Relief of Symptoms Associated with Peripheral Neuropathy
The diseases causing polyneuropathy (PN) are myriad and complex. PN can result from metabolic and systemic insults including diabetes, liver and renal failure, vitamin B12 deficiency, collagen vascular and immune disorders like Guillain-Barre, hypothyroidism, malabsorption from celiac sprue, the remote effects of carcinoma, multiple myeloma, lymphoma, Lyme disease, HIV, and monoclonal gammopathy. Toxins can also cause PN; the most prominent are acrylamide, arsenic, diphtheria, lead, organophosphates and thallium. Many antineoplastic agents result in damage to the peripheral nerves including taxanes, vincristine, cisplatin and other drugs like amiodarone, disulfiram, metronidazole, phenytoin and megadoses of pyridoxine. Lastly, PN is common in inflammatory vascular disorders appearing in half the cases of polyarteritis nodosa and inherited peripheral nerve diseases such as Charcot-Marie-Tooth.
The classification of peripheral neuropathy has become increasingly complex as the capacity to discriminate new subgroups and identify new associations with toxins and systemic disorders improves. Our grasp of the pathophysiologic basis of the clinical PN has increased rapidly, but these advances are primarily descriptive and little progress has been made in understanding the fundamental pathogenic events that underlie the polyneuropathies.
While the treatment of peripheral neuropathy has improved with the use of antiepileptic drugs and antidepressants, it still remains frustrating. Most of the commonly used medications have anticholinergic side effects or cause sedation. At best, they are only partially effective because they do not treat the underlying cause of the neuropathy but only the symptoms.
Recognizing the limitations of pharmaceutical treatment, we previously reported on the therapeutic application of a combination of five micronutrients for management of diabetic neuropathy1:
- alpha-lipoic acid
- vitamin C
Throughout the course of our investigations it became apparent that patients with peripheral neuropathy of unknown origin seemed to benefit from the use of these agents as well. This prompted an extension of our original efforts. We conducted an open label study of patients with peripheral neuropathy of multiple etiologies. It is conceivable that the supplements we used benefit peripheral nerves—regardless of the cause of the neuropathy—because they increase the intracellular ratio of glutathione from its reduced to oxidized form.
About Glutathione (GSH)
The activities of the above five micronutrients intersect at glutathione. Gluta-thione (GSH) is a tripeptide intracellular thiol molecule derived from glycine, L-glutamine and L-cysteine. GSH is an extremely important cell protectant. It is a potent antioxidant and enzyme cofactor whose depletion—by the absence of dietary precursors—results in cell death. It directly quenches reactive hydroxyl free radicals, oxygen free radicals, and biomolecules.2 GSH balance is crucial to intracellular homeostasis, stabilizing the cellular biomolecular spectrum, and facilitating cellular performance and survival. Individuals with inherited deficiencies of the GSH develop hemolytic anemia, spinocerebellar degeneration, and peripheral neuropathy, along with other manifestations. Glutathione-S-transferase (GST), through its inter-actions with GSH, reduces the manifestations of neuropathy in individuals with Charcot-Marie-Tooth disease.3 GST genotypes impact the expression of peripheral neuropathy secondary to taxanes toxicity.4
As a tripeptide, GSH does not survive digestion. Therefore merely consuming GSH will not raise blood levels. The micronutrients used in our study population all impact either the synthesis of GSH or reconstitute reduced GSH from its oxidized state.
N-acetyl-cysteine (NAC) is a reducing agent, a potent antioxidant and an important source of cysteine, the rate- limiting major precursor to the antioxidant glutathione. It is through this mechanism that it protects the liver from overdoses of acetaminophen. It protects the kidneys from contrast-induced nephropathy5 and prevents arsenic- induced neurotoxicity by replenishing GSH.6
Alpha-lipoic-acid (ALA) is a potent antioxidant involved in metabolic reactions in the mitochondria and a cofactor in energy production. In animal models of neuropathy, it reverses the decrease in nerve blood flow.7 ALA is vital for reconstituting reduced GSH after it has neutralized free radicals.
L-carntine (LCA) is a vitamin-like compound that serves as a carrier to transport long-chain fatty acids into the mitochondria for beta-oxidation. Its depletion in rats significantly reduces intracellular GSH and increases toxicity form exposure to carboplatin.8
Vitamin C is the most important water-soluble antioxidant. Adequate vitamin C increases GSH levels in red blood cells. Ascorbate conserves intracellular gluta-thione and probably is a redox GSH cofactor.9 Conversely, GSH and GSH enzymes reconstitute vitamin C after it has neutralized a free radical.
Selenium is a potent antioxidant that works synergistically with vitamin E. It is an important component of the enzyme glutathione peroxidase that works with glutathione to reduce free radicals.
Forty-three patients with documented peripheral neuropathy were recruited for the open label study. All study participants gave their informed signed consent and followed an interventional protocol. There were 28 females and 15 males whose age ranged from 43 to 91 and averaged 69. The duration of their neuropathy ranged from 2 to 15 years. Patients had all failed therapy consisting of antiseizure and antidepressant medi-cations. There were 26 diabetics in the study and the rest had no known etiology and were labeled as neuropathy of unknown origin. Most patients had comorbid conditions including hypertension, obesity and hyperlipidemia.
The participants were followed for nine months and were assessed using modified Wong-Baker FACES pain rating scale to include numbness, overall pain and burning pain to test for correlation in response. Assessments were made at three, five, seven and nine months. Results are reported as percent improvement in all three measures at each marking period in the table below.