Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 13, Number 24, 2007
Contents
Pharmacological Regulators of Intracellular Calcium
Release Channels Pp. 2428-2442
D.J. West and A.J. Williams
[Abstract]
Modulation of Ion Channels in Pulmonary Arterial Hypertension
Pp. 2443-2455
C. Guibert, R. Marthan and J.-P. Savineau
[Abstract]
Involvement of Membrane Channels in Autoimmune Disorders
Pp. 2456-2468
Z. Varga, P. Hajdu, G. Panyi, R. Gáspár
and Z. Krasznai
[Abstract]
Interference of Signalling Cascades of Axon Growth
Inhibitory Molecules as Therapeutic Targets of CNS Lesions
Executive Editor: D. Bagnard
Editorial Pp. 2469
Targeting the Nogo-A Signalling Pathway to Promote
Recovery Following Acute CNS Injury Pp. 2470-2484
A.R. Walmsley and A. K. Mir
[Abstract]
Overcoming Chondroitin Sulphate Proteoglycan
Inhibition of Axon Growth in the Injured Brain: Lessons from
Chondroitinase ABC Pp. 2485-2492
J.A. Del Río and E. Soriano
[Abstract]
Rho-ROCK Inhibitors as Emerging Strategies to
Promote Nerve Regeneration Pp. 2493-2499
T. Kubo, K. Hata, A. Yamaguchi and T. Yamashita
[Abstract]
DNA Vaccine and the CNS Axonal Regeneration
Pp. 2500-2506
D.-y. Nie, G. Xu, S. Ahmed and Z.-c. Xiao
[Abstract]
Eph/ephrin Signaling as A Potential Therapeutic Target
After Central Nervous System Injury Pp. 2507-2518
J. Du, C. Fu and D.W. Sretavan
[Abstract]
Using Nanotechnology to Design Potential Therapies
for CNS Regeneration Pp. 2519-2528
R.G. Ellis-Behnke, L.A. Teather, G.E. Schneider and K.-F.
So
[Abstract]
Physiological Roles of Neurite Outgrowth Inhibitors
at Myelinated Axons in the Central Nervous System–Implications
for the Therapeutic Neutralization of Neurite Outgrowth Inhibitors
Pp. 2529-2537
Q.-H. Ma, W.-L. Yang, D.-Y. Nie, G.S. Dawe and Z.-C. Xiao
[Abstract]
Abstracts
[Back to top]
Pharmacological Regulators of Intracellular Calcium
Release Channels
D.J. West and A.J. Williams
Intracellular Ca2+ release
channels, such as inositol 1,4,5-trisphosphate receptors (IP3Rs)
and ryanodine receptors (RyRs), facilitate the release of
Ca2+ from intracellular storage
organelles in response to extracellular and intracellular
stimuli. Consequently, these large, tetrameric proteins play
a central role in Ca2+ signalling
and Ca2+ homeostasis in virtually
all cells. Recent data suggests that intracellular Ca2+
release channels may also have an important pathophysiological
function in certain disease states, including cardiac arrhythmias
and heart failure. As a result, there has been much interest
in the identification and characterization of novel, selective
regulators of these channels. In this article, we review the
wide array of pharmacological agents that interact directly
with intracellular Ca2+ release
channels and describe the mechanisms underlying their ability
to modify channel function.
[Back to top]
Modulation of Ion Channels in Pulmonary Arterial Hypertension
C. Guibert, R. Marthan and J.-P. Savineau
Pulmonary arterial hypertension (PAH) is a disease characterized
by a progressive increase in pulmonary arterial pressure leading
to right ventricular hypertrophy, right heart failure and
ultimately to death. PAH is a disease of small pulmonary arteries
inducing vascular narrowing leading to a progressive increase
in pulmonary vascular resistance. The therapeutic means that
improve PAH are still very limited and are too often restricted
to heart/lungs transplantation. Numerous forms of pulmonary
hypertension exist. Although it is still unclear as to all
types of PAH share a common pathogenesis, it is generally
admitted that pulmonary vasoconstriction and remodelling of
the arterial wall are key events. In this review, we discuss
pulmonary artery smooth muscle cells (PASMC) ion channels
implication in both phenomena and we examine whether variations
in expression and/or the activity of these channels can contribute
to the development of PAH with special attention to K+,
Cl- and voltage- and non
voltage-activated Ca2+ channels.
For each family of ion channels, we describe their implication
in the control of both membrane potential and resting cytosolic
calcium concentration which are key parameters of PASMC in
PAH. We also provide evidence for an implication of these
channels in not only vasoconstriction but also proliferation
and/or decreased apoptosis of PASMC, phenomena which contribute
to remodelling of pulmonary arterial wall. In this respect,
PAH may be considered as form of vascular “channelopathy”.
