# Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

Authors: W. Todd Penberthy
Journal: PPAR Research
 (2009)

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## 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.


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## Body

## 1. Multiple Sclerosis Treatment and Functional Transcriptomics

Multiple
sclerosis (MS) is the most common demyelinating disease of the central nervous
system. It is a progressive disease with no known cure. MS results in scarring
of CNS tissues termed sclerosis due to autoimmune-mediated attack of
myelin-forming oligodendrocytes and/or myelin sheaths by autoreactive T cells.
The disease affects more than 2.5 million people worldwide; 30% of MS patients
eventually develop paralysis and become wheelchair bound for the rest of their
lives [1, 2].Glucocorticoids
are the primary pharmacotherapeutic approach used to provide relief from acute
attacks of MS and are the most commonly prescribed drugs in the world for
treating autoimmune disorders in general (for a review [3]). While we are far
away from a comprehensive picture of how glucocorticoids control
neuroinflammation, recent studies have revealed central roles for indoleamine
2,3-dioxygenase (IDO; [4, 5]) and interleukin-10 (IL-10; [6]). The importance
of IDO in estrogen-mediated suppression of EAE pathogenesis was demonstrated
previously [7]. IL-10 signaling is required for patients to respond to
glucocorticoid treatment [6], while IL-10-mediated induction of heme-oxygenase-1 (HMOX-1) is required for IL-10 to exert its anti-inflammatory
activity [8]. Increases in HMOX-1 have recently been shown to reverse paralysis
and prevent relapse in animal models of MS [9]. Thus, by boosting IDO and IL-10
or HMOX-1, greater therapeutic benefit against autoimmune demyelinating disease
may be achieved. Alternative clinical MS therapeutics have also been shown to
work via induction of IL-10 or IDO. This includes the amino acid copolymer
glatiramer acetate [10] or interferons [11–18], respectively. It seems difficult,
however, to replicate the endogenous anatomically localized cellular production
of interferon via pharmacological approaches. Interferon treatment is
associated with complications, some of which can be quite serious [19].
Ultimately, no pharmacological agent has been proven to be clinically effective
in patients during the progressive stages of MS [20].The
most common animal model of MS involves injection of myelin sheath-associated
epitopes into mammals, which results in a dose dependent experimental
autoimmune encephalomyelitis (EAE) (for a review see [21]). Lymphocyte-mediated
demyelination proceeds around blood vessels of the CNS, leading to
autoimmune-mediated paralysis typically 10 days to three weeks postinjection.
EAE has been successfully used in the development of clinical therapeutics
[22]). Studies examining the pharmacology of the endogenous PPARγ
activators have consistently revealed that the endogenous molecule 15-deoxy-Δ12,14-prostaglandin
J(2) (15d-PGJ2) can ameliorate the MS clinical symptoms in EAE
[23–27]. 15d-PGJ2 is the most known potent endogenous activator of
PPARs identified to date [25]. By focusing on endogenous molecules, we can
better understand the inherent mechanisms by which the body maintains good
health. This includes the endogenous PPAR activators 15d-PGJ2, two
endocannabinoids (anandamide and 2-arachidonoylglycerol; 2-AG), and nicotinic
acid, which stimulates the localized production of 15d-PGJ2 restricted to professional antigen presenting cells.PPAR
activators are well known for their ability to correct dyslipidemia [27].
Nicotinic acid indirectly activates PPAR
[28, 29] and corrects dyslipidemia, raising high-density lipoprotein (HDL)
concentrations to a greater degree than any known pharmaceutical [30]. The
other most common nicotinamide adenine dinucleotide (NAD) precursor,
nicotinamide, provides dramatic protection against demyelination and improves
behavioral deficits in EAE [31]. Unlike nicotinic acid, nicotinamide provides
little benefit against dyslipidemia since it does not bind to the high-affinity
nicotinic acid G-protein-coupled receptor, and therefore nicotinamide does not
activate PPARγ.
By contrast, nicotinic acid has not been systematically examined in animal
models of MS or in the clinic.Either
nicotinamide or nicotinic acid can serve essential functions as a dietary
precursor to NAD in the cell. Nicotinic acid is the most preferred substrate in
evolution based on metabolite [32, 33] and comparative genomic studies examined
to date (presentation by Mathias Ziegler at PARP 2008 meeting, Tucson, Ariz,
USA). In glia, nicotinic acid provides greater levels of NAD biosynthesis per
mole than nicotinamide or tryptophan by 200- and 500-fold, respectively [34].
Furthermore, neurons appear distinctively inefficient in their ability to
convert dietary NAD precursors to NAD [35].Accordingly,
supraphysiological elevations of NAD are known to exert tremendous neurotrophic
activity. When a neuron is cut with a razor blade, degeneration of axons occurs
typically within one day. Genetic triplication of the nuclear generating enzyme
nicotinamide adenine mononucleotidyl transferase-1 (NMNAT1) however delays
neurodegeneration for 2-3 weeks after excision [36, 37]! This dramatic effect
is mediated via NAD-dependent activation of SIRT-1. Functioning as a
NAD-dependent histone deacetylase, SIRT-1 exerts global changes in the
transcriptome that mimic caloric restriction (for a review of this process see
[38]). Direct SIRT-1-mediated deacetylation of the liver X receptor (LXR)
