Review

Neuroprotection, regeneration and

immunomodulation: broadening
the therapeutic repertoire in
multiple sclerosis
Orhan Aktas, Bernd Kieseier and Hans-Peter Hartung
Department of Neurology, Heinrich-Heine-Universitat Dusseldorf, 40225 Dusseldorf, Germany

Multiple sclerosis (MS), an incurable but manageable

disorder, is characterized by chronic inflammatory
demyelination and neurodegeneration in the central
nervous system. Although the primary cause of this
often devastating disease remains elusive, major therapeutic advances have occurred during the past two
decades. Here, we present a review of current immunomodulatory treatments and outline upcoming therapy
approaches, including biologics and oral alternatives
that might have equivalent or superior efficacy and/or
enhanced tolerability compared with available treatments, and discuss the scientific rationale and expected
benefits and risks for these compounds. We also speculate about alternatives beyond immune-directed
approaches, review novel insights into the neurobiological consequences of sustained brain inflammation and
evaluate future perspectives for neuroprotective and
neuroregenerative treatment strategies for MS.
Treatment of multiple sclerosis: taking the challenge
Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), affecting 0.1% of the general population in Western countries. As
the leading cause of neurological disability in young adults,
MS represents a significant public health issue, with a high
socio-economic burden and a crucial impact on quality of
life. At diagnosis approximately 85% of patients have a
relapsing remitting disease course (RR-MS), characterized
by unpredictable and recurrent episodes of neurological
deficits, such as loss of vision or paralysis, and followed by
periods of remission. Remission is not always complete,
and usually after several years more than two-thirds of
these patients switch to an insidious secondary progressive
course (SP-MS). For 15% of patients, MS is progressive
from the very beginning (primary progressive, or PP-MS).
Since the first concise description of MS provided by JeanMartin Charcot in 1868, this heterogeneous clinical picture
has been linked to typical neuropathological changes, including the presence of multifocal inflammatory, largely
white matter brain and spinal cord lesions, indicating the
fundamental role of immunological processes for disease
pathogenesis (Figure 1).
Corresponding authors: Aktas, O. (orhan.aktas@uni-duesseldorf.de); Hartung,
H.-P. (hans-peter.hartung@uni-duesseldorf.de)

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The approval of immunomodulatory injection therapies

in the early 1990 s heralded a new era and now MS therapy
research is the most active therapeutic field in neurology.
Here, we take the continuing series of clinical trials as an
opportunity to review the upcoming treatment strategies,
ranging from unspecific but oral immunomodulatory drugs
to specific interventions by monoclonal antibodies (mAbs).
We focus on the underlying immunological and neurobiological modes of action, link them to specific disease patterns and point to unexpected side effects originating from
the peculiar immunological characteristics of the CNS. The
observed superior efficacy of selective immunosuppression
by mAbs holds promise for future MS therapy, particularly
in early phases of the disease, when modulation of the
immune system might provide indirect neuroprotection. At
later particularly at progressive stages, even state-ofthe-art selective immunosuppressants such as alemtuzumab or rituximab have failed in MS. Therefore, we review
recently elucidated molecular insights into the diffuse and
neurodegenerative nature of MS, including novel concepts
such as disturbances of channel homeostasis and energy
balance, and work up the resulting options regarding
neuroprotective and regenerative therapies.
Current therapies hopes, experiences and facts
Currently, glatiramer acetate (GA) and the interferon
(IFN)-b variants are established as disease-modifying
immunomodulatory treatments for RR-MS (Table 1).
Although the net clinical gain of these drugs for patients
is considered to be only modest, they show a favorable risk
benefit profile and are used around the world since their
introduction [1]. Although used for relapsing forms of MS,
neither the IFN-bs nor GA have demonstrable significant
effect in relapse-free progressive disease states [2]. Moreover, despite the evidence for efficacy in clinical trials,
interindividual treatment response to these agents is
heterogeneous. A substantial proportion of patients continue to experience relapses or clinical progression with
such ongoing immunomodulation, and escalation therapy
with the nonspecific immunosuppressant mitoxantrone is
warranted [3,4]. However, owing to its potential for cumulative cardiotoxicity and the increased occurrence of
acute leukemia, mitoxantrone is considered a second-line
therapy only, restricted to non-responders to first-line

0166-2236/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2009.12.002 Available online 4 January 2010

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Figure 1. Concepts on lesion formation in MS. Neuropathological analyses have revealed four different patterns of tissue damage (a), claimed to be unique for individual
subjects and thus indicating interindividual heterogeneity in pathogenesis [119]. There is no doubt that antibodies against myelin contribute to autoimmune demyelination
as amplifiers of the encephalitogenic autoimmune attack and enhancer of disease pathology. Moreover, a possible pathogenic role for antibody-mediated CNS damage is
now obvious in neuromyelitis optica, or Devics syndrome, an MS-related but possibly distinct disease entity characterized by the presence of antibodies against the
astrocytic aquaporin-4 water channel and massive complement depositions in affected brains [120124]. Regarding classical MS, a recent study of the pathological events
preceding myelin phagocytosis in nascent MS lesions raised the possibility that primarily non-inflammatory oligodendrocyte cell death might initiate local macrophage
scavenger activity (b), resulting in subsequent amplification of the inflammatory response [125]. It remains disconcerted whether pathological heterogeneity in MS is
largely a result of evolution of lesional pathology (b), rather than pathogenic heterogeneity (a) [126]. One has to keep in mind that in MS and its animal model, EAE, axonal
damage and neuronal death occurs even outside focal inflammatory lesions, and in earliest disease stages [55,56], even in the spinal cord [127,128].

