Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a very strong autoimmune component. Its name is a descriptive term and originates from the observation of multifocal lesions/plaques in the CNS. These lesions of variable size usually involve the white matter of the brain (myelinated axons) but can extend to gray matter too (where the neuronal cell bodies are found) According to WHO the global incidence and prevalence are estimated to be 2.5 per 100,000 person-‐years and 30 per 100,000 persons respectively. MS is a very complex disease with tremendous variability both in its presentation (as any brain areas can be affected potentially giving rise to any neurological symptom) and its clinical course. Its aetiology and pathogenesis is not well understood but, as twin studies have shown, genetic factors may account for 25 to 75% and this leads to the hypothesis that environmental triggers may be implicated in the pathogenesis of MS in susceptible individuals carrying certain genes.
This post is based on an essay I wrote for my course in 2012. It explores the differences between myelinated and non-myelinated axons, the consequences of demyelination and possible therapeutic strategies targeting certain potassium channels.
The integrity of multiple
sclerosis (MS) as a single nosological entity is threatened with strong evidence
highlighting its pathophysiological and clinical heterogeneity. The
pathogenesis of MS is not well understood and its classification as an
autoimmune disease has also been questioned (Kornek,
Lassmann 2003, Ludwin 2006, Ludwin, Raine 2008) The recognition of four immunohistologically
distinct patterns in addition to the recognized variable response to immunomodulatory
therapy, indicates the need for therapies directed to either the potentially
variable underlying pathophysiology or the ubiquitously detrimental effects of
demyelination. Despite the fact that many aspects of MS pathophysiology need to
be elucidated, MS can still be defined as “a
chronic inflammatory disease of the central nervous system (CNS)” characterized
by focal demyelination and partial axonal sparing (Kornek,
Lassmann 2003). The
role of ion and especially potassium channels in both axonal failure and T-cell
activation is pivotal and could provide a basis for the treatment of MS and
other neuroinflammatory or demyelinating diseases. Hence, this essay is going
to be focused on the neurophysiology of action potential (AP) conduction and
the potential of potassium channels as therapeutic targets.
The myelinated and unmyelinated axons
The nervous system of
all invertebrates is characteristic in that it employs two distinct types of
axons, unmyelinated and myelinated, which are found in both the
central (CNS) and peripheral (PNS) nervous systems. Whereas unmyelinated axons can
be considered as bare neuronal processes, the evolutionary advanced myelinated
axons (Hartline, Colman 2007) are intimately associated with glia cells,
which provide them with a regularly intermitted insulation sheath that significantly
alters their biophysical properties and ‘segments’ the axon in functionally
distinct units. The structure of myelinated axons is summarized in figure 1.
These structural modifications are furthermore accompanied by a different
repertoire and distribution of voltage operated ion channels with important
implications on AP propagation.
 |
Figure 1. Longitudinal cross section of a myelinated axon.
The myelin sheath is formed by up to 150 concentric lamelae invested by either oligodendrocytes in CNS or Schwann cells in PNS. The ratio between the myelin sheath thickness and axon diameter is fairly constant i.e. 0.6 (Hildebrand, Hahn 1978). The axon is divided in internode, juxtaparanode (JXP), paranode and node regions. Paranodal axoglial junctions (SpJ) attach the myelin sheath to the axon and prevent lateral diffusion of axolemmal proteins. The nodes (of Ranvier) occur at intervals, which are about 100 times the diameter of the axon (Poliak, Peles 2003). [Diagram adapted from Poliak, Peles (2003)]
The distribution of ion
channels in unmyelinated axons is considered to be homogenous, with
voltage-operated Na+ channels (Nav) reaching a density in the order
of 200
channels/μm2 (Pellegrino
et al. 1984). The subtypes expressed vary according to cell
type but Nav1.2 is considered to be the most important in most unmyelinated
(and premyelinated) axons. Similarly Kv1.1-3, Kv3 and Kv7 are all implicated in
K+ conductance in different cells (Black
et al. 2002, Debanne et al. 2011, Boiko et al. 2001).
On the other hand, the expression of ion
channels in myelinated axons is different in each segment (figure 2). The nodal
region is populated predominantly by Nav1.6, which can be as dense as 1000-1200
channels/μm2 whereas the density in internodes
decreases to 25 channels/μm2 (Caldwell
et al. 2000, Waxman, Ritchie 1993).As far as Kv channels are concerned, they are principally
clustered in the juxtaparanodal regions and are of the Kv1.1 and Kv1.2 subtypes(Nashmi et al. 2000).