leads to activation of LXR with effects on lipid homeostasis and ABCA1 gene
regulation [39]. Similarly, SIRT-1 directly deacetylates and activates
peroxisome proliferator-activated receptor-gamma, coactivator 1 (PGC1α).
Redistribution of the other nuclear NMNAT1-encoding protein to the cytosol
extends the delay in Wallerian degeneration up to seven weeks [40]! While
SIRT-2 is present in the cytosol, it has not been determined which pathway is
most integral to the cytosolic pathway. Common to both nuclear and  cytosolic
forms, however, it is clear that NAD is the central to this neurotrophic
activity.Ultimately
NAD serves crucial functions as a cofactor in over 200 redox reactions or as a
substrate in three categorical enzyme classes: deacetylases (Sirtuins, e.g.,
SIRT-1), ADP-ribosyl transferases (e.g., PARP-1), and ADP cyclases such as
CD38. The two most common MOAs for glia-killing neurons in brain pathologies
involve the free-radical generating enzymes NADPH oxidase and iNOS [41]. Both
of which can lead to increased PARP-1 activity. Thus pharmacological
administration of the NAD precursor nicotinamide provides dramatic protection
from the clinical signs of EAE in a dose-dependent manner, preventing
behavioral defects, minimizing demyelination, and preventing death [31].
Detailed analysis of the pathways controlling NAD levels and function in the
context of multiple sclerosis is reviewed elsewhere [42]. However, nicotinamide
treatment does not result in the production of 15d-PGJ2 with
concomitant activation of PPAR. Collectively these observations suggest
even greater benefit against demyelinating disease from nicotinic acid
treatment than with nicotinamide. In this review we explore nicotinic acid's
effects compared to nicotinamide with focus on describing genes known to be of
greatest interest to MS pathogenesis.Interestingly,
high doses of sustained nicotinamide administration (1–4 grams per day) were
shown to provide remarkable relief in patients with rheumatoid arthritis in the
1940's [43]. Nicotinamide was then historically supplanted in the
treatment of arthritis with the monumental discovery and development of
powerful synthetic corticosteroids occurring thereafter.Today,
glucocorticoids remain a common treatment modality in the management of
rheumatoid arthritis. However, the ability of nicotinamide to ameliorate the
autoimmune aspects of rheumatoid arthritis supports consideration of high-dose
nicotinamide treatment in MS.Nicotinic
acid working through the high-affinity nicotinic acid G-protein-coupled
receptor is particularly well suited for treatment of multiple sclerosis. The
receptor is specifically expressed in one of the primary sources of MS
pathogenesis (microglia). Furthermore this receptor is predicted to be involved
in controlling the proliferation of autoreactive T cells viaPGE2-mediated
induction of IDO within the microglia (Figure 1). Nicotinic acid easily
penetrates the blood brain barrier [44]. Nicotinic acid, but not nicotinamide,
specifically binds to the high-affinity nicotinic acid G-protein-coupled
receptor HM74a/GPR109a whose expression is largely restricted to professional
antigen presenting cells including microglia. Since both nicotinamide and
nicotinic acid contribute to greater NAD synthesis but only nicotinic acid
signals through HM74a activation, we may consider nicotinamide in part a
negative control for HM74a-mediated phenomena. Binding of nicotinic acid to
HM74a leads to a massive release of prostaglandin PGD2 and PGE2 [45–47]. These prostaglandins then mediate the vasodilation that generates a
flushing side effect [48]. PGD2 produced from nicotinic acid
signaling then degrades to form 15d-PGJ2, which activates PPARγ leading to increased expression of ABCA1 and CD36 in macrophages [28, 29]. The
other prostaglandin PGE2 induces expression of IDO in dendritic
cells, resulting in a toleragenic effects on local T cells [49, 50]. IDO serves
specific functions in microglia [51–53], and IDO helps prevent EAE pathogenesis
[52, 54]. Thus nicotinic acid is particularly wellsuited for consideration in
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 phospholipaseA2. 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].Cannabis-derived
natural products including delta-9-tetrahydrocannabinol (Δ9-THC)
also have a long history of significantly delaying the onset of EAE [57–59] and
immune suppression in general [60]. The oromucosal spray known as Sativex
contains these natural products (Δ9-THC
and cannabidiol) and is currently used for treating the neuropathic pain and
spasticity associated with MS [61, 62]. After the isolation of endogenous
molecules that bind to the same G-protein coupled receptors as Δ9-THC,
these “endocannabinoids” were also shown to provide relief from a viral-based
animal model of MS, Theiler's Murine Encephalomyelitis Viral-immune
demyelinating disease (TMEV-IDD; [63, 64]). However, only within the past
several years has it become established that cannabinoids and endocannabinoids
are in fact PPAR activators themselves [65, 66]. Significantly, in some cases
PPARs are required to mediate their actions. This includes the
anandamide-mediated PPARγ-dependent
therapeutically desirable repression of interleukin-2 (IL-2 [67, 68]), a
recently identified MS disease susceptibility gene [69]. Given their ability to
function as endogenous PPAR agonists combined with their potential value in
autoimmune demyelinating disease, anandamide and 2-arachidonoyl glycerol should
be examined with respect to their effects on gene expression related to MS
pathogenesis.