treatments or to highly active relapsing cases. The same

holds true for natalizumab, the first antibody-based
therapy licensed for relapsing MS in 2004, with a complex
riskbenefit ratio (Box 1).
Upcoming therapies: from peril to progress
Despite intensive efforts, it has not been possible to
identify any single etiological agent or event serving as
the critical and unique starting point for the heterogeneous
inflammatory infiltration of the CNS and neurodegeneration processes that underlie MS. Moreover, recent reports
on widespread neurobiological changes that might be independent of an inflammatory attack have ignited the debate
whether MS is primarily inflammatory in nature or
represents a neurodegenerative disease [5]. Irrespective
of these intriguing novel insights, the still-widely accepted

concept of MS pathogenesis, based and continually

explored in its animal models (such as experimental autoimmune encephalomyelitis, EAE [68]), suggests an autoimmune attack against the myelin sheath as the core
process, providing the rationale for currently evaluated
therapeutic approaches (Figure 2).
Nonspecific immunosuppression and
immunomodulation: perspectives for oral therapies
All first-line therapies for MS are available as parenteral
formulations only, which results in issues of compliance
and injection-related side effects that could be avoided with
oral agents. Currently, several are being explored, including nonselective immunosuppressive and immunomodulatory drugs (Table 2). Agents such as cladribine [9,10]
and teriflunomide [11] are antiproliferative compounds
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Table 1. Approved MS therapies

Therapy
Interferon
(IFN)-b1a and -b1b

Glatiramer acetate
(GA; copolymer-1)

Approved/used for
 CIS

Clinical effects
 Reduces relapse rate

 Relapsing forms
of MS
 SP-MS (IFN-b1b)

 Modifies disease
course (CIS)

 CIS

 Reduces relapse rate

 Standardized, randomized mixture of synthetic polypeptides

consisting of L-glutamic acid, L-lysine, L-alanine and L-tyrosine
with a defined molar residue ratio of 0.14:0.34:0.43:0.09
 Limits T lymphocytes by downregulating migration and
proliferation and by induction of anergy and apoptosis
 Induces an immunomodulatory (and possibly reparative)
T lymphocyte phenotype by shift of GA-reactive T cells from
Th1 towards Th2 during treatment and secretion of BDNF
by GA-reactive T cells
 Promotes development of anti-inflammatory type II monocytes

 RR-MS

Suggested mode of action (selection, see Ref. [1] for details)

 Endogenous immunomodulatory cytokine typically
induced during viral infections
 Limits general T lymphocyte activity by suppressing
proliferation and migration
 Targets encephalitogenic Th17 T lymphocyte population
 Downregulates antigen presentation by MHC class II molecules
 Inhibits immune cell migration by increasing the concentration of
soluble adhesion molecules (sICAM-1, sVCAM-1) and decreasing the
concentration of surface-expressed adhesion molecules (VLA-4)
 Stabilizes the bloodbrain barrier by reducing the expression
of matrix metalloproteinase 9
 Has a complex impact on the cytokine profile

Mitoxantrone

 RR-MS
 SP-MS

 Reduces relapse rate

 Attenuates (secondary)
disease progression

 Anthracenedione chemotherapeutic agent

 Eliminates and deactivates immune cells, particularly
monocytes and macrophages
 Inhibits T lymphocyte proliferation and migration
 Inhibits B lymphocyte activation

Natalizumab

 RR-MS
 SP-MS

 Reduces relapse rate

 Attenuates disease
progression

 Humanized IgG4 mAb against a4 subunit of a4b1 integrin

 Blocks T lymphocyte entry into the CNS

BDNF=brain-derived neurotrophic factor; CIS=clinically isolated syndrome; CNS=central nervous system; IgG=immunoglobulin G; MHC=major histocompatibility complex;
RR-MS=relapsing remitting multiple sclerosis; sICAM=soluble intercellular adhesion molecule; SP-MS=secondary progressive multiple sclerosis; sVCAM=vascular cell
adhesion molecule; VLA=very late antigen.

which interfere with metabolic or signalling pathways of

activated immune cells, and thus act as immunosuppressive therapies. Recently announced data from a Phase III
trial of cladribine indicate that even a few short annual
treatment courses reduce clinical and imaging-based disease activity in RR-MS [9], resulting in recent filings for
registration of this oral agent. A more specific immunomodulatory mode of action has been proposed for two agents
currently in advanced clinical trials, dimethylfumarate
(BG00012), a substance belonging to the family of fumaric
acid esters, and laquinimod. Fumaric acid esters were
effective in RR-MS, probably as a result of the activation
of the neuroprotective nuclear factor E2-related factor 2
transcription pathway [12], and promising data with
BG00012 encouraged ongoing Phase III trials [13]. Laquinimod showed efficacy on magnetic resonance imaging
(MRI)-based measures of disease evolution in RR-MS
[14] and could offer an improved riskbenefit ratio compared with its parent substance linomide for which development was stopped because of serious cardiovascular
toxicity.
Selective immunosuppression: targeting novel
molecular switches
Raising the bar of clinical efficacy by immune-directed MS
treatments might require more selective intervention strategies. Antigen-specific approaches to treat MS are based on
the assumption that unwanted autoreactive T cell clones
drive disease progression by orchestrating an immunological attack against myelin antigens [15]. Therefore, the
142

