Nicotinic acid-mediated activation of both membrane and nuclear receptors towards therapeutic glucocorticoid mimetics for treating multiple sclerosis

Abstract

Acute attacks of multiple sclerosis (MS) are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA) is now known to involve induction of indoleamine 2,3-dioxygenase (IDO) and interleukin-10 (IL-10), where IL-10 requires subsequent heme oxygenase-1 (HMOX-1) induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2) can prevent demyelination in experimental autoimmune encephalomyelitis (EAE) animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs) demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ¹²,¹⁴-PGJ₂. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD), without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPARγ-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic acid administration far outweigh any known adverse risks in consideration for the treatment of multiple sclerosis.

Figure 1

Unique mechanisms of action of nicotinic acid on immune function are shown. Nicotinic acid, but not nicotinamide, binds to the high-affinity nicotinic acid G-protein-coupled receptor HM74a/GPR109a that via calcium influx activates phospholipase A₂. This ultimately leads to massive production and release of prostaglandins 15d-PGD₂ and PGD₂ specifically from professional antigen presenting cells (macrophages, dendritic cells, and likely microglia [55]). Thus, nicotinamide, which also provides NAD, functions in part as a negative control for HM74a-dependent effects in experimentation. PGE₂ was previously identified as promoting differentiation of plasmacytoid dendritic cells to a T cell toleragenic phenotype via induction of IDO expression and activity [49, 50]. Consequently nicotinic acid may provide a similar T cell toleragenic effect. 15d-PGD₂ spontaneously degrades to produce 15Δ-PGJ₂, the most potent endogenous activator of PPARγ. This may be central to the explanation of how nicotinic acid but not nicotinamide corrects dyslipidemia, raising HDL levels higher than any known pharmaceutical including all PPARγ agonists while also lowering LDL, VLDL, and triglycerides [30, 56].

Figure 2

Glucocorticoids exert well-established relief from MS attacks, which last up to 30 days. Glucocorticoids exert immunoregulatory effects via transcriptional regulatory signaling in large part through GITR to IDO ([4, 5]) and IL-10 to HMOX-1 [8, 70, 71]). GITR activation is also known to lead to increased IL-10 production [72]. The representative glucocorticoid target genes of interest examined in this study with desirable effect are shown in bold. Multiple sclerosis patients are specifically lacking in CD46-stimulated IL-10 secretion and suffer from an over-proliferation of myelin autoreactive T cells.