Figure 2. Immunofluorescence
image revealing the localization of Nav and Kv channels. Nav1 (green fluorescence)
are present at the nodes of Ranvier. Kv1 are localized to the juxtaparanodal
surface of the axons (blue fluorescence). The two sets of channels are “segregated
by membrane diffusion barriers established by contactin and
contactin-associated proteins (caspr, red) associated with paranodal tight
junctions.”[From Rash (2010)]
Biophysical Properties and Action Potential Propagation
The existence of electrochemical gradients and that of relatively selective ion channels whose conductance is voltage dependent and which are embedded in an otherwise impermeable membrane, allowed Hodgkin and Huxley (1952) to represent the membrane as an electric circuit and hence reduce the action potential to an electrical phenomenon driven by ion currents. The most important components are the resistances against Na+ and K+ currents (RNa, RK), which are time and voltage dependent, and the membrane capacitance, CM(figure 3).
However, AP propagation does not only depend on the excitability of the membrane but also on the cable structure of the axon, which is a series of membrane units linked by the conductive properties of the axoplasm and extracellular fluid. This view introduces the parameter of longitudinal resistance, which together with RM determine the longitudinal spread of current, i.e.
Biophysical Properties and Action Potential Propagation
The existence of electrochemical gradients and that of relatively selective ion channels whose conductance is voltage dependent and which are embedded in an otherwise impermeable membrane, allowed Hodgkin and Huxley (1952) to represent the membrane as an electric circuit and hence reduce the action potential to an electrical phenomenon driven by ion currents. The most important components are the resistances against Na+ and K+ currents (RNa, RK), which are time and voltage dependent, and the membrane capacitance, CM(figure 3).
However, AP propagation does not only depend on the excitability of the membrane but also on the cable structure of the axon, which is a series of membrane units linked by the conductive properties of the axoplasm and extracellular fluid. This view introduces the parameter of longitudinal resistance, which together with RM determine the longitudinal spread of current, i.e.
whereas the time it
takes for the voltage to change is directly proportional to CM and RM(Holmes
2010).
As expected, the electric
properties of the unmyelinated axons allow the slow propagation of continuous
Aps (figure 4.A). On the other hand, the
high density of Nav1.6 in the nodes of myelinated axons allow the generation of
stronger currents which are not dissipated in the internodes because the myelin
sheath can lead to an 8000-fold increase of the intermodal RM and similar decrease of CM(Aidley 2001). Therefore, nodal
activation can provide more than 5 times the needed current to depolarize the
following node (Kaji et al. 2000). Hence AP propagation is saltatory and, due to overall low CM
and higher current densities, could be even 10 times faster (figure 4.b).
However, one major
determinant of conduction velocity (vc)
is the axonal diameter (D) and
Rushton (1951) showed that whereas in unmyelinated axons
Vc α SQRT(D)
in myelinated axons,
and therefore predicted that below a critical diameter unmyelinated fibres may conduct faster than myelinated ones; but this critical diameter is different in CNS and PNS because of variations in myelination and minimal nodal space (Ritchie 1982). See figure 5. However, as the critical diameter in CNS (0.2 μm; Swadlow, Waxman 2012) is very close to the minimal axonal diameter (0.1 μm), myelination in the CNS is fundamental. The later value is determined by stochastic models, which predict that spontaneous activation of channels can initiate APs in axons with smaller diameter (Faisal et al. 2005).
In addition, one of the most important aspects of myelination along the tremendous increase in vc, is its impact on metabolic demands. With the use of stochastic/biophysical models, Neishabouri1 and Faisal (2011) calculated that APs in myelinated axons could be 70 times less energy demanding than in unmyelinated axons of the same diameter, but at the expense of wiring density.
Finally, Yamazaki et al. (2007,2010) demonstrated that
depolarization of oligodendrocytes can increase the AP vc of the axons which they supply, revealing the
potential for synchronous modulation of multiple myelinated axons. This means
that myelination does not only offer metabolically cheaper and faster APs but
also the potential for additional systematic modulation. Whether this occurs in vivo however, is unclear.
Action Potentials in demyelinated axons
The other side of the
coin, however, is that demyelination can have detrimental effects on AP
conduction. A decrease in myelin thickness leads to a decrease in membrane
resistance and an increase in capacitance. Consequently, current is dissipated along
the internode and current density reaching the next node is reduced along with vc (Mcdonald
1963). Computer simulations
(Reutskiy et al.
2003, Koles, Rasminsk.M 1972)
predict that when the myelin thickness of a single internode is reduced to less
than 2-3%, conduction fails. Paranodal demyelination may also cause conduction
failure due to increased nodal capacitance (Sumner
et al. 1982).
But altered conduction
is not caused just by changes in the passive properties of the demyelinated
axon. Disruption of molecular organization and alterations in function and
expression of ion channels seem pivotal and some authors even consider MS as a
channelopathy(Ehling
et al. 2011). Nav channels disperse and expression of
Nav1.2 and Nav1.6 increases but some aggregations of Nav1.6 are still evident.
