Transcript Neuropathy

Inflammation, pain & numbness
Neuropathic pain
• Chronic pain condition resulting from damage to
nerves in the peripheral or central nervous system.
• It presents with an increased sensitivity of pain
(hyperalgia) & pain response to a usually nonpainful stimulus (allodynia) such as cold or light
• Diagnosis of neuropathic pain is suggested when a
patient reports pain that is out of proportion to the
Soliton – Sound pulse ( does not disperse)
• Cell membranes have ‘freezing point’ (when
consistency changes from fluid to gel-like).
• Just slightly below organism's body temperature.
• Gel allows for propagation of solitons.
• Action potential traveling along a neuron results in a
slight increase in temperature followed by a
decrease in temperature.
• Decrease not explained by Hodgkin-Huxley model
(electrical charges traveling through a resistor
always produce heat).
Soliton (Self-propagating membrane wave)
• Traveling solitons do not lose energy.
• Temperature profile supports Soliton model.
• Signal traveling along a neuron results in a slight
local thickening of membrane & outward force.
• This effect is not explained by Hodgkin-Huxley
model but clearly consistent with Soliton model.
• Traveling wave changes membrane density & width.
• Membrane contains many charged, polar substances
& pulse creates piezoelectric electrical effect.
Anesthetics - Freezing nerves
• Meyer-Overton noted strength of chemically
diverse anesthetics is proportional to their lipid
solubility (in olive oil).
• Do not act by binding to protein ion channels?
• Act by dissolving in & changing fluidity of lipid
membrane, simply changing ‘melting point’.
• Dissolving agents lower membrane ‘freezing point’.
• Larger difference between body temperature and
freezing point inhibits propagation of solitons.
Pulse propagation in biological
• Lipids of biological membranes display chain
melting transitions.
• During transition, heat capacity, volume & area
compressibilities & and relaxation times maximize.
• Compressibilities are nonlinear functions of
temperature & pressure near melting transition.
• If membrane state is above melting transition,
solitons will involve changes in lipid state.
Solitons propagate without distortion
• Membranes absorb heat & dissipating both lateral
order & chain order of lipid molecules.
• Transition causes increase in volume of ≈4% &
increase in area of ≈25%.
• Low & high temperature phases are called solidordered & liquid-disordered (simultaneous change in
lateral crystalline arrangement & chain order).
• Also known as gel & fluid phase.
• There is a minimum velocity of a soliton.
• Maximum amplitude & minimum velocity similar
to propagation velocity in myelinated nerves.
Peripheral Nerves - three parts
• Cell Body is the part of nerve that stores DNA &
determines health of nerve cell.
• Dorsal Root Ganglion is collection of cell bodies
for all sensory nerves in one spinal nerve root.
• Axon acts as electrical wire, conducting messages
from peripheral tissues to Dorsal Horn of spinal
• Myelin Sheath acts as electrical insulation for
axon, improving conduction speed & ensuring no
cross-talk between adjacent axons. Thicker the
layer of myelin, faster conduction speed of nerve.
Schwann cells produce myelin as they wrap them
selves around groups of axons in nerve bundles.
Disease of the cell body
• Poisons & toxins may affect metabolic processes of
axon cell body, commonest being excessive alcohol
(25-30% of all cases), pernicious anemia (deficiency
of vitamin B-12), exposure to heavy metals, other
vitamin deficiencies & industrial hydrocarbons.
• Liver & kidney failure can cause metabolic
derangement in cell bodies, leading to axonal
Interference with nerve blood supply
(vasa nervorum) causes progressive
axonal damage
• Chronic peripheral vascular disease & Diabetes
Mellitus poor sugar control accelerates
arteriosclerosis (narrowing of arteries) leading to
occlusion of vasa nervorum & progressive loss of
peripheral nerve function.
• Rheumatological conditions like RA, SLE, PAN
(Polyarteritis Nodosa), Sjogren's Syndrome (dry
everything) & Wegener's Arteritis can all produce
inflammation of small arteries (arteritis) supplying
peripheral nerves, leading to arterial occlusion &
nerve failure.
Peripheral Neuropathy
Dapsone neuropathy is a form of peripheral
neuropathy that develops in patients using Dapsone.
Diphtheritic neuropathy is a form of rapidly
developing peripheral neuropathy caused by a toxin
produced by Corynebacterium diphtheriae.