## 2. The Gold Standard of Transcriptomic Modeling for Treating Multiple Sclerosis, Glucocorticoid Target Genes: IDO
& IL-10

Glucocorticoids comprise the most widely used drug class for providing rapid relief in acute attacks of MS. Thus, the immediate effect of glucocorticoids on target genes is the current gold standard for pharmacotherapeutic gene induction in MS treatment. Unfortunately, there is no reduction in relapse rate following glucocorticoid therapy, and relief is only temporary, lasting up to 30 days following a clinical attack. Given these limitations, there is an interest in sustained regulation of therapeutically beneficial glucocorticoid target genes by alternative approaches. Two recent studies suggest that both IL-10 and IDO likely mediate and determine the extent of glucocorticoid effects (Figure2;
IL-10 [6], IDO [4, 5]).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.Recent
studies in glucocorticoid-resistant asthma patients also implicate vitamin D as
a factor in glucocorticoid effectiveness [6]. In these patients, the addition
of dexamethasone does not cause an increase in IL-10 secretion from CD4+ cells.
However, the addition of vitamin D3 with dexamethasone therapy in this
population restores glucocorticoid-mediated induction of IL-10 [6]. The authors
suggest that vitamin D can help restore glucocorticoid responsiveness. The
combination of glucocorticoid with vitamin D is known to stimulate
differentiation of CD4+ T cells to regulatory T cells (Treg) and causes
substantial release of IL-10 (Figure 2, [73]). The role of vitamin D in
preventing EAE models of MS is well established [74, 75], and there is a clear
inverse correlation between vitamin D intake and MS occurrence (for a review
see [76, 77]). These observations suggest the possibility of providing
glucocorticoid therapy in conjunction with vitamin D to extend therapeutic
effects. Furthermore, the results illustrate the importance of ensuring that
beneficial nuclear receptor agonists are supplied in adequate concentrations to
prevent a rate limiting reduction in therapeutic benefit during acute MS
attacks.It
should also be mentioned that vitamin D has recently been determined to be an
inhibitor of PARP-1 [78]. PARP-1 is the primary enzyme responsible for
inflammation-induced depletion of cellular NAD (Figure 1). High-affinity PARP-1
inhibitors such as minocycline [79] have already proven beneficial in reducing
clinical symptoms of MS in EAE models. Minocycline is currently being evaluated
in the clinical treatment of MS [80–83]. PARP-1 appears to play an important
role in MS pathogenesis.Glucocorticoids
strongly induce expression of TNFRSF18/glucocorticoid-induced TNFR-related (GITR) gene, which leads to induction of the enzyme controllingde novo NAD biosynthesis, indoleamine 2,3-dioxygenase (IDO). Most
significantly the induction IDO activity is required for the full
glucocorticoid anti-inflammatory effect [4, 5]. Inhibition of IDO activity
exacerbates experimental autoimmune encephalomyelitis [52, 54]. All indications
are that IDO induction may hinder autoimmune demyelination by starving
autoreactive T cells of the essential amino acid tryptophan. Th1-derived
cytokines tumor necrosis factor-α (TNF-α)
or interferon-γ (IFN-γ)
induces transcription and activates IDO thus functioning as a timed feedback
mechanism for limiting cytokine-stimulated proliferation of autoreactive T
cells (for a review see [84]). The full potential for pharmacological exploitation
of tryptophan depletion to promote immunotolerance in autoimmune disease
remains largely unaddressed [85].