modulation of such deleterious T lymphocytes constitutes

a key strategy for therapies that might interfere with the
immunological synapse [16], consisting of an antigen (e.g.
a peptide from a myelin-derived protein) embedded within a
major histocompatibility complex (MHC) molecule on the
surface of an antigen-presenting cell (e.g. macrophage),
which is recognized by a specific receptor on a T lymphocyte
(T cell receptor). The major challenge of such antigenspecific approaches is that the target antigen(s) of the
deviated immune response in MS have not been identified
with certainty and that an initially focused immune
response broadens as the disease evolves with spreading
of epitopes and a consequently diversified immunological
attack [17].
Biologics such as recombinant antibodies might provide
additional selective treatment strategies for MS (Table 2)
[18]. A possible candidate is alemtuzumab, which causes
sustained depletion of T lymphocytes from the circulation
upon binding to CD52, a glycosylphosphatidylinositolanchored 2128 kDa protein with unknown function on
the surface of mature lymphocytes, monocytes, macrophage and some dendritic cells [19]. In earlier studies,
alemtuzumab suppressed clinical and MRI signs of inflammation in active SP-MS patients [20] but failed to beneficially impact on disability progression, indicating that once
established neurodegeneration might be uncoupled from
extracerebral inflammatory processes. Alemtuzumab is
now being tested in early stages of RR-MS where it has
shown superior clinical efficacy compared with standard
IFN-b therapy [21]. However, the observed rare but severe

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Box 1. Biologics as selective, powerful and challenging MS therapies: lessons from natalizumab
This humanized antibody targeting the a4 integrin subunit blocks
migration of activated immune cells into the CNS and reduced
disease progression and relapse rate in two phase III trials in RR-MS
[99,100]. Progressive multifocal leukoencephalopathy (PML), a lifethreatening opportunistic infection of oligodendrocytes, has emerged
as a rare, serious adverse event and could limit the broader use of
natalizumab. PML is usually confined to immunocompromised
individuals, e.g. HIV patients, and is caused by the reactivation of a
latent infection with the ubiquitous JC DNA polyomavirus (JCV).
CD8+ cytotoxic T cells appear crucial to recognize and destroy JCVinfected cells in the brain. The risk of developing PML on natalizumab
treatment appears to increase with its duration. Most cases occurred
after 24 months of exposure [101,102]. PML has also been reported in
non-MS patients on treatment with rituximab, alemtuzumab and
efalizumab, as well as for conventional immunosuppressants [102
104]. Profound immunosuppression increases replication of JCV in
the kidney and promotes virus entrance in the blood [105]. An obvious

explanation invokes compromised immunosurveillance of the brain.

Natalizumab was found to induce a sustained decrease in the CD4/CD8
ratio in the cerebrospinal fluid [106109]. Additional reasons for the
emergence of PML might be unique to the mode of action of
natalizumab. Natalizumab has been shown to elevate levels of
circulating B lineage cells and mobilize VLA-4+ CD34+ hematopoietic
stem cells from the bone marrow, all potential JCV carriers, and to
promote transcription factors required for JCV replication [110].
Moreover, in light of the substantial discrepancy between high viral
prevalence and low disease incidence, one has to consider virus- or
host-specific factors such as specific virus capsid protein phenotypes,
and not only the immune status, as relevant for PML manifestation
[111]. For the lymphocyte-depleting monoclonal antibody alemtuzumab, an increased frequency of B cell-related autoimmune thyroid
disorders and idiopathic thrombocytopenic purpura was reported,
probably originating from a B cell pool skewed towards immature
phenotypes after alemtuzumab treatment [21,112] (Figure I).

Figure I. The polyoma virus JC (JCV) resides in latent form in the bone marrow, kidnesy and lymphoid tissue but is usually not detected in the blood of
immunocompetent individuals. Rearrangement of the regulatory region sequence of the virus is required for reactivation of JCV to result in progressive multifocal
leukoencephalopathy (PML). This is usually counteracted by a CD8 T lymphocyte mediated immune response. If this protective response is compromised, JCV may
infect oligodendrocytes, proliferate and induce productive lytic infection with subsequent PML. Natalizumab may flush B cell precursors, potential harbors of JCV, from
the bone marrow into the blood and with few cells allowed access invade the CNS en passant. Natalizumab may promote PML conceivably also through activation of
transcription factors necessary for viral replication.

side effects (Box 1) call for further strategies preserving the

impressive clinical efficacy but minimizing the risk. One
alternative with a so-far favorable risk profile could be
daclizumab, a mAb to CD25, the a-subunit of the interleukin-2-receptor (IL-2R) on T cells. In MS, first-therapy
studies showed a significant suppression of newly occurring inflammatory MRI lesions and clinical activity [22,23].
Interestingly, this monoclonal antibody appears not to
suppress T cell proliferation mediated through the highaffinity receptor (a, b, g IL-2R subunits) but is associated
with intermediate affinity IL-2R-mediated expansion of a
subset of natural killer (NK) cells that express the marker
CD56 at high levels. This subset has immunoregulatory
properties.
Other biologics aim at targeting the homeostasis of B
lymphocytes that have more recently been recognized to