Heavy metal neuropathy is a group of peripheral
neuropathies caused by excessive levels of arsenic,
gold, lead, mercury, platinum or thallium.
In-Tele-Health © 2002 (from Hyperhealth Pro CD-ROM)
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Healthy nerve cells in the brain contain support
structures called microtubules, which guide
nutrients within the cell. A special kind of protein,
tau, makes microtubules stable.
Tau is changed chemically in elderly people,
especially those with Alzheimer's disease. It begins
to pair with other threads of tau & they become
tangled. When this happens, microtubules
disintegrate, collapsing the neuron's transport
This may result first in communication malfunctions
between neurons causing memory loss & later in
triggering apoptotic cell death.
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Primal scream for oxygen
• Ischemic neuropathy results from acute or chronic
ischemia of involved nerves.
• Entrapment neuropathy is a focal nerve lesion
produced by constriction or mechanical distortion of
• Entrapment neuropathy tends to occur at particular
sites within the body.
• Compression neuropathy is focal nerve lesion that
occurs when sustained pressure is applied to a
localized portion of nerve.
Diabetic Neuropathy
• Diabetes mellitus-related ailments of peripheral
nervous system, autonomic nervous system or
cranial nerves.
• Peripheral form of diabetic neuropathy causes a
dulling of senses of pain, temperature & pressure,
especially in lower legs & feet.
• Autonomic effects of diabetic neuropathy results in
alternating bouts of diarrhea & constipation,
retinopathy, impotence & impaired heart function.
In-Tele-Health © 2002 (from Hyperhealth Pro CD-ROM)
Neuropathy & B Vitamins
• New prescription form of folic acid, vitamin B6 &
vitamin B12 to treat diabetic neuropathy.
• This prescription supplement boosts the production
of nitric oxide which in turn relieves neuropathy.
• The March 2003 issue of Diabetes Care found that
alpha lipoic acid significantly & rapidly reduced
frequency & severity of symptoms of the most
common form of diabetic neuropathy.
Hypothyroid neuropathy
• More than 50% of severely hypothyroid patients
have damage to peripheral nerves & experience
“pins” & “needles”.
• Beghi, E., et al. Hypothyroidism and polyneuropathy.
Journal of Neurology, Neurosurgery and Psychiatry.
52:1420-1423, 1989.
• Travel reported 80% of trigger point patients had
low metabolisms.
• In-Tele-Health © 2002 (from Hyperhealth Pro CD-ROM)
Number & morphology of mitochondria
within cell regulated by mitochondrial
fission & fusion machinery.
• Mitochondria are morphologically dynamic
organelles, continuously dividing & fusing to form
small individual units or interconnected networks
within the cell’s cytoplasm.
• They reach an equilibrium between these two states
in healthy cells by regulating the relative rates of
organelle fusion & fission.
• Multiple parts of mitochondrial morphogenesis
machinery can positively & negatively regulate
Cellular senescence
• Sustained elongation of mitochondria was
associated with decreased mitochondrial membrane
potential, increased reactive oxygen species
production & DNA damage.
• Sustained mitochondrial elongation induces
senescence-associated phenotypic changes that can
be neutralized by mitochondrial fragmentation.
• One key function of mitochondrial fission might be
prevention of sustained extensive mitochondrial
elongation that triggers cellular senescence.
Imbalance in mitochondrial fission &
fusion may underlie both familial and
sporadic neurodegenerative disorders.
• Hereditary mutations in the mitochondrial fusion
GTPases optic atrophy-1 & mitofusin-2 cause
neuropathies in humans.
• There is increased mitochondrial fission in
Parkinson’s disease models.
• Mitochondrial fission induced by two proteins,
PTEN-induced kinase 1 & parkin (which are mutant
in familial forms of Parkinson’s).
Impairing the mitochondrial fission and
fusion balance: a new mechanism of
neurodegeneration. Ann N Y Acad Sci.
• Mutant huntingtin (disease-causing protein in
Huntington’s disease) alters mitochondrial
morphology & dynamics.
• Rotenone (pesticide that induces Parkinson’s
symptoms) & amyloid-beta peptide (linked to
Alzheimer’s) both initiate mitochondrial fission.
• Mitochondrial fission is early event in ischemic
stroke & diabetic neuropathies.