## 3. Enzymatic Target Genes of Interest to MS

Regulation
of immune function ultimately requires some kind of enzymatic biochemistry. Three
particularly desirable drug-mediated target gene inductions of interest in MS
are IDO, mitochondrial superoxide dismutase (SOD2), and heme oxygenase-1
(HMOX-1). Increased expression of IDO [52, 54], SOD2 [86], or HMOX-1 [8] has
been shown to exert protection against EAE pathogenesis. Thus, we are
interested in small molecules that affect transcription of these genes.
Here three respective paragraphs are devoted to discussing why transcriptional
induction of  these genes is expected to provide benefit in MS therapy.The
tryptophan depleting enzyme indoleamine 2,3-dioxygenase (IDO) is also
beneficial in EAE disease models of MS [52, 54], where IDO expression in
microglia is tightly regulated by cytokines during inflammation [51–53]. In
fact, IDO is centrally involved in nearly every examined autoimmune disease
(for a review see [85]). As described above, IDO even appears central to the
mechanism of glucocorticoid-mediated anti-inflammatory effects [4, 5]. IDO
mediates the most dramatic example of immunotolerance, fetal acceptance.
Accordingly, IDO over-expression also prevents both transplant rejection [87]
and the lethality of graft versus host disease [88]. Sometimes, the mechanism
of enzyme action in the liquid immune system resembles microbial competition
(for a review [84]). Professional antigen presenting cells (macrophages,
dendritic cells, and microglia) use IDO activation to deplete local
extracellular tryptophan. The effect is autotoleragenic through tryptophan
starvation of tryptophan-sensitive circulating T cells. Professional antigen
presenting cells exploit this primitive biochemical competition for nutrients
to control T cell proliferation. The simplicity of the mechanism makes IDO
particularly attractive for pharmacological intervention [85].New
studies reveal that increased heme oxygenase-1 (HMOX-1) can dramatically
reverse paralytic EAE and prevent relapse [9]. This is in agreement with
previous pharmacological analysis in EAE [89]. Absence of HMOX-1 enhances
demyelination in EAE, while induction of HMOX-1 with hemin or cobalt
protoporphyrin can delay EAE onset. IL-10, a critical glucocorticoid target
gene as described above, requires HMOX-1 activity to exert its
immunosuppressive effects and is a known inducer of HMOX-1 [8]. Lastly, the end
product of HMOX-1-catalyzed reaction, carbon monoxide, can itself mediate
beneficial effects against EAE and is currently being considered as an MS
therapeutic [9]. Heme oxygenase catalyzes the degradation of heme to produce
iron, carbon monoxide, and biliverdin, the latter of which is subsequently
degraded to produce the potent antioxidant bilirubin. HMOX-1 gene
transcription is under the control of electrophile response elements that
mediate extremely responsive transcriptional inducibility in response to
oxidative stress ([90] and unpublished observations in zebrafish larvae).
Consequently, HMOX-1 is often elevated in disease states as the body attempts
to deal with oxidative pathosis.A
mere doubling of mitochondrial superoxide dismutase protein encoded by SOD2 via
retroviral-mediated gene insertion strongly protects against EAE-mediated
demyelination [86]. Increased oxidative stress, including decreases in
superoxide dismutase, is a challenge in MS patients [91]. Amyotrophic lateral
sclerosis (ALS) is a more severe CNS disease than MS, causing massive
degeneration of motor neurons. SOD1 mutations are the only identified genetic
link to familial amyotrophic lateral sclerosis [92]. Increased SOD2 is known to
provide protection against mutated SOD1 neurotoxicity [93, 94]. Superoxide
dismutase serves essential functions as an endogenous free-radical scavenging
antioxidizing enzyme. Loss of function of mitochondrial superoxide dismutase
2 (SOD2) results in perinatal lethality [95], while loss of cytosolic superoxide
dismutase 1 (SOD1) results in hepatocellular carcinoma in mice [96]. Given that
mitochondria are a well-established Achilles' heel on the way to cell death, it
is worth considering that increased SOD2 expression may delay cell death due to
SOD1 mutations. Modest increases in SOD2 are also known to increase lifespan in
metazoans, where the pathway is now believed to involve reduction in insulin
signaling [97].