play a crucial role in the perpetuation of ongoing encephalitogenic immune responses through antibody synthesis or
by antigen presentation and subsequent T cell proliferation [24]. Anti-myelin antibodies amplify autoimmune
demyelination [25], and recent observations have raised
the question of whether antibody responses against
primary neuronal structures such as neurofilaments also
contribute to autoimmune neurodegeneration [26,27]. An
alternative hypothesis in progressive MS could be occurrence of compartmentalized sustained B cell activation
that is independent of systemic immunity [28]. These
aggregate data provide a strong rationale for B celldirected immunotherapies, such as the anti-CD20 mAb
rituximab. Indeed, rituximab-induced B cell depletion
has recently been demonstrated to confer therapeutic
benefit in MS, not only in severe MS cases but also in
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Figure 2. Therapeutic approaches to neuroimmunomodulation. The neuropathology of MS links the heterogeneous clinical presentation to a characteristic pattern,
reflected by multifocal inflammatory brain and spinal cord white matter lesions of different age. Despite intensive efforts, no infectious agent could be identified to date. The
presumed autoimmune hypothesis was ignited by the animal model EAE. Here, immunization with myelin antigens or the transfer of activated myelin-specific T
lymphocytes results in MS-like CNS inflammation [129]. As one might expect from any type of model, EAE has several drawbacks limiting the transfer of novel findings to
MS [8]. Nevertheless, the different EAE variants have provided useful insights for the evaluation of possible therapeutic targets. (a) According to current immunological
concepts, preexisting self-reactive T lymphocytes, specific for CNS autoantigens such as myelin basic protein, escape immunoregulatory mechanisms, persist and undergo
expansion in lymphatic tissues outside the brain such as the spleen or lymph nodes. Activation enables these lymphocytes to approach the bloodbrain barrier, following a
gradient of chemokines, and to interact with adhesion molecules expressed on brain endothelial cells. Following penetration of the bloodbrain barrier, these lymphocytes
become reactivated by local antigen-presenting cells (perivascular macrophages or dendritic cells) within the perivascular space, and finally invade the CNS parenchyma.
They now create a proinflammatory environment and recruit further immunocompetent cells such as B cells and antibody-secreting plasma cells, as well as macrophages
or microglia. The concept of a myelin-specific immune attack is also compatible with the recently recognized neurodegenerative features of MS [98]. Apparently, neuronal
damage can occur as collateral damage during autoimmune demyelination [50,130]. This phenomenon might be explained by unexpected crossreactivity between myelin
and neuronal antigens resulting in cumulative autoimmune responses [131,132]. (b) The putative modes of action for the new MS drug candidates are heterogeneous and
comprise the interaction with various cellular and molecular counterparts within the immune and the nervous system. T-shaped lines in red indicate blocking of target
structures or pathways, and red arrows indicate possible therapeutic interactions. APC, antigen-presenting cell (such as macrophage or dendritic cell); OG, oligodendrocyte;
Pc, plasma cell; S1P-R, sphingosine 1 phosphate-receptor; Th, T helper cell; VLA-4, very late antigen-4.

more mild RR-MS [29]. A subset of patients with PP-MS

that show signs of inflammatory activity also appear to
receive benefit from this monoclonal [30]. Based on the
encouraging proof-of-principle experience with rituximab,
depleting antibodies such as ocrelizumab and ofatumumab
that recognize the same CD20 antigen are currently being
evaluated.
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Targeting immune cell migration (and more):

unexpected endogenous pathways
Additional selective compounds explore alternative pathways to modulate immune cell mobility. The heterogeneous interactions of invading immune cells with the
bloodbrain barrier [31], a complex structure composed of
heterogeneous subcompartments [32], as well as the sub-

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Table 2. Compounds currently tested in phase II/III trials for MS therapy (selection of promising and innovative approaches)
Compound
Leukocyte depletion
Alemtuzumab

Daclizumab

Mode of action

Route of Indication currently

application tested [Phase]

 Humanized IgG1 mAb to CD52, a surface antigen of unknown i.v.

function present on lymphocytes, monocytes and dendritic cells
 Depletes T and, to a lesser extent, B lymphocytes
 T cell depletion is sustained, B cell depletion is transient
 Increases levels of BAFF and regulatory T lymphocytes (Treg)
i.v./s.c.
 Humanized IgG1 mAb to CD25, the a-subunit of
the IL-2 receptor of T lymphocytes
 Increases number of immunoregulatory CD56bright NK cells
 Decreases number of CD8+ T lymphocytes

B lymphocyte depletion and inhibition

Ofatumumab (HuMax-CD20)  Human IgG1 mAb to CD20
 Depletes mainly CD20+ B lymphocytes (not plasma cells)
 Humanized IgG1 mAb to CD20
Ocrelizumab
 Depletes mainly CD20+ B lymphocytes (not plasma cells)
 Chimerical IgG1 mAb to CD20
Rituximab
 Depletes mainly CD20+ B lymphocytes (not plasma cells)
General immunosuppressive
 Synthetic adenosine deaminase-resistant
Cladribine
nucleoside analog with selective lymphocyte activity
(2-chlorodeoxyadenosine)
 Disrupts DNA synthesis and repair in lymphocytes
 Impedes migration of T cells and monocytes
 Modulates chemokine and cytokine levels
 Antimetabolite related to leflunomide used for
Teriflunomide
rheumatoid arthritis
 Inhibits nucleotide synthesis
Broader/unknown mechanism of action
 Immunomodulator related to linomide with unknown
Laquinimod
molecular target
 Induces immunological Th1Th2 shift
Dimethyl fumarate (BG00012)  Activates transcription factor NF-E2-related factor (Nrf) 2
 Upregulates anti-oxidant response elements
 Related to other fumaric acids already used for psoriasis
Immune cell trafficking
Fingolimod (FTY720)

BAF312
Firategrast (SB683699)
Neuroprotective
Amiloride
Lamotrigine
Topiramate

 Modulates activation of G-protein-coupled

sphingosine 1-phosphate (S1P) receptors 1, 35: mediates
persistent signalling via internalized S1P1 receptors
 Influences migration by trapping lymphocytes in
lymph nodes and thus reducing their recirculation to
peripheral inflammatory tissues
 Differentially retains effector memory cells or
proinflammatory CD4 Th17 cells
 Might diminish astrogliosis by modulating S1P1 and
3 receptors on astrocytes
 Might promote remyelination by acting on
oligodendrocyte S1P5 receptors
 Modulates activation of S1P receptors 1 and 5
 Blocks a4 integrin subunit (small molecular drug)







Blocks acid-sensing ion channel-1 (ASIC1)

Blocks voltage-sensitive Na+ channels
Inhibits excitatory neurotransmission
Blocks voltage-sensitive Na+ channels
Enhances GABA-activated chloride channels
Modulates kainate and AMPA receptors

Ref.

