Current Pharmaceutical Design - Volume 11, Issue 10, 2005

Spinal cord injury (SCI) is followed by a series of dynamic changes in the injured spinal cord and the environment that influence the extent of structural and functional recovery. All therapeutic interventions work toward one goal: to restore balance in the spinal cord by promoting regenerative pathways and depressing the degenerative factors (Fig. 1). Caution comes from awareness that acute effects are not always sustained enough to lead to long-term restoration of spinal cord function, and that experimental results from animal models do not always translate into clinical success in injured people. Nonetheless, rapid progress has been seen in the past two decades in the research and pharmaceutical intervention required to repair the spinal cord. This Special Issue presents some of the major approaches. In the leading article, Tsai and Tator highlight the various paths toward a cure for SCI. The neuroprotective strategies include the use steroids and other anti-inflammatory agents as well as agents that are anti-ischemic, that antagonize glutamate excitoxicity, that are anti-apopototic, and that enhance axonal function [1]. The regenerative strategies are designed to overcome the inhibitory factors, create a regeneration-inducing environment with implants of synthetic or biological matrices, supplement neurotrophic factors, and transplant cells and tissue. The benefits and shortcomings of these approaches are discussed. This serves as an excellent introduction to the next group of reviews that addresses some of the specific areas. SCI is associated with primary and secondary pathology. The role of inflammation and immune reactions in tissue repair is no doubt crucial. Contrary to the conventional wisdom that inflammation is universally deleterious, accumulating evidence presented by Popovich and others indicates that inflammatory cells and mediators may facilitate endogenous repair processes when applied in adequate concentrations at the appropriate time. In this issue, Jones, McDaniel, and Popovich review the multiple faces and players involved in inflammatory-mediated injury and repair [2]. By contrast, cell elimination, as induced by radiation therapy, has been shown to significantly improve histological and electrophysiological parameters after contusion SCI in the rat [3]. In her review, Kalderon not only provides convincing results but also summarizes the window of opportunity, the principles of radiotherapy, and the involvement of the blood-brain and blood-spinal cord barrier (BBB) in the process. Also related to BBB function with specific emphasis on the transport systems for neurotrophic and inflammatory cytokines, Kastin and Pan stress potential strategies against myelin-associated growth inhibitory factors [4]. These approaches target the inhibitory molecules themselves, their NgR receptor, and intracellular pathways. In parallel, Phinney and Isakova discuss progress in the use of bone marrow - derived mesenchymal stem cells to promote regeneration. The history, derivatization, differentiation, technical expertise, as well as therapeutic effects of these mesenchymal stem cells are described in fine detail [5]. Further, Xiang, Pan, and Kastin [6] discuss some general mechanisms involved in spinal cord repair, serving to contrast and complement the strategies proposed by Tsai and Tator at the beginning of the Issue. This concludes the first half of the Special Issue.

The journey toward a cure for spinal cord injury (SCI) has taken many paths. In this article, we review these paths, and highlight the clinical applications of these experimental repair strategies. Initial strategies involved attempts at neuroprotection with steroids and other anti-inflammatory drugs. Other anti-ischemia treatments, agents to eliminate the damage from excitotoxicity, and anti-apoptotic agents were also tried. Another avenue involved enhancing the function of the remaining uninjured axons by measures to produce remyelination and medications to improve axonal conduction. In the last two decades there has been a major effort to enhance spinal cord axonal regeneration through a variety of techniques including neutralization of neurite inhibition, administration of neurotrophic factors, implantation of synthetic channels, and transplantation of a variety of cell types. Indeed, several of these strategies have been so promising in animals that clinicians have been stimulated to explore their potential human application. We also examine the different experimental models of SCI used to assess repair, and discuss how the injury model impacts on the assessment of axonal regeneration and functional recovery after SCI. The mechanisms of recovery that may be involved after SCI will be analyzed, and their relevance toward finding a cure for human SCI. Unfortunately, the goal of producing significant functional regeneration of the human spinal cord has not yet been achieved despite the many strategies that have been developed. It is our hope that improved understanding of the mechanisms underlying functional recovery will lead to successful therapeutic strategies in humans.

Spinal cord trauma activates the immune system and elicits leukocyte recruitment to the site of injury. This increase in immunological activity contributes to acute lesion expansion over a period of days to weeks following the initial trauma. At the same time, inflammatory cells and mediators facilitate endogenous repair processes such as axonal sprouting and remyelination. Thus, to be effective, therapies that target the immune system must limit the destructive effects of neutrophil, macrophage and lymphocyte activation, while simultaneously preserving their reparative functions.