At the same time fast activating juxtaparanodal Kv1.1 and Kv1.2 become exposed
and distributed along the axon and may become coupled to Nav (Arroyo
et al. 2004, Black et al. 2006, Rasband et al. 1998).
The function of
juxtaparanodal Kv in normal mature axons is not clear but they probably stabilize
the membrane potential and prevent aberrant repetitive firing especially during
myelination or even remyelination (Vabnick
et al. 1999). The slow nodal KCNQ2 may have a similar function (Devaux et al.
2004).
However,
in demyelinated axons, it is generally believed that the increased expression
of the now exposed and spread juxtaparanodal channels leads to membrane
hyperpolarization and hence conduction block (Nashmi, Fehlings 2001). It should be noted however that other authors (Ehling et al. 2011) suggest that the extracellular K+ homeostasis is outbalanced, due to an “increased K+ outward flux from axons and a decreased K+ buffering by glia cells, [which] then postpones the K+ reversal potential to more positive values.” This in turn results in progressive membrane depolarization and conduction block due to Nav inactivation. This is a very different mechanism from membrane hyperpolarization related to increased K+ conduction but could potentially apply in some situations.Conduction block is the basis for all negative symptoms of MS and inhibition of Kv offers a great therapeutic potential as discussed later.
A brief digression about the soliton model and lipid channels
It is important to note that in recent years the traditional view on AP propagation and the role of the membrane has been greatly challenged. Heimburg and Jackson (2005,2007) whilst considering thermodynamical and mechanical observations not accounted by the H-H model, proposed that AP propagation could be described in terms of a reversible electromechanical pulse (soliton) that “depend[s] on the presence of cooperative [membrane] phase transitions in the nerve”(figure 7). Evermore, Heimburg in a recent review (2010) showed that biological membranes under physiological conditions can form “lipid channels” whose lifetimes and ion conductances are similar to those of protein channels. It can be appreciated that the application of these novel views has important implications on the understanding of physiology and on the validity of electrophysiological and computer simulation data. Even if they have already elucidated the mechanisms of anesthetics, theirrelevance on demyelination is yet to be shown. Nevertheless, the potential of K+ channels in the treatment of demyelinating conditions is still being considered and will be discussed in the following sections.
Neuronal K+ channels as therapeutic targets
Our understanding of the
role of fast activating potassium channels evolved together with their
recognition as possible therapeutic targets. Bostock et al. (1981) showed that application of the non-specific K+
channel blocker 4-aminopyridine (4-AP) could restore conduction in models of
demyelination by increasing the amplitude and duration, despite increasing their
refractoriness. It was also found that it could reduce temperature dependent
block. Later, it was shown that 4-AP restored conduction by inhibiting exposed Kv1.1
and Kv1.2 channels particularly when present in the nodes (Rasband
et al. 1998).
The fact that 4-AP had
been used clinically for the treatment of other conditions, quickly led to the
first open labeled study by Jones et al.
(1983), n=10, which gave preliminary evidence for some benefits (improvement in
vision or spasticity) along with side effects such as disorientation and painful
dysaesthesias. In 2002 the first Cochrane systematic review(Solari et al. 2002) was published based on 6 RCTs (n=198) out of
74 identified studies, which considered 4-AP or the similar compound 3,4-diaminopyridine
versus placebo. Some significant improvements were noticed in terms of visual
and motor function, and ambulation but none in terms of cognitive function and
fatigue when assessed. Based on four studies, 35% of treated patients felt some
improvement against 5% in placebo group (p < 0.0001). Significant adverse
effects included seizures and confusion (3%). The authors concluded that the
benefits of aminopyridines “may be overestimated” since in most trials the
primary endpoints were not specified and due to the potential for significant
publication bias.
Nevertheless, the work of Goodman
et al. and especially the publication
of a phase III clinical trial(Goodman et al.
2009) led
to the approval of a 4-AP extended release formulation by FDA in 2010(FDA
2010). The
study showed that 35% of the treatment cohort responded with a reversible
increase in walking speed of 25.2%. For details see figure 8. However, it could
be argued that 4-AP is no wonder drug, as it is beneficial for only a minority
of patients (although consistently for the short duration of the study) at the
expense of potential adverse effects and as it is not warranted that
improvements in a 25-feet-walk will be translated in an increased quality of
life. Moreover, long-term effects were not assessed.
Limitations of neuronal Kv blockers
There are two main
reasons why aminopyridines may not be as efficacious for the treatment of MS as
one would expect. First of all, MS is a
heterogeneous disease characterized by significant axonal loss occurring in
both active and chronic lesions in the range of 20 to 90%(Kornek, Lassmann 2003). Of course, axon loss significantly
contributes towards permanent deficits, which cannot be addressed by any
strategy aiming in improving AP conduction.