RR-MS [III]

[1921,113,114]

RR-MS [III]

[22,23,115]

i.v.

RR-MS [I/II]

[116]

i.v.

RR-MS [II]

[117]

i.v.

RR-MS [II]

[29,30]

Oral

RR-MS [III]

[9,10]

Oral

RR-MS [II]

[11]

Oral

RR-MS [III]

[14]

Oral

RR-MS [III]

[12,13]

Oral

RR-MS [III]

[3440]

PP-MS [III]

Oral
Oral

RR-MS [II]
RR-MS [II]

Oral
Oral
Oral

Planned: RR-MS [II] [74]

SP-MS [II ambiguous] [118]
RR-MS [II]
[61]

AMPA=a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; ASIC1=acid-sensing ion channel 1; BAFF=B cell activating factor; GABA=g-aminobutyric acid; IFN=interferon;
MRI=magnetic resonance imaging; MBP=myelin basic protein; s.c.=subcutaneous; i.v.=intravenous; HLA=human leukocyte antigen; RR-MS=relapsing-remitting MS; SPMS=secondary progressive MS; PP-MS=primary progressive MS.

sequent impact of chemokines [33], low-molecular weight

cytokines that guide immune cells from primary to secondary immune organs to target issue, offer additional
options to restore dysregulated immune cell trafficking.
Upon phosphorylation, the sphingosine 1-phosphate (S1P)
receptor modulator fingolimod (FTY720) mediates persistent signalling via internalized S1P1 receptors [34,35]. As a

consequence, lymphocytes are trapped in lymph nodes and

prevented from recirculation (lymphocyte egress) [36].
Another S1P receptor subtype, S1P5 is expressed on oligodendrocytes and neurons and might exert independent
reparative effects (see below) [37]. Notably, fingolimod can
cross the bloodbrain barrier. Encouraging Phase II study
data showed that blockade of lymphocyte egress decreases
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the manifestation of inflammatory lesions in RR-MS
[38,39] and prompted the initiation of advanced clinical
studies, including more specific S1P modulators such as
BAF312 (Table 2). Meanwhile, positive results of a head-tohead comparison of fingolimod with standard IFN-b
therapy have been reported [40]. However, a suspicious
clustering of cases with malignant skin cancers and viral
infections was also observed [38], among them two cases of
lethal herpes simplex and varicella encephalitis as well as
a case with focal hemorrhagic encephalitis of unknown
origin [41]. Recently, the kininkallikrein system exerting
a variety of immunological functions [42] has been identified as an additional and hitherto unknown pathway
controlling encephalitogenic immune cell migration. The
kinin receptor B1 critically regulates the homing of encephalitogenic T cells into the CNS and targeting B1 might
attenuate disease in MS animal models [43]. Blunting
activity of the bradykinin-cleaving angiotensin converting
enzyme has been reported to induce potent regulatory T
cells and also to modulate encephalitogenic T cell autoimmunity [44,45], justifying clinical studies in MS. Taken

Trends in Neurosciences Vol.33 No.3

together, these data indicate that although efficient blockade of selected components of the immune system might
produce the desired clinical impact, it might also have
uncommon serious adverse effects that clearly mandate
vigorous monitoring programs and a continual assessment
of the riskbenefit ratio.
The horizon of future therapies: perspectives for
neurobiological approaches
Current immune-based therapies and prospects suggest a
narrow window of therapeutic opportunity with such
agents and point to the need to also focus on the challenging and neurodegenerative processes observed in MS.
Considerable advances have been achieved regarding
our understanding of the multifaceted damage pattern
to neurons and glia in the CNS in MS. Starting with the
rediscovery of axons as immediate rather than subsequent victims of the inflammatory process [46,47],
the timing and the precise molecular mechanisms responsible for these irreversible pathological changes are being
intensively studied (Figure 3) [15]. Axonal transection