Finally, we present examples of some substances acting on
ion channels and thus potentially constituting innovative
therapeutic approaches of PAH.
[Back to top]
Involvement of Membrane Channels in Autoimmune Disorders
Z. Varga, P. Hajdu, G. Panyi, R. Gáspár
and Z. Krasznai
Ion channels are ubiquitous transmembrane proteins that
are involved in a wide variety of cellular functions by selectively
controlling the passage of ions across the plasma membrane.
Among these functions many immune processes, including those
in autoimmune reactions, also rely on the operation of ion
channels, but the roles of ion channels can be very diverse.
Here the participation of ion channels in three different
roles in autoimmune processes is discussed: 1. ion channels
in effector immune cells attacking other tissues causing autoimmune
diseases, such as multiple sclerosis; 2. ion channels as direct
targets of the immune system whereby loss of channel function
leads to disease, as in myasthenia gravis; 3. ion channels
whose function is modulated in the target cells by an apoptotic
signal transduction cascade, such as the Fas/Fas ligand pathway.
The numerous tasks that ion channels perform in autoimmune
disorders and the wealth of information that has been gathered
about them in recent years together provide a good basis for
the design and production of drugs that may be effectively
used in the therapy of these diseases.
[Back to top]
Editorial: Interference of Signalling
Cascades of Axon Growth Inhibitory Molecules as Therapeutic
Targets of CNS Lesions
While thought to be irremediable for a long time, nervous
system lesions are may be close to be treatable. This hope
comes from the fantastic progress in identifying the molecular
nature of neurite growth inhibitory factors accumulated in
the lesion sites and contributing to the lack of nerve regeneration.
A wide range of secreted or membrane bound factors have been
shown to trigger growth inhibitory pathways. In parallel to
the elucidation of the molecular mechanisms involved, multiple
approaches devoted to antagonize inhibitory factors have been
designed worldwide. In this special issue we decided to present
current advance of some of the famous strategies such as the
anti-Nogo strategy [1] or the use of condhroïtinases
[2] together with related developments such as the interference
of the Rho/ROCK pathway [3] or the application of the new
concept of DNA vaccine to growth inhibitory factors [4]. Guidance
molecules which normally contribute to brain wiring during
development are now entering the dance of the factors impeding
nerve regeneration. This potential reservoir of new therapeutic
targets is discussed here for the eph/ephrins family [5].
Thus, there is no doubt that our knowledge of growth inhibitory
factors has never been so good to tempt therapeutic interventions
but what about the in vivo situation? Do we have appropriate
technological tools to reach the lesion site and inactivate
the factors in the right place? As presented in the review
by Ellis-Behnke and colleagues [6], the use of nanotechnology
may have an outstanding impact on our capacity to interfere
with inhibitory growth factors. Hence, we also included a
review by the group of Z.C. Xiao [7] reminding that these
factors are not solely expressed in case of lesion but also
have physiological roles, often not fully understood. As discussed
in this paper, a particular effort must be maintained to better
understand the complex biological functions of all of these
molecules. This should be at some point considered as an absolute
prerequisite to ensure the design of therapeutic without high
risk of severe adverse effects.
References
[1] Walmsley AR, Mir AK. Targeting the Nogo-A Signalling Pathway
to Promote Recovery Following Acute CNS Injury. Curr Pharm
Des 2007; 13(24): 2470-2484.
[2] Del Río JA, Soriano E. Overcoming Chondroitin Sulphate
Proteoglycan Inhibition of Axon Growth in the Injured Brain:
Lessons from Chondroitinase ABC. Curr Pharm Des 2007; 13(24):
2485-2492.
[3] Kubo T, Hata K, Yamaguchi A, Yamashita T. Rho-ROCK Inhibitors
as Emerging Strategies to Promote Nerve Regeneration. Curr
Pharm Des 2007; 13(24): 2493-2499.
[4] Nie D-y, Xu G, Ahmed S, Xiao Z-c. DNA Vaccine and the
CNS Axonal Regeneration. Curr Pharm Des 2007; 13(24): 2500-2506.
[5] Du J, Fu C, Sretavan DW. Eph/ephrin Signaling as A Potential
Therapeutic Target After Central Nervous System Injury. Curr
Pharm Des 2007; 13(24): 2507-2518.
[6] Ellis-Behnke RG, Teather LA, Schneider GE, So K-F.Using
Nanotechnology to Design Potential Therapies for CNS Regeneration.