Celiac neuropathy
• Celiac disease is often associated with neurological
symptoms such as MS or neuropathy. Hadjivassiliou,
M., et al. Does cryptic gluten sensitivity play a part in neurological
illness? Lancet. 347:369-371, 1996.
• Of 15 untreated celiac patients, 11 (73%) had at least 1
hypoperfused brain region compared with only 1 (7%) of
15 celiac patients on a gluten-free diet & none of controls.
• Cerebral perfusion was significantly lower in untreated
celiac disease patients compared with healthy controls in 7
of 26 brain regions.
• No differences in cerebral perfusion in celiac disease
patients on gluten-free diet & healthy controls. “Regional
Cerebral Hypoperfusion in Patients With Celiac Disease,”
Addolorato G, Di Giuda D, et al, Am J Med, March 1,
2004;116:312-317. [email protected]) 42425
Adrenal exhaustion
• Cause or effect of chronic pain.
• Pain, flab, bloat, hypotension.
• Low levels steroids (inflammatory pain) &
catecholamines (bruxing & hyperactive nerves).
• Ineffective thyroid.
Peripheral neuropathy of B1 deficiency:
Symmetrical distal weakness: legs (foot dorsiflexors)
& hands (wrist extensors).
Burning feet; lancing pain; calf tenderness.
Sensory loss. Tendon reflexes reduced in legs.
Autonomic neuropathy  orthostatic hypotension.
• Magnesium is also needed for myelin sheath
to stay healthy.
• Lack of magnesium is essential cause of
cramps, constipation & irritability, can leave
one’s nerves feeling ragged.
• Nerves become hypersensitive to pain without
enough magnesium.
• Try an Epson salt bath (1-2 cups), take
magnesium twice daily.
Cell adhesion molecules in
inflammatory or neuropathic pain
Integrins, receptors for extra cellular matrix proteins,
are present on pain-mediating sensory neurons.
• ‘Hyperalgesia’ caused by prostaglandin E2 (PGE2) &
epinephrine (EPI), carrageenan, & ‘neuropathic
hyperalgesia’ caused by taxol.
Integrin signaling in inflammatory & neuropathic pain in
the rat.Eur J Neurosci 2004 Feb;19(3):63442 (ISSN: 0953-816X)Dina OA; Parada CA; Yeh J;
Chen X; McCarter GC; Levine JD
Depts of Medicine & Oral & Maxillofacial Surgery,
Division of Neuroscience and Biomedical Sciences
Program, NIH Pain Center (UCSF), CA 94143-0440.
Cell adhesion molecules in
inflammatory or neuropathic pain
Monoclonal antibodies (mAbs) against the alpha1 or
alpha3 integrin subunits, which participate in laminin
binding, selectively blocked PGE2 hyperalgesia
• Block of EPI hyperalgesia was mimicked by other
peptides containing the RGD integrin-binding
sequence (mAb against alpha5 subunit, which
participates in fibronectin binding, blocked only EPIinduced hyperalgesia).
• mAb against beta1 integrin subunit, common to
receptors for both laminin & fibronectin, inhibited
hyperalgesia caused by PGE2 & EPI & taxol, (as did
reduction of beta1 integrin expression by intrathecal
injection of antisense oligodeoxynucleotides).
C-Peptide Replacement Prevents
Painful Diabetic Neuropathy in Rats
• C-peptide replacement prevents progressive thermal
hyperalgesia & C-fiber loss (no effect hyperglycemia).
• C-peptide replacement seemed to exert its effects by
increasing the availability of nerve growth factor &
improving insulin expression…led to reduction in
various nociceptive peptides (substance P & calcitonin
gene-related peptide).
• Replacement of insulinomimetic C-peptide prevents
abnormalities of neurotrophins, their receptors &
nociceptive neuropeptides (in rat model of diabetes),
resulting in the prevention of C-fiber pathology &
nociceptive sensory nerve dysfunction.
Ann Neurol 2004;56:827-835, Sima et. al.
Variants of COMT Gene Influence Pain
• Three variants of catecholamine-O-methyltransferase
(COMT) gene influence pain sensitivity & risk of
developing chronic pain condition.
• Presence of a low pain sensitivity COMT variant
greatly reduced the risk of developing myogenous
temporomandibular joint disorder (TMD).
• First demo that genetic variation influences both
human pain perception & risk for developing a chronic
pain condition."
• COMT variant influenced risk of TMD. Presence of
just one low pain sensitivity haplotype cut risk 2-3X.