Figure 3. Neuronal dysfunction, destruction and failed regeneration in the course of chronic inflammation. (a) Recent studies indicate that even subtle immunological
alterations should be the focus of significant attention for neurodegenerative processes: apparently, immune mechanisms observed in the course of mild and chronic
inflammation crucially contribute to neuronal dysfunction and promote CNS degeneration in the course of MS. Magnetic resonance spectroscopy studies revealed
remarkable changes within the so-called NAWM (normal-appearing white matter) at disease onset: significantly reduced levels of NAA, a marker for neuronal integrity,
indicates profound and widespread neuronal dysfunction which cannot be explained by the anatomical localization of the inflammatory lesions within the white matter [67].
Classical neuropathological studies have described dendritic pathology within the cortex of MS patients. Indeed, MS patients might exhibit a relevant cognitive decline
from the very beginning [133]. Moreover, during acute inflammatory relapses, MS patients show reversible neurological deficits. The mechanisms responsible for this
disperse dysfunction represent a relevant therapeutic target. (b) Novel insights suggest a complex damage scenario comprising the impact of inflammatory tissue
alterations such as reactive oxygen species (ROS), nitric oxide (NO), tissue acidosis, myelin-specific antibodies or death ligands, on the myelin sheath, the corresponding
oligodendrocyte and the axon itself. The disturbed ion homeostasis is reflected by an increased Ca2+ influx, leading to the harmful activation of Ca2+-dependent proteases
such as calpain, and a persisting increase in intra-axonal Na+ concentrations, leading to limited nerve conduction. These general alterations are associated with a prominent
failure of mitochondria which are not able to meet the energy needs, and with a loss of essential neurotrophic support as a result of demyelination. (c) Local regeneration
within a typical inflammatory MS plaque upon immune cell-mediated damage depends on the preservation of local progenitor cells and their capacity to migrate and
differentiate to, e.g. remyelinating oligodendrocytes (OG). The inflamed tissue itself is characterized by metabolic changes which, in turn, inhibit the activation of
endogenous repair processes. The presence of a strong astroglial scar inhibiting spontaneous tissue restoration has also to be considered. If remyelination takes place, the
resulting myelin sheaths are typically thinner and shorter, compared with developmental myelination. Importantly, the myelin sheath also provides trophic support for the
axon and decreases the neuronal vulnerability towards further inflammatory insults. Thus, neurobiological efforts to enhance endogenous repair processes including
remyelination and neuronal restoration represent an important approach beyond pure immunomodulatory or suppressive regimens.

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within acute lesions was associated with the local accumulation of macrophages, microglia as well as T cells. Several
mechanistic studies have demonstrated the capacity of T
cells to mediate collateral neuronal damage upon activation in vitro and in vivo [4854]. Moreover, neuronal cell
death and synaptic damage was found in the human cortex
[55], and linked to cortical demyelination which had been
neglected so far in studies that have used standard histochemistry methods [56]. Remarkably, these cortical
lesions lack lymphocytic infiltrates and are characterized
by activated microglia. Quantitative studies of the socalled normal appearing white matter (NAWM), devoid
of macroscopic inflammatory lesions, demonstrated a substantial reduction of axonal density [15].
In addition to axonal damage, either immediate or
subsequent to acute and massive inflammatory infiltration, chronic neurodegeneration continuously proceeds
(Figure 3a) and represents the major clinical determinant
of accumulating and irreversible disability in progressive
disease phases [57]. This insidious process is mainly driven
by minute inflammation, possibly sustained by innate
immune mechanisms [58], which might contribute to the
widespread presence of chronically activated microglia in
the MS brain even outside focal lesions. Persisting inflammation detected in various MS stages (both relapsing and
progressive) [59] challenges basic neuronal homeostasis
and particularly affects demyelinated axons which lack
myelin-derived support and might thus be prone to
changes of ion concentrations or inflammatory secretions
that might otherwise not be harmful [60]. The latter comprise a plethora of mediators, including proteolytic
enzymes such as matrix metalloproteases, cytokines, oxidative products and free radicals as integral components of
emerging concepts of neurodegeneration (Figure 3b).
Failed energy metabolism: ion channel homeostasis as a
potential therapeutic target
In the center of these concepts are reactive oxygen and
nitrogen species such as nitric oxide (NO) which are found
in raised concentrations in MS and which could directly
contribute to neurodegeneration. According to this concept
[61], NO inhibits mitochondrial respiration and leads to
subsequent energy failure within the axon [62]. The resulting ATP deficiency results in a gradual loss of function of
the Na+/K+ ATPase and a collapse of transmembrane ionic
gradients. This process is amplified by simultaneous perhaps immune-related demyelination. The acute loss of a
myelin segment leads to a conduction block which can be
mitigated by insertion of Na+ v1.6 channels along the
denuded sodium channel poor axolemma, resulting in
inefficient non-saltatory conduction along the injured segment [63]. This in turn results in a persisting Na+ influx
and, consequently, membrane depolarization. In response
to the unforeseen ionic imbalance, the energy-independent
Na+/Ca2+ exchanger starts to reverse its operation by
exporting Na+ and importing Ca2+ into the intra-axonal
compartment, thus leading to excessive intracellular Ca2+
concentrations. The axonal Ca2+ overload might be further
boosted by an independent, glutamate-dependent injury
mechanism. Neuropathological studies revealed that
macrophages and microglia found in close vicinity to dys-

