrane
deterioration in the brain
PMID 26021285, PMID 23983777
15 9/14/15 Ginkgo Biloba Clinical Applications
• 
• 
• 
• 
• 
Neurodegenerative Dx
Ischemic stroke
Neuropsychiatric disease (MDD, ADHD, Anxiety)
Neuropathic pain
Migraine
PMID: 26059355, PMID: 26059355. PMID: 17763047,
PMID: 26021285, PMID: 24867850, PMCID: PMC3084934
Ginkgo Biloba Dosages
•  120-600mg/day
CAUTION: Do not take with Ibuprofen or
anticoagulants
Phenolic Compounds
•  Phytochemical – Bioactive nonessential nutrients from
plants
•  In the plant essential for reproduction, growth and
defense (pathogens, parasites, predators)
•  Abundant in fruits and vegetables
PMID: 20043255
16 9/14/15 Phenolic Compounds Properties
Antioxidant activity
Scavenging free radicals
Induction of cell-cycle arrest and apoptosis
Inhibition of signal transduction pathways including
nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κ B), activator protein-1 (AP-1), mitogenactivated protein kinases (MAPK)
•  Modulation of enzyme activities in detoxification,
oxidation, and reduction
•  Anti-inflammatory properties by stimulation of the
immune system
•  Neuroprotective
• 
• 
• 
• 
PMID: 20043255
Phenolic Compounds
• 
• 
• 
• 
• 
Quercetin
Curcumin
Stilbeniod (Resveratrol)
Flavonoids
Coumarin
PMID: 20043255
Quercetin
•  Bioflavonoid found in vegetables, fruits, herbs, leaves,
seeds, red wine, tea, coffee, beer, and several medicinal
plants
•  Converted from rutin in bloodstream
•  Inhibits cytokine release from human mast cells
PMID: 24152430, PMID: 16569342
17 9/14/15 Quercetin
•  Cell-protective
−  Antioxidant
−  Antinociceptive
−  Anti-inflammatory
•  Analgesic
•  Suppresses oxidative stress and inflammatory response
in microglia
PMID: 24152430, PMID: 25744406 , PMID: 24095694
Quercetin Clinical Applications
• 
• 
• 
• 
Neuropathic pain
? Fibromyalgia
Neurodegenerative dx
Depression
PMCID: PMC3835704, PMID: 16569342, 24188794,
PMCID:14499317, 26146123 PMCID: PMC4192974,PMC4192974
Quercetin Dosage
•  12.5-25mg/kg
•  1,136-2,272mg/day
18 9/14/15 Curcumin
•  Curcuminoid
•  The yellow pigment in Turmeric and yellow mustard
PMID: 20043255
Curcumin
•  Mediates anti-inflammatory effects through
downregulation of inflammatory transcription factors,
enzymes, and cytokines
•  Promotes microglia anti-inflammatory phenotype
•  Blocks expression and signaling of TNFα
•  Anti-inflammatory effects mediated through suppression
of transcription factor NF-κB
•  May inhibit NO production
PMID: 19110321, PMID: 17199240, PMC3535097
Curcumin Properties
• 
• 
• 
• 
Antibacterial
Antiproliferative
Anti-inflammatory
Antiviral
PMID: 19110321, PMID: 17199240, PMC3535097
19 9/14/15 Curcumin Clinical Applications
• 
• 
• 
• 
Neurodegenerative dx
OA
RA
Therapeutic value against most chronic diseases
including:
− neoplastic
− neurological
− cardiovascular
− pulmonary
− Metabolic