Hum Mol Genet 2005;14:1-9, Dr. Luda Diatchenko.
Dr. Jon-Kar Zubieta
Feb 2003
Less u-opioid
system activation in
met/met individuals
as compared to
Less endorphins at
work than in those
with met/val
More u-opioid
system activation in
val/val folks
compared to
More endorphins at
work than in those
with met/val
COMT or catechol-O-methyltransferase
Metabolizes catecholamines, which are heavily linked to
dopaminergic & adrenergic / noradrenergic
neurotransmission and endorphins.
• COMT functions by metabolizing dopamine & freeing
brain receptors for binding endorphins to u-opioid receptors,
which leads to pain relief.
• More potent the COMT polymorphism functioning in
body, more dopamine gets metabolized & more endorphins
are allowed to bind.
Zubieta, Jon-Kar et al.: COMT val158met Genotype Affects
u-Opioid Neurotransmitter Responses to a Pain
Stressor. Science. Feb, 2003; 299(5610): 1240
Zubieta, Jon-Kar et al.: Regional Mu Opioid Receptor
Regulation of Sensory and Affective Dimensions of Pain.
Science. Aug, 2002; 293(5528): 311
Thiamine - B1 - Beriberi
• Nervous system involvement is termed dry beriberi.
• Usually occurs when poor caloric intake & relative physical
inactivity are present.
• Presents as peripheral neuropathy characterized by
symmetric impairment of sensory, motor & reflex functions
of extremities, especially in distal aspects of lower limbs.
• Associated pain, paresthesias &/or cramps may be present.
• Histologically, the lesions comprise a degeneration of
myelin in muscular sheaths without inflammation.
• Can lead to Wernicke encephalopathy  sequence of
symptoms, including vomiting, horizontal nystagmus,
palsies of eye muscles, fever, ataxia, & progressive mental
impairment leading to Korsakoff syndrome (1/2 recover).
Thiamine - B1 - Beriberi
• Wet beriberi is cardiovascular involvement of deficiency.
• Result from high caloric intake & high level of activity
without the required thiamine for carbohydrate metabolism.
• Chronic form of wet beriberi consists of 3 stages. First
peripheral vasodilation occurs  high cardiac output state.
• Then salt & water retention is mediated through the
kidneys’ renin-angiotensin-aldosterone system. As
vasodilation progresses, the kidneys detect a relative loss of
volume & respond by conserving salt.
• Tachycardia, edema & high arterial & venous pressures can
lead to myocardial injury expressed as chest pain.
Thiamine (Vitamin B-1)
Benfotiamine (Allithiamine, a lipid-soluble
derivative of vitamin B1 with high bioavailability)
• Benfotiamine improves vibratory perception
threshold & nerve conduction velocity.
• Benfotiamine users experience a 50% reduction in
diabetic nerve pain, along with an increased ability
of the nerves to detect an electrical current, respond
to electrical stimulation, and regulate the heartbeat.
• Similarly, Benfotiamine prevents this loss of
control from happening at all in diabetic dogs.
• In human trial, fat-soluble Benfotiamine (3.6X)
proved its effectiveness, while standard watersoluble thiamin failed.
Benfotiamine inhibits intracellular formation of
advanced glycation end-products in vivo.
• Intracellular formation of AGE N-[Epsilon]-(carboxymethyl) lysine (CML) inversely correlates with diabetic
vascular complications independently from glycemia.
• Benfotiamine did not significantly affect HbA1c levels (at
entry: 7.18 ± 0.86%; at conclusion 6.88 ± 0.88%).
• Levels of CML decreased by 40%. Levels of intra cellular
methylglyoxal were reduced by almost 70%.
• Thiamine derivatives are effective inhibitors of both
intracellular glyco-oxidation & AGE formation.
Diabetes. 2000 May; 49(Suppl1): A143(P583).
Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes
Benfotiamine blocks three major pathways of
hyperglycemic damage & prevents experimental
diabetic retinopathy.
The three: hexosamine pathway, AGEs formation &
diacylglycerol-protein kinase C pathway.
• In retinas of diabetic animals, benfotiamine therapy
inhibited these three pathways & NF-kB activation
by activating transketolase & also prevented
experimental diabetic retinopathy.
Nat Med 2003 Mar; 9(3): 294-9.
Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T,
Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier
M, Bergfeld R, Giardino I, Brownlee M.