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trophic axons highly express glutaminase, the major intracellular source of glutamate synthesis. Obviously,
subsequent overshooting activation of excitatory glutamate receptors might also contribute to increased intracellular Ca2+ levels [64]. Dutta et al. [65], studying lesions
of progressive MS patients, observed in the majority of
demyelinated axons direct fingerprints of Ca2+-dependent
protease activity such as fragmented neurofilaments and
depolymerized microtubules [65]. In the same study, transcript profiling revealed a decrease of mRNA levels of
mitochondrial genes, indicating an impaired activity of
mitochondrial enzyme complexes of the electron transport
chain and supporting the hypothesis that a mismatch
between energy demand and ATP availability drives
degeneration. These findings were recently confirmed
[66] and suggest damage mechanisms beyond direct
immune cell-mediated axonal and neuronal destruction.
Moreover, such subtle alterations might explain diffuse
reductions for N-acetylaspartate (NAA) observed in the
NAWM of RR-MS patients, sometimes even very early in
the disease course [67,68].
Viewed in this light, certain aspects of the neurodegenerative process might allow MS to be legitimately classified
as a channelopathy, mainly caused by energy failure, and
therapies limiting ongoing Na+ and reactive Ca2+ entry
into the axon might provide a novel neuroprotective
approach [61]. This goal could be achieved by sodium
channel-blocking compounds such as phenytoin, a clinically validated anticonvulsant which has shown therapeutic efficacy in EAE [69]. In addition to a direct effect
on axons, phenytoin also interferes with inflammatory
effector mechanisms, as it strongly reduces immunological
effector functions of activated Na+ v1.5 channel-expressing
microglia [69,70]. However, it is noteworthy that a recent
report indicates abrupt withdrawal of phenytoin results in
immediate exacerbation and even fatalities in EAE [71].
Although the precise mechanisms underlying this rebound
effect have not been elucidated yet, a possible contribution
of the so-far neglected Na+ v1.5 and v1.6 channels on
macrophages has been suggested [61], and a clinical Phase
II study in PP-MS was halted. For lamotrigine, another
sodium channel blocker, the results of a placebo-controlled
therapy trial in SP-MS were recently announced. Although
the primary endpoint, a beneficial impact on brain tissue
volume loss, was missed, patients taking lamotrigine significantly improved in walking speed, although the study
was not designed to measure such an effect as a major
outcome. Results from a placebo-controlled therapy trial in
RR-MS with topiramate, an anticonvulsant with a complex
mechanism of action [72], are pending.
A similarly complex regulation has been recently
described for TWIK-related acid-sensitive potassium
(TASK) channels which allow the regulated efflux of potassium ions. Although inflammatory plaques of human MS
patients displayed profoundly lowered expression of both
TASK isoforms 1 and 3, the same channels were also found
to influence T cell effector function in EAE [73], hampering
the transfer of these findings into clinical scenarios. Similarly, the search for further molecular candidates resulted
in the identification of the proton-gated acid-sensing ion
channel 1 (ASIC1) as a potential therapeutic target [74].
147

Review
ASIC1 contributes to axonal dysfunction and degeneration
in inflammatory lesions by augmenting neuronal Na+ and
Ca2+ influxes during tissue acidosis, and experimental
ASIC1 blockade by amiloride conferred axonal integrity
in the EAE model. Again, an old drug, already approved for
treatment of arterial hypertension, offers new hope for
primary neuroprotection and the basis for a future therapeutic trial. One has to keep in mind that, similar to the
other targets discussed above, ASIC1 is also expressed on
immune cells, thus the safety and efficacy of such channel
blockers for neuroprotection in MS remains uncertain.
Failed neuroregeneration: how to enhance endogenous
regeneration?
Experimental data suggest that in MS, deleterious neurodegenerative processes commence early and are already
established in the brain at the time of the first clinical
manifestation. Therefore, in addition to studying immunedirected prophylactic or neuroprotective strategies, there
is also an urgent need to discover regenerative approaches,
with the goal to restore and repair the injured tissue ab
initio (Figure 3c). In light of demyelination as a predominant neuropathological feature in MS, and the particular
vulnerability of denuded axons towards otherwise mild
inflammatory alterations, restoration of myelin sheath
integrity is a crucial issue [75]. Even within an acute
inflammatory brain lesion, spontaneous remyelination is
possible and regularly observed [76], yet a significant
feature of the disease is remyelination failure, probably
as a result of a differentiation block of oligodendroglial
progenitor cells (OPCs) [77]. Thus, regenerative treatment
approaches have aimed at restoring the myelin sheath by
transplanting exogenous myelin-forming cells [75]. However, the success of such cell replacement therapies is
clearly hampered by the multifocal (and sometimes even
diffuse) manifestation of MS lesions, hence requiring challenging neurosurgical procedures, and posing an immunological threat as a result of tissue incompatibility between
the donors and recipients immune systems. There might
be little benefit to be gained by delivering remyelinating
cells into inflammatory MS lesions that already contain
abundant progenitor cell populations with the capacity to
generate new oligodendrocytes [78]. Remyelination failure
is substantially caused by the hostile proinflammatory
environment that typically initiates and sustains demyelination [75] and to which, if not controlled, any new tissue
growth would be subject. Moreover, similar to other regenerative processes in the body, the overall remyelination
capacity in the CNS declines with age [79].
Regarding the underlying molecular mechanisms of
observed natural but limited remyelination, a recent study
revealed the substantial role of the leucine rich repeat and
Ig domain containing-1 (LINGO-1) which is exclusively
expressed on neurons and negatively regulates myelination. In EAE, systemic treatment with an antagonistic
LINGO-1 antibody leads to functional recovery and
increased axonal integrity without affecting the encephalitogenic immune response [80], justifying early clinical
studies in humans. Another possible strategy to enhance
endogenous remyelination is the identification of intracellular pathways repressing the final differentiation of
148

