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 non-painful stimulus (allodynia) such as cold or light pressure.

• Diagnosis of neuropathic pain is suggested when a patient reports pain that is out of proportion to the injury.

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 membranes

• 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 solid-ordered & 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 cord.

• 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. http://www.coventrypainclinic.org.uk/nervepain-peripheralneuropathy.htm

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 failure. http://www.coventrypainclinic.org.uk/nervepain-peripheralneuropathy.htm

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.

http://www.coventrypainclinic.org.uk/nervepain

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 system.

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 nerve.

• 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 apoptosis.

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. 2008;1147:283-92.

• 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. g.addolorato@rm.unicatt.it) 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

• 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):634-42  (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 EPI-induced 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 Sensitivity

• 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.

More u-opioid system activation in val/val folks compared to heterozygotes. More endorphins at work than in those with met/val genotype.

Less u-opioid system activation in met/met individuals as compared to heterozygotes. Less endorphins at work than in those with met/val genotype.

Dr. Jon-Kar Zubieta Feb 2003

GENE FOR PAIN TOLERANCE

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.

http://www.emedicine.com/med/topic221.

                                                                                                   

                   

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 water-soluble thiamin failed.

Benfotiamine inhibits intracellular formation of advanced glycation

end-products in vivo.• Intracellular formation of AGE N-[Epsilon]-(carboxy-

methyl) 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 HP.

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 neuropathy. • 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 dialysis.

• 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 up-

regulate gene transcription & thereby protein synthesis.

• 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 saline-treated control rats.

• Low-dose group showed no difference from the control.

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 & thrombocytopenia.

• 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):1245-1251, 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 glucose-treated 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.

Capsaicin

• 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, 1991.

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 0.5-1gm /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.

• In-Tele-Health © 2002 (from Hyperhealth Pro CD-ROM)

Biotin• 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 neuropathy.• 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.

Lecithin

•   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). 

Inositol• 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.

Glutathione

• 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.

Taurine• 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 bilobalide-treated 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.

DHA

• Some cases of neuropathy are caused by docosahexaenoic acid (DHA) deficiency (and in these cases supplemental DHA causes regression of neuropathy).

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 non-eicosanoid 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, 1990.

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.

Lynne5@networld.com• Essential oils Lavender, Geranium & Roman

Chamomile have all been used topically to help relieve nerve pain. Mix the following:

3 drops Roman Chamomile Oil3 drops Geranium Oil2 drops Lavender Oil

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• 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.

Sleep

• 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.