Effectiveness of different benfotiamine dosage
regimens in treatment of painful diabetic
• High dose (4 x 2 capsules/day = 320mg
benfotiamine/day + other Bs) & medium dose (3
capsules/day = 120mg + other Bs), was compared
to benfotiamine alone (3 tablets/day = 150 mg) in
diabetic patients suffering from painful peripheral
diabetic neuropathy.
• Benfotiamine is most effective in large doses with
other Bs, although all doses beneficial.
Arzneimittelforschung 1999 Mar; 49(3): 220-4.
Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M,
Kempler P.
Pyridoxine – B6 – P-5-P
• Vitamin B6 deficiency could not be demonstrated
in patients with chronic renal failure on high-flux
• Vitamin B6 supplementation was effective in
improving polyneuropathy symptoms of various
etiologies, possibly because of vitamin B6 resistance
in these patients.
Okada, H., et al. Vitamin B6
supplementation can improve peripheral polyneuropathy in
patients with chronic renal failure on high-flux hemodialysis
& human recombinant erythropoietin. Nephrol Dial
Transplant. 15:1410-1413, 2000.
Pyridoxine – B6 – P-5-P
• Ten diabetes mellitus type 1 diabetic neuropathy patients
with symptoms of B6 deficiency were supplemented with
150mg of pyridoxine / day (taken as 3 x 50mg doses).
• Most patients experienced some initial relief of pain and
paresthesia within 10 days. Improvement continued
throughout the experimental period with amelioration or
resolution of symptoms.
• Most noted that their “eyes felt better”. After experiment,
7 of 10 requested to continue supplementing B6.
• Within 3 weeks of quitting B6, other 3 experienced
recurrence of diabetic neuropathy symptoms.
Jones, C. L., et al. Pyridoxine deficiency: A new factor in
diabetic neuropathy. J Am Pod Assoc. 68:646-653, 1978.
Excess Pyridoxine – B6 – P-5-P
• Vitamin B6 in excess of 500mg / day can cause excessive
membrane stabilization & neuropathy.
• Excessive vitamin B6 causes more conversion of
stimulatory glutamic acid to calming & stabilizing GABA
(gamma aminobutyric acid).
Bendich, A., et al. Vitamin B6 safety issues. Annals of the
New York Academy of Sciences, USA. 585:321-330, 1990.
Monograph: vitamin B6. Alternative Medicine Review.
6(1), 2001.
• Most reported cases of vitamin B6-induced neuropathy
have involved the intake of 500 mg or more per day for at
least two years.
• Non-excessive dosages of supplemental vitamin B6 prevent
& alleviate neuropathy.
Methylcobalamin – B12
• Low B12 = pernicious anemia (& nerve damage).
• Ultra-high dose of methylcobalamin may upregulate gene transcription & thereby protein
• Ultra-high dose of B12 speeds rate of nerve
regeneration in rats with acrylamide neuropathy.
• Used amplitudes of compound muscle action
potentials (CMAPs) after tibial nerve stimulation as
index of regenerating motor fibers.
• After intoxication with acrylamide, all rats
experienced equally decreased CMAP amplitudes.
Methylcobalamin – B12
Rats divided into 3; rats treated with ultra-high
(500 micrograms/kg body weight, intraperitoneally)
& low (50 micrograms/kg) doses of
methylcobalamin & saline control.
• Rats treated with ultra-high dose B12 experienced
significantly faster CMAP recovery than salinetreated control rats.
• Low-dose group showed no difference from the
Watanabe, T., et al. Ultra-high dose methylcobalamin
promotes nerve regeneration in experimental acrylamide
neuropathy. J Neurol Sci. 122(2):140-143, 1994
Pernicious Anemia: Presentations
Mimicking Acute Leukemia
• B12 deficiency can produce severe alterations
in bone marrow morphology & function with
associated megaloblastic anemia.
• …serious constellation of symptoms can affect
all organ systems in body resulting in
neurological, mucosal, gastrointestinal &
constitutional changes.
• Pernicious anemia is caused by autoantibodies
produced vs intrinsic factor, a protein produced
in stomach necessary for absorption of vitamin
B12 in small intestine.
Pernicious Anemia: Presentations
Mimicking Acute Leukemia
Typical hematological presentation of pernicious
anemia includes increased mean cell volume (MCV),
hyper segmented neutrophils, hemolysis with
reticulocytosis & sometimes leukopenia &
• Changes rapidly resolve soon after parenteral
administration of vitamin B12.