− psychological diseases
PMCID: PMC3535097, PMID: 22427192
Curcumin Dosage
80-500mg/day
•  Pairing curcumin with Black Pepper (Piperine)
•  Curcumin phytosomes complexed with
Phosphatidylcholine (Meriva or BCM-95)
•  Curcumin nanoparticles (Theracumin)
•  Water-soluble curcumin (Polyvinylpyrrolidone)
PMID: 17199240
Resveratrol
•  Cardioprotective phytoalexin found in red wine –
“French Paradox”
•  Mechanism by which range of beneficial effects is still
unclear
•  Effective inhibitor of cyclooxygenase activity in vivo
•  Main stilbene generated in considerable amounts in the
skin of grapes, raspberries, mulberries, pistachios and
peanuts
PMID: 18684235, PMID: 21688389
20 9/14/15 Resveratrol Pharmacokinetics
•  Well absorbed after oral administration, but has low
bioavailability
•  Rapidly metabolized in intestine and liver
•  Caution with interpretation of In Vitro vs In Vivo studies
PMID: 18684235 , PMID: 21688389, PMCID: PMC4499410
Resveratrol Properties
• 
• 
• 
• 
• 
• 
• 
Anti-carcinogenic
Antioxidant (ROS)
Anti-proliferative
Pro-apoptotic
Anti-inflammatory
Analgesic
Anti-aging
PMID: 18684235 , PMID: 18684235
Resveratrol Clinical Applications
•  Neuropathy
•  Neuroprotection stroke, TBI, spinal cord injuries
•  Adjuvant with morphine to restore the antinociceptive
effect of morphine
•  Modulation of the hippocampus plasticity and
suppression of chronic low-level inflammation resulting
in improvement in age related mood and memory
function
•  Down regulates microglial activation
•  Neuropsychiatric disorders
PMID: 26277384, PMID: 26078221, PMID: 25627672 PMID: 25727173 , PMID: 18684235 , PMID: 24717328
21 9/14/15 Resveratrol Dosage
•  Health benefits found from dosing between 5mg-5gms
(some supplements containing compounds to enhance
action, others containing pure resveratrol)
PMID: 21688389
Omega-3 Fatty Acids
• 
• 
• 
• 
• 
Polyunsaturated fatty acids (n-3 PUFAs)
Not synthesized in the body
Eicosapentaenoicacid (EPA) – fatty fish
Docosahexaenoic acid (DHA) – fatty fish
Alpha-linoleic acid (ALA) – flax seed, canola, soybean,
walnuts, leafy green vegetables
PMID: 26243838
Omega-3 Fatty Acids Actions
• 
• 
• 
• 
• 
Anti-neuroinflammatory (CNS and peripheral)
Crucial in normal neuronal development
Anti-oxidant
Neuroprotective
Regulatory function on growth factors and neuronal
plasticity
PMID: 26036964, PMID: 25889069, PMID: 25815252, PMID: 25468770, PMID: 24735929
22 9/14/15 Omega-3 Fatty Acids
“The integrity of dendritic spines, the postsynaptic
component of excitatory synapses, dictates synaptic
efficacy. Interestingly, dysgenesis of dendritic spines has
been found in many neurological diseases associated with
ω-3 polyunsaturated fatty acid (PUFA) deficiency and
cognitive decline. In contrast, supplemented ω-3 PUFAs,
such as docosahexaenoic acid (DHA), can partly
correct spine defect.”