Trends in Neurosciences Vol.33 No.3

progenitors. As recently reported, differentiation of oligodendrocyte progenitors during remyelination (upon toxic
experimental demyelination) is regulated by histone deacetylases, offering novel epigenetic clues for myelin repair
strategies [79]. Regarding the underlying molecular mechanisms, the cyclin-dependent kinase inhibitor p57kip2 as
well as the Notch pathway might represent potent candidates, as they are responsible for the regulation of oligodendroglial differentiation and, at the same time,
modulated in the course of autoimmune neuroinflammation [8183]. Perhaps surprisingly, the above discussed
lymphocyte egress blocker, fingolimod, has recently been
shown to have a favorable impact on OPC homeostasis and
remyelination processes by modulating the S1P5 receptor
in vitro [37] and could thus uniquely combine immunomodulatory with neuroreparative properties.
Neuronal restoration
Many pathological conditions in the brain are characterized
by insufficient replacement of damaged neurons and poor
rewiring of axons, thus accounting for fixed and irreversible
clinical deficits. Several lines of evidence indicate that functional repair based on axonal outgrowth is hampered by
abundantly expressed myelin-associated inhibitory factors
in the CNS. Among them, the myelin component Nogo-A has
already been the focus of considerable attention, as it interacts with the neuronal Nogo receptor complex and limits
axonal sprouting in a contact-dependent manner. In experimental models of spinal cord injury, significant functional
recovery was achieved upon antibody-mediated blockade of
Nogo interactions [84]. These findings encouraged similar
studies in animal models of MS, yielding conflicting results
in independent studies. Indeed, Nogo has multifaceted roles
in the course of autoimmune demyelination and also influences the encephalitogenic immune response [85,86]. Thus,
prior to considering Nogo modulation as a future regenerative approach in MS, many issues remain to be elucidated to
dissect pure neurobiological from rather immunological
Nogo functions [86].
Very little is known about the contribution of other
inhibitory structures such as the prominent scarring in
MS lesions. The extracellular matrix within these scars
mainly consists of collagen fibers which themselves exert
a repulsive effect on sprouting axons [87]. Moreover, regarding neuronal regeneration in MS lesions, recent animal
experimental and human studies indicate that inflammation might trigger the proliferation of neural progenitors
both in the subventricular zone [88] as well as in chronic
lesions [89]. However, the final differentiation into mature
and integrated neurons obviously fails in MS and EAE
[89,90]. The cellular composition of chronic lesions is typically dominated by the abundant presence of activated
astrocytes, a uniform and very early reaction of the CNS
tissue in the course of autoimmune demyelination [91,92].
This so-called reactive astrogliosis [93] might be relevant for
tissue stabilization in the acute injury phase but seems to be
responsible for inadequate neuronal regeneration later on
[94]. Recent reports suggest a cardinal role for basal metabolic changes of the CNS environment. Obviously, subtle
modulation of the redox equilibrium found even in mild
inflammation impairs the proliferation of neural or more

Review
restricted glial stem cells [9597] and lead to the generation
of astrocytes at the expense of neurons [97]. In the latter
study, the altered differentiation pattern was mediated by
the histone deacetylase silent information regulator 1
(Sirt1), which serves as a sensor for the redox potential in
neural stem cells and directs their differentiation via the
modulation of the basic helixloophelix transcription factor
hairy/enchancer of split 1 (Hes1) and the subsequent inhibition of proneuronal mammalian achaete-scute homolog 1
(Mash1). Another recent study implicated the related sonic
hedgehog (Shh) pathway [90]. Apparently, proinflammatory
IFN-g secreted during autoimmune demyelination inhibits
Shh-mediated differentiation of neural progenitors and
results in the disruption of the neurogenic rostral migratory
stream. As mild and sustained inflammatory processes
occur not only in MS but also in several other neurological
diseases, such as stroke, spinal cord injury or primary
neurodegenerative diseases [98], the characterization of
these regulatory circuits could help to reinforce the endogenous restoration programs of the brain.
Concluding remarks and outlook
With the successful introduction of immunomodulatory
therapies, we have witnessed major therapeutic advances
in MS during the past two decades. The dominant inflammatory pathology of the disease focuses upcoming therapies on aberrant immunological processes. Drug
development will optimistically shortly offer oral alternatives to current parenteral agents. Experimental
approaches that bridge immunological and neurobiological
aspects of the disease are underway and will provide a
better understanding of the molecular steps leading to
inflammation-mediated axonal dysfunction and failure of
remyelination (Box 2). Targeting these processes, which
arise from the interface of immune response and brain
Box 2. Outstanding questions
 What are the molecular pathways of chronic neuronal dysfunction
in the course of mild but persisting CNS inflammation?
 What are appropriate endpoints and biomarkers for therapeutic
studies of neuroprotective, remyelinating and repair-promoting
therapies?
 Is neurodegeneration always driven or conditioned by inflammation?
 Which role does innate immunity play in the neurodegenerative
stages of MS?
 What are the determinants of lesion localization within the CNS
white and gray matter?
 How can we target the astroglial network for treating inflammatory neurodegeneration?
 How can we better identify immunological and neurobiological
subgroups of MS patients?
 How can we identify responders to immune-based therapies?
 How can we selectively modulate the activated immune system
without impairing beneficial immune reactions?
 Could resident CNS immunity be modulated by deactivating
microglia?
 How can we target sequestered compartmentalized immune
responses in the brain (drugs need to penetrate the bloodbrain
barrier)?
 How can we foster endogenous repair mechanisms to promote
remyelination, axonal survival and outgrowth?
 Is there prospect for cell-based therapies as replacement or
delivery vehicles?

Trends in Neurosciences

Vol.33 No.3

homeostasis, might offer novel therapeutic avenues to

control autoimmune inflammation and to prevent neurodegeneration in this still incurable disorder.
Acknowledgements
The authors wish to thank Dr. Stephen C. Reingold, New York, for helpful
discussions. Supported by Forschungskomission, Medical Faculty, HHU,
the Deutsche Forschungsgemeinschaft (SFB-Transregio 43), the
Heinrich- und Erna-Schaufler-Stiftung, and KKNMS (German
Competence Network on Multiple Sclerosis).

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