• In severe disease, the initial look of the bone marrow
can reveal hyper cellular blastic changes resembling
acute leukemia.
South Med J 97(3):295-297, 2004. ©Lippincott Williams & Wilkins
Cristi Aitelli, BS, Lori Wasson, DO & Ray Page, DO, PHD
Vitamin E
• Treated 36 diabetic patients & 9 non-diabetic
patients with either placebo or 1,800 IU vitamin E
for 4 months. Crossed over to other treatment for
further four months.
• At the end of study, retinal blood flow & kidney
function improved in those taking vitamin E.
• Supplemental vitamin E may help to prevent
nephropathy & diabetic neuropathy in diabetes
mellitus type 1 patients.
Bursell, S. E., et al. High-dose vitamin E supplementation
normalizes retinal blood flow and creatinine clearance in
patients with type 1 diabetes. Diabetes Care. 22(8):12451251, 1999.
Lipoic Acid
• R-lipoic acid by itself may be 10X more effective than
other forms of lipoic acid.
• R-lipoic acid is “mitochondrial antioxidant.” Key
component of mitochondrial dehydrogenase, which may
help to slow the natural aging process in animals"
• Memory loss in old rats associated with brain
mitochondrial decay & RNA/DNA oxidation: Partial
reversal by feeding acetyl-L-carnitine &/or R-alpha-lipoic
acid - Proc Natl Acad Sci USA 2002 Feb 19;99(4):2356-61.
• “Electron microscopic studies in hippocampus showed that
ALCAR &/or LA reversed age-associated mitochondrial
structural decay.”
Lipoic acid
• ATPase activity has been suggested as a contributing factor
in development of diabetic neuropathy.
• Lipoic acid reduces lipid peroxidation & glycosylation &
can increase the (Na(+) + K(+))- & Ca(++)-ATPase
activities in high glucose-exposed red blood cells (RBC).
• Significant stimulation of glucose consumption by RBC in
the presence of lipoic acid (mixture of S and R
sterioisomers) both in normal & high glucose-treated RBC.
• Lipoic acid significantly lowered the level of glycated
hemoglobin (GHb) & lipid peroxidation in RBC exposed to
high glucose concentrations.
Lipoic acid
• High glucose treatment significantly lowered activities of
(Na(+) + K(+))- & Ca(++)-ATPases of RBC membranes.
• No differences in lipid peroxidation, GHb & (Na(+) +
K(+))- & Ca(++)-ATPase activity levels in normal glucosetreated RBC with & without lipoic acid.
• Lipoic acid can lower lipid peroxidation & protein
glycosylation & increase (Na(+) + K(+))- and Ca(++)ATPase activities in high-glucose exposed RBC.
• May be how lipoic acid delays or inhibits development of
neuropathy in diabetes.
Jain, S. K., et al. Lipoic acid decreases lipid peroxidation
& protein glycosylation & increases (Na(+) + K(+))- &
Ca(++)-ATPase activities in high glucose-treated human
erythrocytes. Free Radic Biol Med. 29:1122-1128, 2000.
• Topically-applied capsaicin cream has been found
to reduce pain associated with diabetic neuropathy
by about 50-80%.
• This alkaloid may also be useful for treating the
pain associated with other types of neuropathy.
• Capsaicin Study Group. Treatment of painful
diabetic neuropathy with topical capsaicin.
Archives of Internal Medicine. 151:2225-2229,
Acetyl-L-carnitine (ALC)
• Moyle, G. J., et al. Peripheral neuropathy with nucleoside
antiretrovirals: risk factors, incidence & management.
Drug Saf. 19(6):481-494, 1998.
• Quatraro, A., et al. Acetyl-L-carnitine for symptomatic
diabetic neuropathy. Diabetologia. 38(1):123, 1995.
• Scarpini, E., et al. Effect of acetyl-L-carnitine in the
treatment of painful peripheral neuropathies in HIV+
patients. J Periph Nerv Syst. 2:250-252, 1997.
• ALC tried for pain in 16 HIV+ patients affected by painful
distal symmetrical neuropathy. Patients treated with 0.51gm /day ALC i.m. or i.v. for 3 weeks. Pain intensity
measured before & after by Huskisson's analogic scale. In
open study: 10 patients (62.5%) improved, 5 (31.25%) were
same, one worsened.