## 4. Common Pathways and Characteristics of Nonsteroidal Endogenous Antineuroinflammatory Molecules

The endogenous nonglucocorticoid molecules shown to provide protection against MS
or animal models thereof (EAE or TMEV-IDD) have a distinguishing common set of
characteristics. By “endogenous,” We are referring not only to those molecules
which are synthesized endogenously but also the vitamins, which are endogenous
in the sense that they must be present for survival regardless of the site of
synthesis. This list includes nicotinamide
[31], vitamin D [74, 75], retinoic acid [24], 15d-PGJ2 (12–16;
[23–27]), and the endocannabinoids [63, 64] (Figure 1). Natural product
cannabinoids have also been shown to ameliorate EAE progression [98], thus
further supporting the notion for a potential role for endocannabinoids in
preventing autoimmune-mediated demyelination.First,
these molecules generally function as transcription factor ligands, which work
through peroxisome proliferator-activated receptor PPARα,
PPARγ,
or vitamin D receptors, all of which must heterodimerize with retinoid X
receptor-alpha (RXR) to mediate transcriptional effects (Figure 1). Second,
these molecules are antiangiogenic. Vascular endothelial growth factor (VEGF)
levels are elevated in virtually all known autoimmune diseases, and reduction of
VEGF production tends to minimize autoimmune disease pathogenesis (for a review
[99]). This is predicted since autoimmune diseases are diseases of
hyperproliferation, and similar to solid tumors, they respond favorably when
treated with antiangiogenics as discussed above. Third, many of the molecules
that are effective against EAE also correct dyslipidemia, often raising
high-density lipoprotein (HDL) while lowering triglycerides and low-density lipoprotein
(LDL). Nicotinic acid/niacin provides the greatest boost of HDL levels of any
known molecule, regulates angiogenesis, and activates PPARγ
indirectly by producing 15d-PGJ2 via the high-affinity nicotinic
acid G-protein-coupled receptor HM74a/GPR109a located on professional antigen
presenting cells [28, 100]. However, nicotinic acid has not been examined in the
context of MS therapy. Thus, additional consideration of nicotinic acid as a
potential MS therapeutic is certainly warranted.Virtually every endogenous molecule known to provide
protection against animal models of MS is distinguished as also possessing
antiangiogenic activity. This list of MS ameliorating antiangiogenic
molecules includes vitamin D [101], 15d-PGD2 [102, 103], retinoic acid
(effects on EAE [104–107]; effects on angiogenesis [108–110]), and anandamide
[111]. We have observed that NAD precursors exert positive angiogenic
activities in the developing zebrafish (data not shown). This is likely due to
the proven role of the NAD-responsive enzyme SIRT-1 in stimulating growth phase
angiogenesis [112]. However, nicotinic acid seems likely to potentially possess
antiangiogenic activities stemming from PGD2 production within
professional antigen presenting cells which are expected to be anatomically
localized to sites of inflammation. Thus, nicotinic acid may exert effects on
angiogenesis independent of the developmental context, instead being dependent
on the cellular localization of the GPR109a-expressing prostaglandin-producing
professional APCs.


