Current Pharmaceutical Design - Volume 13, Issue 24, 2007

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.

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.

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.

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 condhroitinases [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 Rio 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.

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.

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.

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 oligodendrocyte- 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.

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.

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.

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.

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.