• Biotin may help to reverse neuropathy & large doses of
supplemental biotin help severe (diabetic) neuropathy.
• Biotin in high doses was given for 1-2 years to three
diabetic patients suffering from severe diabetic peripheral
• Within 4-8 weeks, marked improvement in clinical and
laboratory findings.
• In diabetes, a deficiency, inactivity or unavailability of
biotin results in disordered activity of pyruvate carboxylase
 accumulation of pyruvate and/or depletion of aspartate,
both important in nerve metabolism.
Koutsikos, D., et al. Biotin for diabetic peripheral
neuropathy. Biomed Pharmacother. 44(10):511-514, 1990.
• Choline & inositol - two parts of lecithin
especially important for nerve function.
• Acetylcholine carries nerve messages across
nerve synapses.
• Lecithin along with B-vitamins help keep
myelin healthy.
• Degeneration of myelin sheath will cause
hypersensitive nerves. Pain, pins & needles
sensation can result.
• Take 3 capsules three times daily for two
weeks, then 3 capsules once daily.
More oil
Natural, unheated vegetable oils contain
lecithin & essential fatty acids needed to protect
& insulate nerves.
• Try 2-3 tablespoons of oil per day, more for
therapeutic use.
• Sesame oil massage is main therapy in India
for nervous (vata) conditions.
• Oil massaged over spine absorbs directly into
central nervous system (cod liver oil, Chinese
snake oil, emu oil).
• Clements, R. S., et al. Dietary myo-inositol intake and
peripheral nerve function in diabetic neuropathy.
Metabolism. 28:477, 1979.
• Twenty diabetic neuropathy patients experienced
significant improvement in sensory nerve function after
total daily inositol intake increased from 772 to 1648 mg.
• Gregersen, G., et al. Oral supplementation of myoinositol:
Effects on peripheral nerve function in human diabetics and
on the concentration in plasma, erythrocytes, urine and
muscle tissue in human diabetics & normals. Acta
Neuroliga Scand. 67:164-171, 1983.
• Salway, I. G., et al. Effect of myo-inositol on peripheral
nerve function in diabetes. The Lancet. II:1282-1284,
1978. Diabetes mellitus patients on 1gm inositol /day had
significant increases in amplitude of nerve action potentials.
• Rat study demonstrates ability of supplemental
glutathione to exert antioxidant effects that prevent
(diabetic) neuropathy in diabetes mellitus subjects.
• Ueno, Y., et al. Dietary glutathione protects rats
from diabetic nephropathy and neuropathy. Journal
of Nutrition. 132(5):897-900, 2002.
N-acetylcysteine (NAC)
• N-acetylcysteine (NAC) is precursor to glutathione, a free
radical scavenger & inhibitor of TNF-a.
• Oral NAC reduced decline of motor nerve conduction
velocity in diabetic rats. Structural analysis of sural nerve
showed significant reduction of fibers undergoing myelin
wrinkling & inhibition of myelinated fiber atrophy.
• NAC treatment had no effect on blood glucose levels or on
nerve glucose, sorbitol & cAMP contents.
• NAC corrected decreased glutathione levels in RBCs,
increased lipid peroxide levels in plasma & increased
lipopolysaccharide-induced TNF-a activity in sera of
diabetic rats. Sagara, M., et al. Inhibition of development
of peripheral neuropathy in streptozotocin-induced diabetic
rats with NAC. Diabetologia. 39(3):263-269, 1996.
• In diabetes, increased oxidative stress, disruption of signal
transduction pathways & endothelial dysfunction implicated
in pathogenesis of experimental diabetic neuropathy (EDN).
• The development of nerve conduction slowing in diabetes
is accompanied by depletion of beta-amino acid taurine.
• Taurine functions as antioxidant, calcium modulator &
vasodilator, taurine depletion may provide a pathogenetic
link between nerve metabolic, vascular & functional deficits
complicating diabetes.
• Taurine depletion in the vascular endothelium and
Schwann cells of the sciatic nerve may contribute to the
neurovascular and metabolic deficits in EDN.
Pop-Busui, R., et al. Depletion of taurine in experimental diabetic
neuropathy: implications for nerve metabolic, vascular &
functional deficits. Exp Neurol. 168(2):259-72, 2001.