## 5. Discussion

Greater
emphasis should be placed on exploring combinatorial approaches to treating
autoimmune demyelinating disease. Numerous studies have detected increased
therapeutic effectiveness in a variety of disease contexts when simultaneously
activating both subunits of the PPAR:RXRα heterodimer (Figure 1). Most significantly, this combination of 15d-PGJ2 with 9-cis retinoic acid exerts an
additive effect in ameliorating EAE [24]. In
vitro this mixture exerts a cooperative inhibition of microglial cell
activation [113] and a cooperative antiproliferative effect on coronary artery
smooth muscle cells [114]. The combination of PPARγ
ligands with 9-cis retinoic acid
increases the killing of multiple myeloma cells [115] and cooperatively suppresses
expression of ADAMTS4/Aggregecanase-1 [116], a protein stimulated by IL-1 that
erodes articular cartilage in arthritic disease. This latter effect alone
strongly suggests that the combination of 15d-PGJ2 and 9-cis retinoic acid may be particularly
useful for the treatment of the autoimmune disease rheumatoid arthritis.It
seems most likely that additional activation of other nuclear receptors may
exert a synergistic therapeutically beneficial effect in treating MS. For
example, vitamin D or endocannabinoids may also exert cooperative effects. New
studies indicate that both cannabinoid receptorsCB1 and CB2 must be activated in order to stimulate myelination [117]. Extrapolation
suggests that more than one molecule would be required for any potential recovery
from MS neurodegeneration. Even glucocorticoids are not enough to prevent
relapse rate. A teleost-based EAE model should be considered toward achieving
higher throughput in an animal model for directly comparing the many small
molecule permutations of potential drug combinations for their therapeutic
value in treating MS.Positron
emission tomography studies performed in mice have shown that nicotinamide
penetrates the mammalian blood-brain barrier [118]. High doses of oral
nicotinic acid are well established in their ability to help treat the CNS
disease schizophrenia [119–121]. Dramatic increases in NAD were detected in the
spinal cord of mice subcutaneously injected with pharmacological doses of
nicotinamide with concomitant profound protection against behavioral defects,
demyelination, and death from EAE [31]. Thus drug delivery aspects and
pharmacokinetics of oral nicotinic acid or nicotinamide for treating MS are not
expected to be an issue.Given
that glucocorticoids such as methylprednisolone are universally accepted as the
first approach for treating acute attacks of MS. These glucocorticoids may be
considered as the current gold standard for attempts to model desirable ligand-induced transcriptomic effects to treat MS. Glucocorticoids work in large part
through induction of IDO and IL-10, the latter of which exerts its effects in
part via HMOX-1 induction [8]. Consistent with a critical role for these
specific glucocorticoid-target genes in providing relief against MS, ectopic
studies have revealed that small increases in gene expression of the enzymes
HMOX-1 [9], IDO [52, 54], or the mitochondrial superoxide dismutase (SOD2;
[86]) prevent or reverse autoimmune demyelination.The
endogenous PPAR ligand activators 15d-PGJ2 and anandamide prevent
demyelination in animal models of MS. Nicotinic acid, while untested in
EAE models, is unique because of its ability to stimulate production of
prostaglandins 15d-PGJ2 and PGE2, the latter of which
increases IDO expression [49, 50]. Additionally, pharmacological nicotinic acid
by increasing NAD concentrations is expected to activate SIRT-1, which has a
protective effect against neurodegeneration involving microglia [37, 122].
Experimentally, combinatorial activation of PPARs, retinoid X receptor, and/or
vitamin D receptor generally provides additive benefit against EAE. A higher
throughput teleost-based EAE model is needed to compare the various
pharmacological permutations.In summary, more emphasis should be placed on
developing a nonsteroidal antineuroinflammatory cocktail for treating MS
starting with pharmacological doses of nicotinic acid, 15d-PGJ2,
nicotinamide, anandamide, vitamin D, and 9-cis retinoic acid toward extending the time frame of MS therapeutic benefit
provided by glucocorticoids while minimizing dangerous side effects. Studies
performed using animal models of MS indicate that there are multiple potentially
rate-limiting factors controlling immune-mediated demyelinating disease
progression. The range of possible nutritional and biochemical deficiencies in
the etiology of MS, which may adversely affect the healing process, is complex.
Thus it would be most prudent to consider combinatorial approaches as a means
for providing the most reliable therapeutic treatment of multiple sclerosis.



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