The second reason is that aminopyridine treatment is limited by its significant
toxicity and it was a surprising finding that at the diluted clinical doses, 4-AP
does not restore conduction in
demyelinated rat axons in vitro and in vivo, but rather enhances
neurotransmitter release and muscle action(Smith
et al. 2000). Wu et
al.(2009) even support that the latter effect is due to high
voltage-activated Ca2+ channel stimulation.
Moreover, Judge and Bever
(2006) argued in a recent review that the epileptogenic effects of
aminopyridines are due to blockade of highly sensitive presynaptic Kv1.4, which
means that more selective agents are needed. This need is also supported by
findings of Bacia et al.(2004) that
pharmacological doses of 4-AP can inhibit remyelination in cuprizon animal
models. Whether this is due to effects on K+ channels or not is not
clear. Nevertheless, deletion of Kir4.1 in mouse models causes severe hypomyelination
underlining the importance of Kv channels(Neusch
et al. 2001). Despite these, the existence of
multiple venom-derived peptides with “exquisite Kv selectivity and potency”
(Judge, Bever Jr. 2006)
may offer the basis for the development of new and more elegant but less toxic analogues.
Furthermore, even if
selective agents are designed that would act only on demyelinated axons, it can
be expected that Kv blockade may induce/exacerbate hyperexcitability states and
ectopic impulses in susceptible fibres(Baker, Bostock 1992) therefore producing positive symptoms such as
dysaesthesias. On the other hand, Coggan et
al.(2010) after using a computational model of a demyelinated axon
concluded that “voltage-gated potassium conductance is not critical” for
hypo/hyperexcitability states and that it is the ratio between Na+(gNA) and leak (voltage-independent
K+; gL) conductance
which is critical; explaining so the low efficacy of 4-AP and the need for high
doses. Hence, they
suggest that modulation
of the gNA/gL ratio is more important; but the validity
and
significance of these
conclusions need to be further investigated.
Kv channels and Immunomodulation
However, the role of Kv is
not limited just to nerve conduction and their implication in T-cell activation
offers new opportunities for intervention. The pivotal role of different T-cell
subtypes in MS has been for long recognized(Severson, Hafler 2010) and the activation and differentiation of naïve
T-cells into “tissue-homing” effector memory cells (TEM; Sallusto et al.
1999) seems
to be an important step in its pathogenesis; as revealed by their high
infiltration in lesions of MS patients or animal models(Beeton et al. 2003, Rus et al. 2005). The activation of T-cells is calcium dependent and is promoted/maintained
by Kv1.3 and the calcium dependent KCa3.1 channel. Moreover, activation induces differential expression of
the channels in different subtypes (figure 9). As a result, chronically
activated TEM show selective responsiveness to Kv1.3 blockade whereas
the other T-cell subtypes can be rescued by increased expression of KCa3.1(Chandy et al. 2004). This means that Kv1.3 blockade could offer
selective targeting of activated TEM involved in MS without general
immunosuppression. Use of a selective Kv1.3 blocker [ShK(L5)] in animal models
resulted in 70%
suppression of TEM and either prevented or significantly reduced the
severity of experimental autoimmune encephalomyelitis, without noticeable
toxicity or compromising acute infection clearance in rats and rhesus monkeys(Beeton et al. 2005, Matheu et al. 2008, Pereira et al.
2007). However,
reactivation of CMV was noticed and it should be further noted that Kv1.3-knock-out mice experience
increased/altered metabolism, indicating that Kv1.3 subserves other functions
too(Xu et al. 2003). The first phase I trial was announced this year(Kineta 2012).
Conclusion
Even though a
comprehensive description of AP generation and propagation in myelinated and
unmyelinated axons was beyond the scope of this essay, it was recognized that both
types of axons rely on the same biophysical principles. The evolution of the myelin sheath as a
radical means to increase AP propagation velocity, reduce metabolic demands and
possibly change neuronal computation, was associated with a novel organization
of ion channels and axo-glial interrelations. The consequences of demyelinating
diseases such as MS on AP conduction can be detrimental but Kv blockers
targeting the juxtaparanodal Kv1.1 and Kv1.2 can restore AP conduction in vitro and ex vivo. The use of the nonselective 4-AP may beneficial for a
minority of patients but is substantially limited by its toxicity and low
potency. Moreover, even there is a need for the development of more selective
and potent neuronal Kv blockers, significant clinical benefits for the
treatment of negative symptoms in MS may not be warranted due to the
significance of axonal loss and perhaps less critical role of Kv conductance. Nonetheless,
the use of novel selective Kv1.3 blockers targeting effector memory T-cells arises
as a promising imunomodulatory therapeutic strategy for the treatment of MS or
other autoimmune diseases, due to the potentially low toxicity and
immunosuppressive effects.
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