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.

Full text

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Hindawi Publishing Corporation
PPAR Research
Volume 2009, Article ID 853707, 11 pages
doi:10.1155/2009/853707
Review Article
NicotinicAcid-Mediated Activation of Both Membraneand
NuclearReceptors towards TherapeuticGlucocorticoidMimetics
forTreating MultipleSclerosis
W.Todd Penberthy
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way P.O. Box 670524,
2938 CVC Mail Loc-0524, Cincinnati, Ohio 45237, USA
Correspondence should be addressed to W. Todd Penberthy, wtpenber@yahoo.com
Received 1 December 2008; Accepted 22 February 2009
Recommended by Antonio Brunetti
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
membraneG-protein-coupledreceptorsandnuclearperoxisomeproliferatingantigenreceptors(PPARs)demonstrablyameliorate
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
over50yearsclinicallywithouttoxicity,andraisesHDLconcentrationstoagreaterdegreethananypharmaceutical,thusproviding
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.
Copyright © 2009 W. Todd Penberthy. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1.MultipleSclerosisTreatment and
FunctionalTranscriptomics
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 glu-
cocorticoid treatment [6], while IL-10-mediated induction

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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 local-
ized cellular production of interferon via pharmacological
approaches. Interferon treatment is associated with compli-
cations, 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 mam-
mals, which results in a dose dependent experimen-
tal 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 postin-
jection. EAE has been successfully used in the development
of clinical therapeutics [22]). Studies examining the phar-
macology of the endogenous PPARγ activators have con-
sistently 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-PGJ2is 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 (anan-
damide and 2-arachidonoylglycerol; 2-AG), and nicotinic
acid, which stimulates the localized production of 15d-PGJ2
restricted to professional antigen presenting cells.
PPARactivatorsarewellknownfortheirabilitytocorrect
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, nicoti-
namide, provides dramatic protection against demyelina-
tion 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 effectismediated viaNAD-dependentactivationof
SIRT-1. Functioning as a NAD-dependent histone deacety-
lase, 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 perox-
isome proliferator-activated receptor-gamma, coactivator 1
(PGC1α). Redistribution of the other nuclear NMNAT1-
encodingproteintothecytosolextendsthedelayinWallerian
degenerationuptosevenweeks[40]!WhileSIRT-2ispresent
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.ThetwomostcommonMOAsforglia-killingneurons
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-dependentmanner,preventingbehavioraldefects,min-
imizing 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-PGJ2with 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 discov-
ery 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

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PPAR Research3
NAD
NAD
(depletion)
(depletion)
Nicotinamide Anandamide 2-arachidonoylglycerol
?
D : VDR
Generated molecule
Nuclear transcriptional
regulation
Cell cycle arrest; antitumorigenic
(or apoptosis or catastrophic necrosis
correlating with extent of NAD depletion)
NAD dysequilibrium during neuroinflammation
Sirtuins
e.g. SIRT-1
(−)NF-kb , histones, PGC1 , p53, Ku70, WRN
nuclear receptors: LXR, AR, & ER
(+) TFAM, SOD2,
PEPCK-C, UCP2
PGE2
15d-PGJ2
15d-PGJ2
X : PPARs
GPR109A/HM74A
( expressed in microglia)
Nicotinic acid
Damaged
DNA
NADPH oxidase.. OO•
iNOS.. NO•
PARP-1
activation !!
PAR
nicotinamide
Inflammation
Molecules
Membrane receptor
Cytotrophic
(+) IDO
(–) tryptophan
(microglia-associated T cells)
Immunotoleragenic
Target genes
Biochemical endpoint
Functional endpoint
RA : RXR
Better circulation
(+) HDL
(–) VLDL and triglycerides
(+) CD36, ABCA1, FABP4, PEPCK-C
(+) IL-10
(+) HMOX-1
(+) antioxidant
Anti-inflammatory
NAD
O
O
OH
O
N
H
OH
OH
O
CO2H
N
NH2
O
N
O
OH
TNFαR
(−) TNFα
α
α
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-PGD2and PGD2specifically 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-PGD2spontaneously 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].
autoimmune aspects of rheumatoid arthritis supports con-
sideration of high-dose nicotinamide treatment in MS.
Nicotinic acid working through the high-affinity nico-
tinic 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 via PGE2-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
presentingcellsincludingmicroglia.Sincebothnicotinamide
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.
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 demyeli-
nating 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 therapeuti-
cally 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 com-
bined with their potential value in autoimmune demyelinat-
ing disease, anandamide and 2-arachidonoyl glycerol should
be examined with respect to their effects on gene expression
related to MS pathogenesis.

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Glucocorticoids
(methylprednisolone
or dexamethasone)
GITR/TNFRS18
(pDCs and macrophages;
microglia?)
IL-10
(T & macrophages;
microglia?)
HMOX-1
(macrophages &
microglia?)
regs
Vitamin D
+
IDO
(professional
antigen
presenting cells)
Immunosuppression
Immunotolerance
Neural dysfunction and pain
TNFα
(macrophages
& microglia?)
Figure 2: Glucocorticoids exert well-established relief from MS attacks, which last up to 30 days. Glucocorticoids exert immunoregulatory
effectsviatranscriptionalregulatorysignalinginlargepartthroughGITRtoIDO([4,5])andIL-10toHMOX-1[8,70,71]).GITRactivation
is also known to lead to increased IL-10 production [72]. The representative glucocorticoid target genes of interest examined in this study
withdesirableeffectareshowninbold.MultiplesclerosispatientsarespecificallylackinginCD46-stimulatedIL-10secretionandsufferfrom
an over-proliferation of myelin autoreactive T cells.
2.The Gold Standard of Transcriptomic
Modelingfor TreatingMultiple 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 gluco-
corticoid target genes by alternative approaches. Two recent
studies suggest that both IL-10 and IDO likely mediate and
determine the extent of glucocorticoid effects (Figure 2; IL-
10 [6], IDO [4, 5]).
Recentstudies in glucocorticoid-resistant
patientsalsoimplicatevitaminDasafactoringlucocorticoid
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
cellstoregulatoryTcells(Treg)andcausessubstantialrelease
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 ensur-
ing that beneficial nuclear receptor agonists are supplied in
adequate concentrations to prevent a rate limiting reduction
in therapeutic benefit during acute MS attacks.
asthma
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.
Glucocorticoidsstrongly
TNFRSF18/glucocorticoid-induced TNFR-related (GITR)
gene, which leads to induction of the enzyme controlling
de 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].
induceexpressionof
3.EnzymaticTarget Genesof Interestto 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],orHMOX-1[8]hasbeenshowntoexert
protection against EAE pathogenesis. Thus, we are interested
in small molecules that affect transcription of these genes.

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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 immunotoler-
ance,fetalacceptance.Accordingly,IDOover-expressionalso
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 trypto-
phan 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,acriticalglucocorticoidtargetgeneasdescribedabove,
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 demyeli-
nation [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.
ModestincreasesinSOD2arealsoknowntoincreaselifespan
in metazoans, where the pathway is now believed to involve
reduction in insulin signaling [97].
4.Common Pathways and
Characteristicsof NonsteroidalEndogenous
AntineuroinflammatoryMolecules
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-
activatedreceptorPPARα,PPARγ,orvitaminDreceptors,all
ofwhichmustheterodimerizewithretinoidXreceptor-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 pro-
ductiontendstominimizeautoimmunediseasepathogenesis
(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 dys-
lipidemia, 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-PGJ2via
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