(Chang et al., 2015)
PMID: 25889069
Omega-3 Fatty Acids Therapeutic
• 
• 
• 
• 
• 
Neuropsychiatric conditions
Neuroprotective post stroke and TBI
Neuropathic pain
Migraines
Neurodegenerative disease
PMID: 26243838, 21721919, 20090445, 24770761, 23886520, 26036964, 26260547, PMCID: PMC440491
Omega-3 Fatty Acids Dosage
•  ≥ two 3.5oz (oily) fish servings/week
•  1.5-9gms/day EPA/DHA
PMID: 24694001
23 9/14/15 Vitamin D (25-hydroxyvitamin D)
•  Produced in the skin after exposure to sunlight
•  Can be obtained through food
•  Important for calcium homeostasis and maintenance of
skeletal health
•  Conflicting results from studies on inverse relationship
between deficiency and self-reporting pain
•  Debate on what constitutes Vitamin D deficiency
PMID 25946084, PMID 17599737, PMID 24438771
Vitamin D (25-hydroxyvitamin D)
•  Immunomodulatory effects on inflammatory arthritis
•  Inversely associated with activity, severity, and functional
disability of disease in patients with early inflammatory
polyarthritis (IP)
•  Low levels result in heightened central sensitivity, nonspecific musculoskeletal pain, chronic widespread pain,
fibromyalgia, low back pain, headache, and lumbar spinal
stenosis
PMID: 17599737, PMID 2473075
Vitamin D Clinical Applications
•  Neuropsychiatric disorders
•  Neurodegenerative disease
PMID: 22211682, PMCID: PMC4008710, PMID: 25713056
24 9/14/15 Vitamin D (Calcifediol)
•  Low serum levels especially common in patients with
severe pain and fibromyalgia syndrome (FMS)
PMID: 24438771
Vitamin D Dosage
•  Each 10-ng/ml increase in 25(OH)D à decrease in
DAS28 score and CRP level
•  Each 25 nmol/L decrease in 25(OH)D à increase in pain
intensity
•  IOM: 600 IUs (800 à 70+)
•  Recommendation may be higher without adequate sun
exposure
PMID 17599737, PMID 2473075, PMID 25946084
Vitamin D Blood Levels
•  Normal Vitamin D 25-hydroxy level is 30-100ng/ml
•  I believe ideal level is 50-60ng/ml
25 9/14/15 My Recommendations
• 
• 
• 
• 
• 
• 
• 
• 
Omega-3 fatty acids – 1.5-9gms/day
Vitamin D blood level – 50-60ng/ml
Liposomal glutathione – Readisorb .5-1tps/day
NAC – 600mg TID
CoQ10 – 100-300mg TID
Ginkgo extract – 240-600mg
Curcumin – Meriva-SR 200mg QD-BID
Trans-resveratrol – 125mg
1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 20, 22, 23, 24, 25, 26, 27, 29, 32, 33, 34, 35, 36
I kindly thank you
for your attention.
Gary Kaplan, DO, DABFP, DABPM, FAAMA
Medical Director, Kaplan Center for Integrative Medicine
Clinical Associate Professor, Georgetown University
School of Medicine
THE KAPLAN CENTER
For Integrative Medicine
Experts in relieving chronic pain & illness
6829  Elm Street, Suite 300
McLean,VA 22101
703-532-4892
www.kaplanclinic.com
26 9/14/15 Glutathione References
1.  Antioxid Redox Signal. 2014 Oct 20;21(12):1766-801. doi: 10.1089/ars.2013.5745. Epub 2014 May 5.Redox control of microglial function:
molecular mechanisms and functional significanceRojo AI1, McBean G, Cindric M, Egea J, López MG, Rada P, Zarkovic N, Cuadrado A. PMID:
24597893
2. Eur J Pain. 2006 Oct;10(7):573-9. Epub 2005 Oct 7.Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by
N-acetyl-L-cysteine in rats.Naik AK1, Tandan SK, Dudhgaonkar SP, Jadhav SH, Kataria M, Prakash VR, Kumar D. PMID: 16214382
3. J Neurochem. 2010 Jan;112(1):77-91. doi: 10.1111/j.1471-4159.2009.06435.x. Epub 2009 Oct 15.
N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy.
Kamboj SS1,Vasishta RK, Sandhir R. PMID: 19840221
4. Antioxidant responses and cellular adjustments to oxidative stress Cristina Espinosa-Dieza,Verónica Miguela, Daniela Mennerichb, Thomas Kietzmannb,
Patricia Sánchez-Pérezc, Susana Cadenasc, Santiago Lamasa, , doi:10.1016/j.redox.2015.07.008 PMID: 26233704
5. Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study.
Salem HF, Ahmed SM, Hassaballah AE, Omar MM.
Drug Des Devel Ther. 2015 Jul 20;9:3705-27. doi: 10.2147/DDDT.S85302. eCollection 2015.
PMID: 26229435
6. Curr Opin Clin Nutr Metab Care. 2015 Jan;18(1):89-95. doi: 10.1097/MCO.0000000000000134.Glutathione redox imbalance in brain disorders.