Curr Pharm Des 2007; 13(24): 2519-2528.
[7] Ma Q-H, Yang W-L, Nie D-Y, Dawe GS, Xiao Z-C. Physiological
Roles of Neurite Outgrowth Inhibitors at Myelinated Axons
in the Central Nervous System–Implications for the Therapeutic
Neutralization of Neurite Outgrowth Inhibitors. Curr Pharm
Des 2007; 13(24): 2529-2537.
Dominique Bagnard
INSERM U575
Physiopathologie du Système Nerveux
Centre de Neurochimie
5 rue blaise Pascal
67084 Strasbourg
France
E-mail-Dominique.Bagnard@inserm.u-strasbg.fr
[Back to top]
Targeting the Nogo-A Signalling Pathway to Promote
Recovery Following Acute CNS Injury
A.R. Walmsley and A. K. Mir
Functional recovery following acute CNS injury in humans,
such as spinal cord injury and stroke, is exceptionally limited,
leaving the affected individual with life-long neurological
deficits such as loss of limb movement and sensation leading
to a compromised quality of life. As yet, there is no effective
treatment on the market for such injuries. This lack of functional
recovery can at least in part be attributed to the restriction
of axonal regeneration and neuroplasticity by several CNS
myelin proteins that have been shown to be potent inhibitors
of neurite outgrowth in vitro, namely myelin-associated
glycoprotein (MAG), Nogo-A and oligodendrocyte myelin glycoprotein
(OMgp). Nogo-A contains multiple neurite outgrowth inhibitory
domains exposed on the surface of myelinating oligodendrocytes
located within its amino-terminal region (amino-Nogo-A) and
C-terminal region (Nogo-66). Although structurally dissimilar;
Nogo-66, MAG and OMgp exert their inhibitory effects by binding
the GPI-linked neuronal Nogo-66 receptor (NgR) that transduces
the inhibitory signal to the cell interior via transmembrane
co-receptors LINGO-1 and p75NTR
or TROY. Although the receptor(s) for amino-Nogo-A are unknown,
amino-Nogo-A and NgR ligands mutually activate the small GTPase
RhoA. Consistent with their neurite outgrowth inhibitory function,
approaches counter-acting Nogo-A using function-blocking antibodies,
NgR using peptide antagonists and receptor bodies or RhoA
using deactivating enzymes have been shown to significantly
enhance axonal regeneration and neuroplasticity leading to
improved functional recovery in animal models of acute CNS
injury. These in vivo findings thus provide
a sound basis for the development of an effective treatment
for acute CNS injuries in humans.
[Back to top]
Overcoming Chondroitin Sulphate Proteoglycan
Inhibition of Axon Growth in the Injured Brain: Lessons from
Chondroitinase ABC
J.A. Del Río and E. Soriano
The presence of numerous axon-inhibitory molecules limits
the capacity of injured neurons in the adult mammalian central
nervous system (CNS) to regenerate damaged axons. Among others,
chondroitin sulphate proteoglycans (CSPGs) enriched in glycosaminoglycan
(GAG) chains, acting intracellularly via Rho GTPase
activation and cytoskeletal modification, prevent axon re-growth
after injury. However, axon regeneration can be induced by
modulating the extrinsic environment or the intrinsic neural
response to axon extension. Among other strategies, the use
of chondroitinase ABC (ChABC) to degrade GAGs and decrease
CSPG-associated inhibition has been analyzed. Recent reports
have extended the use of this enzyme, in combination with
cell transplantation or pharmacological treatment. The steady
advances made in these combinations offer promising perspectives
for the development of new therapies to repair the injured
nervous system.
[Back to top]
Rho-ROCK Inhibitors as Emerging Strategies to
Promote Nerve Regeneration
T. Kubo, K. Hata, A. Yamaguchi and T. Yamashita
Several myelin-associated proteins in the central nervous
system (CNS) have been identified as inhibitors of axonal
regeneration following the injury of the adult vertebrate
CNS. Among these inhibitors, myelin-associated glycoprotein
(MAG), Nogo, and oli-godendrocyte-myelin glycoprotein (OMgp)
are well characterized. Recently, the repulsive guidance molecule
(RGM) was included as a potent myelin-derived neurite outgrowth
inhibitor in vitro and in vivo. The discovery
of the receptors and downstream signals of these inhibitors
enabled further understanding of the mechanism underlying
the failure of axonal regeneration. The activation of RhoA
and its effector Rho kinases (ROCK) after the ligation of
these inhibitors to the corresponding receptors has been shown
to be a key element for axonal growth inhibition. Blockade
of the Rho-ROCK pathway reverses the inhibitory effects of
these inhibitors in vitro and promotes axonal
regeneration in vivo. Therefore, the Rho-ROCK inhibitors
have a therapeutic potential against injuries to the human
CNS, such as spinal cord injuries.