Ginkgo biloba (Bilobalides)
• Bilobalides (diterpene part of Ginkgo biloba)
alleviate neuropathy by accelerating repair of
damaged motor nerves.
• Bilobalides exert trophic & protective effects on
neurons & on Schwann's cells (many neuropathies).
• Rearrangement of regenerated innervations occurs
more rapidly in bilobalide-treated animals.
Bruno, C., et al. Regeneration of motor nerves in bilobalidetreated rats. Planta Medica. 59(4):302-307, 1993.
• Ginkgo biloba extract alleviates mechanical & cold
allodynia in a rat model of neuropathic pain.
Kim YS, Park HJ, Kim TK, Moon DE, Lee HJ. Anesth Analg.
2009 Jun;108(6):1958-63.
• Some cases of neuropathy are caused by
docosahexaenoic acid (DHA) deficiency (and in
these cases supplemental DHA causes regression of
Hoffman, D.R., et. al. Effects of supplementation
with omega-3 long-chain polyunsaturated fatty acids
on retinal and cortical development in premature
infants. American Journal of Clinical Nutrition.
57:807S-812S, 1993.
Gamma-Linolenic Acid (EPO)
• Gamma-Linolenic Acid (480 mg / day) alleviates
symptoms of (diabetic) neuropathy.
• Horrobin, D. F. Use of gamma-linolenic acid in diabetic
neuropathy. Agents Actions Suppl. 37:120-144, 1992.
• Horrobin, D. F. The effects of gamma-linolenic acid on
breast pain and diabetic neuropathy: possible noneicosanoid mechanisms. Prostaglandins Leukot Essent
Fatty Acids. 48(1):101-104, 1993.
• Jamal, G. A., et al. The effect of gamma-linolenic acid on
human diabetic peripheral neuropathy: a double-blind
placebo-controlled trial. Diabetic Medicine. 7(4):319-323,
Essential oils for nerve damage
• Nerve Damage - Essential oil combination - 5 ml. Also available in 10 ml. roller ball bottle with carrier oil
for $5 more. Ingredients: Helichrysum, Cypress,
Geranium, Juniper, Peppermint.
[email protected]
• Essential oils Lavender, Geranium & Roman
Chamomile have all been used topically to help
relieve nerve pain. Mix the following:
3 drops Roman Chamomile Oil
3 drops Geranium Oil
2 drops Lavender Oil
• Antioxidant flavonoids
(listed in order of decreasing potency)
Quercetin (a flavonol in vegetables, fruit
skins, onions)
Xanthohumol (a prenylated chalcone in hops
& beer) – US patent 5,679,716 inhibits bones
resorption & osteoporosis.
Isoxanthohumol (a prenylated flavanone in
hops and beer)
Genistein (an isoflavone in soy)
• Pro-oxidant flavonoids
Chalconaringenin (a non-prenylated chalcone
in citrus fruits)
Naringenin (a non-prenylated flavanone in
citrus fruits)
NGF – Nerve Growth Factor
• For Alzheimer’s, diabetic & peripheral neuropathy.
• Ashitaba (Angelica Keiskei Koidzumi) in Japan
‘longevity herb,’ healthy function bowels, stimulates
immunity, anti allergic, anti bacterial, anti fungal &
anti viral, stimulates NGF, plant produces B12.
• Yellow polyphenols (chalcones) or prenylflavoniod,
one of xanthones (St. Johns Wort, traces in hops).
• Phenolic prenylflavonoids (100mM) cytotoxic &
anti proliferative in culture of 500,00 tumor cells.
NGF – Nerve Growth Factor
• Extracts of Ashitaba, hops, edible Chrysanthemum
& Gajutsu (white turmeric) have high activity in
enhancement of NGF production.
• Zedoary root is a component of the gastrointestinal
remedy, Swedish Bitters. Zedoary root possesses
the odor of camphor & taste of slightly bitter ginger.
When chewed, the roots turn saliva yellow, similar
to turmeric, contains several specific sesquiterpenes.
• Four coumarins (from hydroxycinnamic acid),
xanthohumol & two sesqueterpenoids are active.
• Herbal Sleep - balanced with many elements
to support proper nervous system function.
• Formula does promote restful sleep when
taken at bedtime, however it will not make
you sleepy taken during the day.
• Valerian, passion flower & hops have a
successful history of use with nerve pain.
• Take 2 capsules three times daily.