Gu F1, Chauhan V, Chauhan A. PMID: 25405315
7. Int J Mol Sci. 2013 Oct 18;14(10):21021-44. doi: 10.3390/ijms141021021.Impaired glutathione synthesis in neurodegeneration.
Aoyama K1, Nakaki T. PMID: 24145751
8. Dev Neurosci. 2000 Sep-Dec;22(5-6):384-92.Microglial cells in culture express a prominent glutathione system for the defense against
reactive oxygen species.Hirrlinger J1, Gutterer JM, Kussmaul L, Hamprecht B, Dringen R. PMID: 11111154
9. Curr Opin Clin Nutr Metab Care. 2015 Jan;18(1):89-95. doi: 10.1097/MCO.0000000000000134.Glutathione redox imbalance in brain disorders.
Gu F1, Chauhan V, Chauhan A. PMID: 25405315
10. Mol Neurobiol. 2014 Dec;50(3):1059-84. doi: 10.1007/s12035-014-8705-x. Epub 2014 Apr 22.The glutathione system: a new drug target in
neuroimmune disorders.Morris G1, Anderson G, Dean O, Berk M, Galecki P, Martin-Subero M, Maes M. PMID: 24752591
11. PLoS One. 2012;7(4):e35677. doi: 10.1371/journal.pone.0035677. Epub 2012 Apr 19.Oxidative stress correlates with headache symptoms in
fibromyalgia: coenzyme Q₁₀ effect on clinical improvement.
Cordero MD1, Cano-García FJ, Alcocer-Gómez E, De Miguel M, Sánchez-Alcázar JA. PMID: 22532869
12. Nutrients. 2012 Oct; 4(10): 1399–1440.Published online 2012 Oct 9. doi: 10.3390/nu4101399
PMCID: PMC3497002Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases
William M. Johnson,1,2 Amy L. Wilson-Delfosse,1 and John. J. Mieyal1,2,*
Glutathione References
13. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and
neurodegenerative disease. Norden DM1, Muccigrosso MM1, Godbout JP2
Neuropharmacology. 2015 Sep;96(Pt A):29-41. doi: 10.1016/j.neuropharm.2014.10.028. Epub 2014 Nov 13. PMID 25445485
14. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Norden DM1, Godbout JP.
Neuropathol Appl Neurobiol. 2013 Feb;39(1):19-34. doi: 10.1111/j.1365-2990.2012.01306.x. PMID 23039106.
15. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione.
Richie JP Jr1, Nichenametla S, Neidig W, Calcagnotto A, Haley JS, Schell TD, Muscat JE. Eur J Nutr. 2015 Mar;54(2):251-63. doi:
10.1007/s00394-014-0706-z. Epub 2014 May 5 PMID: 24791752
16. Liposomal Glutathione Supplementation Restores TH1 Cytokine Response to Mycobacterium tuberculosis
Infection in HIV-Infected Individuals.
Ly J1,2, Lagman M1,2, Saing T1, Singh MK1,2, Tudela EV1,2, Morris D2, Anderson J2, Daliva J2, Ochoa C3, Patel N3, Pearce D4,
Venketaraman V J Interferon Cytokine Res. 2015 Jul 2. PMID: 26133750
17. Glutathione supplementation improves macrophage functions in HIV.
Morris D1, Guerra C, Khurasany M, Guilford F, Saviola B, Huang Y,Venketaraman VJ Interferon Cytokine Res. 2013 May;33(5):270-9.
doi: 10.1089/jir.2012.0103. Epub 2013 Feb 14 PMID: 23409922
18. Allen J, Bradley RD. Effects of Oral Glutathione Supplementation on Systemic Oxidative Stress Biomarkers in Human
Volunteers. Journal of Alternative and Complementary Medicine. 2011;17(9):827-833. doi:10.1089/acm.2010.0716.
19. Schmitt B,Vicenzi M, Garrel C, Denis FM. Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual
form of GSH on oxidative stress markers: A comparative crossover study. Redox Biol. 2015 Jul 29;6:198-205. doi:
10.1016/j.redox. 2015.07.012. PMID: 26262996
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