[Back to top]
DNA Vaccine and the CNS Axonal Regeneration
D.-y. Nie, G. Xu, S. Ahmed and Z.-c. Xiao
Vaccines have been considered in treating many CNS degenerative
disorders, including Alzheimer’s disease (AD), Parkinson’s
disease (PD), Huntington’s disease (HD), epilepsy, multiple
sclerosis (MS), spinal cord injury (SCI), and stroke. DNA
vaccines have emerged as novel therapeutic agents because
of the simplicity of their generation and application. Myelin
components such as NOGO, MAG and OMGP are known to trigger
demyelinating autoimmunity and to prevent axonal regeneration.
For these reasons DNA vaccines encoding NOGO, MAG and OMGP,
and fragments thereof, make them suitable vehicles for treatment
of SCIs and MS. We need to obtain a deeper understanding of
the immunologic mechanisms underlying the neuroprotective
immunity to optimize the design of DNA vaccines for their
use in clinical setting. In this review, we discuss recent
findings suggesting that DNA vaccines hold a promising future
for the treatment of axonal degeneration and demyelination.
[Back to top]
Eph/ephrin Signaling as A Potential Therapeutic Target
After Central Nervous System Injury
J. Du, C. Fu and D.W. Sretavan
Recent work indicates that the expression of Eph and
ephrin proteins is upregulated after injury in the central
nervous system (CNS). Although to date, much of the interest
in these protein families in the nervous system has been on
their roles during development, their presence in the adult
CNS at multiple time points after injury suggest that they
play significant roles in key aspects of the nervous system’s
response to damage. Several fundamental features of Eph and
ephrin biology, such as bidirectional signaling, promiscuity
of ligand-receptor binding, and potential cis regulation
of function, present challenges for the formulation of rational
and effective Eph/ephrin based strategies for CNS axon regeneration.
However, recent work that have identified specific functions
for individual Ephs and ephrins in injury-induced phenomena
such as axon sprouting, cellular remodeling, and scar formation
has begun to tease apart their contributions and may provide
a number of potential entry points for beneficial therapeutic
intervention.
[Back to top]
Using Nanotechnology to Design Potential Therapies
for CNS Regeneration
R.G. Ellis-Behnke, L.A. Teather, G.E. Schneider and K.-F.
So
The nanodelivery of therapeutics into the brain
will require a step-change in thinking; overcoming the blood
brain barrier is one of the major challenges to any neural
therapy. The promise of nanotechnology is that the selective
delivery of therapeutics can be delivered through to the brain
without causing secondary damage. There are several formidable
barriers that must be overcome in order to achieve axonal
regeneration after injury in the CNS. The development of new
biological materials, in particular biologically compatible
scaffolds that can serve as permissive substrates for cell
growth, differentiation and biological function is a key area
for advancing medical technology. This review focuses on four
areas: First, the barriers of delivering therapies to the
central nervous system and how nanotechnology can potentially
solve them; second, current research in neuro nanomedicine
featuring brain repair, brain imaging, nanomachines, protein
misfolding diseases, nanosurgery, implanted devices and nanotechnologies
for crossing the blood brain barrier; third, health and safety
issues and fourth, the future of neuro nanomedicine as it
relates to the pharmaceutical industry.
[Back to top]
Physiological Roles of Neurite Outgrowth Inhibitors
at Myelinated Axons in the Central Nervous System–Implications
for the Therapeutic Neutralization of Neurite Outgrowth Inhibitors
Q.-H. Ma, W.-L. Yang, D.-Y. Nie, G.S. Dawe and Z.-C. Xiao
It has long been recognized that the central nervous system
(CNS) exhibits only limited capacity for axonal regeneration
following injury. It has been proposed that myelin-associated
inhibitory molecules are responsible for the nonpermissive
nature of the CNS environment to axonal regeneration. Experimental
strategies to enhance regeneration by neutralizing these inhibitory
molecules are rapidly advancing toward clinical application.
It is therefore important that the physiological distribution
and functions of these supposed inhibitory molecules should
be understood. In this review, we examine the distribution
of these inhibitors of neurite outgrowth in relation to the
longitudinal polarization of the myelinated axon into the
node of Ranvier and associated domains and explore their potential
domain specific physiological functions. Potential implications
for the therapeutic strategy of neutralizing these inhibitory
molecules to promote neural repair are discussed.
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