Dr. Ron’s Research Review – December 19, 2012

This week’s research review focuses on niacinamide for autoimmune disease.

Penberthy proposes that niacinamide may be beneficial for autoimmune disease. (Penberthy 2007)

During the pellagra epidemics of the 1920's, greater than seventy percent of the cases were women, which is equivalent to the frequency of autoimmune diseases observed in women today.

The symptoms of pellagra resemble the most common autoimmune diseases.

NAD precursors prevent or ameliorate several autoimmune diseases: type 1 diabetes, rheumatoid arthritis

The main action is decreasing Interferon-gamma (IFN-gamma), a pro-inflammatory factor and signature cytokine of Th1-dominated autoimmune processes.

Nicotinamide decreases IFN-gamma induced expression of the lymphocyte ligand intercellular adhesion molecule-1 and HLA-DR expression in cultured thyroid cells from patients with Grave's disease  with decreased expression of ICAM-1 in endothelial cells

Nicotinamide decreases MHC class II gene expression stimulated by TNF-alpha/IFN-gamma in islets .

Nicotinamide is also known to decrease IFN-gamma expression in high risk individuals for type 1 diabetes

Nicotinamide may also be beneficial for Hashimoto’s Disease

Thyroid disorders are the most common autoimmune diseases making up greater than 50% of all autoimmune diseases

Hashimoto’s occurs in women with a frequency that is greater than 50x that of man.

Supplementation using the energy-modulating vitamins including the NAD pre-cursors (niacin or niacinamide), riboflavin, and coenzyme Q may be beneficial.

Dr. Ron
Articles

Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease

            (Penberthy 2007) Download

Cells at the maternal-fetal interface express indoleamine 2,3 dioxygenase (IDO) to consume all local tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells. Thus it makes sense to consider IDO induction towards tolerance for autoimmune diseases in general. Approaches to cell specific therapeutic IDO induction with NAD precursor supplementation to prevent the collateral non-T cell pathogenesis due to chronic TNFalpha-IDO activated tryptophan depletion in autoimmune diseases are reviewed. Tryptophan is an essential amino acid most immediately because it is the only precursor for the endogenous biosynthesis of nicotinamide adenine dinucleotide (NAD). Both autoimmune disease and the NAD deficiency disease pellagra occur in women at greater than twice the frequency of occurrence in men. The importance of IDO dysregulation manifest as autoimmune pellagric dementia is genetically illustrated for Nasu-Hakola Disease (or PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of tryptophan causing neurodegeneration. Administration of NAD precursors rescued entire mental hospitals of dementia patients literally overnight in the 1930's and NAD precursors should help Nasu-Hakola patients as well. NAD depletion mediated by peroxynitrate PARP1 activation is one of the few established mechanisms of necrosis. Chronic elevation of TNFalpha leading to necrotic events by NAD depletion in autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete NAD. Pharmacological doses of NAD precursors repeatedly provide dramatic therapeutic benefit for rheumatoid arthritis, type 1 diabetes, multiple sclerosis, colitis, other autoimmune diseases, and schizophrenia in either the clinic or animal models. Collectively these observations support the idea that autoimmune disease may in part be considered as localized pellagra manifesting symptoms particular to the inflamed target tissues. Thus pharmacological doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) should be considered as potentially essential to the therapeutic success of any IDO-inducing regimen for treating autoimmune diseases. Distinct among the NAD precursors, nicotinic acid specifically activates the g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic prostaglandins PGE(2) and PGD(2). Next, PGD(2) is converted to the anti-inflammatory prostaglandin, 15d-PGJ(2). These prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma respectively. Nicotinamide prevents type 1 diabetes and ameliorates multiple sclerosis in animal models, while nothing is known about the therapeutic potential of nicotinamide riboside. Alternatively the direct targeting of the non-redox NAD-dependent proteins using resveratrol to activate SIRT1 or PJ34 in order to inhibit PARP1 and prevent autoimmune pathogenesis are also given consideration.

References

Penberthy, W. T. (2007). "Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease." Curr Drug Metab 8(3): 245-66.