Following injury, as part of the wound-healing process, cell proliferation occurs mostly to replace damaged cells and to reconstitute the tissue back to normal condition/function. In the spinal cord some of the dividing cells following injury interfere with the repair processes. This interference occurs at the later stages of wound healing (the third week after injury) triggering chronic inflammation and progressive tissue decay that is the characteristic pathology of spinal cord injury. Specific cell elimination within a critical time window after injury can lead to repair in the acutely injured spinal cord. Cell proliferation events can be manipulated/modified by x-irradiation. Clinically, numerous radiation protocols (i.e., radiation therapy) have been developed that specifically eliminate the rapidly dividing cells without causing any noticeable/significant damage to the tissue as a whole. Radiation therapy when applied within the critical time window after injury prevents the onset of chronic inflammation thus leading to repair of structure and function. Various aspects of the development of this cell-elimination strategy for repair in acute spinal cord injury by utilizing radiation therapy are being reviewed. Topics reviewed here: identifying the window of opportunity; and the beneficial repair effects of radiation therapy in a transection injury model and in a model relevant to human injury, the contusion injury model. The possible involvement of cellular components of the blood-spinal cord barrier as the trigger of chronic inflammation and/or target of the radiation therapy is discussed.

Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin associated glycoprotein). The effects of these inhibitors on axonal regeneration can be reduced by administration of specific antagonists, some of which are commercially available for experimental investigation. There are three aspects of therapeutic manipulations: targeting the inhibitory proteins, antagonizing the known receptor, and inhibiting the intracellular signal transduction of these inhibitory molecules. Infusion of an antibody against Nogo improves behavioral deficits and enhances corticospinal tract regeneration in animals after stroke and spinal cord injury (SCI). Similarly, peripheral injection of a mouse monoclonal antibody directed against MAG results in dramatic preferential motor reinnervation in mice after transection of the femoral nerve, indicating that interference with the repellant function of MAG facilitates reinnervation of correct pathways by motor neurons. Further, antagonism of the Nogo receptor by the peptide NEP 1-40 (Nogo extracellular peptide residues 1-40) can promote axonal regeneration in rats after SCI. Blockade of signal transduction also can be effective. The p75 neurotrophin receptor probably represents the signaling part of the receptor complex for neurite growth inhibitors. There is evidence in vitro that the inhibitory actions of MAG and myelin are blocked if neurons are primed with a variety of neurotrophins. Thus, there are several therapeutic approaches to overcome the actions of endogenous neurite growth inhibitors so as to promote CNS regeneration.

Mesenchymal stem cells resident in adult bone marrow are best characterized by their capacity to differentiate into connective tissue cell types such as adipocytes, chondrocytes, osteoblasts and hematopoiesis-supporting stroma. Accordingly, these cells are being evaluated in human clinical trials for efficacy in treating genetic diseases of bone, to speed hematopoietic recovery after bone marrow transplantation and reduce the severity of graft versus host disease. In the past few years MSCs have also been reported to exhibit a broad degree of plasticity commensurate with other adult stem cell populations, including the ability to differentiate in vitro and in vivo into non-mesodermal cell types such as neurons and astrocytes. MSCs have also been reported to promote repair and regeneration of nervous tissue within the central and peripheral nervous system, although the mechanism by which this occurs remains indeterminate. Herein, we review evidence purporting the differentiation of MSCs into neural cell lineages and evaluate the utility of MSCs as cellular vectors for treating neurological disorders and spinal cord injury. Based on our analysis of their transcriptome, we also theorize how the varied functions of MSCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease.

Spine cord injury (SCI) leads to devastating functional loss below the level of injury. Partially explained by the presence of a non-permissive environment, the injured spinal cord does not mount adequate regeneration to reestablish functional connections. Therefore, it is important to identify the cellular and molecular factors and their interactions that affect axonal regeneration within the changed environment. This review will discuss the current understanding of the neuronal and glial factors and the extracellular matrix in the spinal cord that inhibit axonal growth, and it will summarize some major approaches for facilitation of regeneration. The strategies are classified into the following categories: penetration of the blood-brain barrier; modulation of caspase activity to reduce apoptosis; stem cells and tissue implantation; administration of neurotrophic factors, including viral vector-mediated delivery; and modulation of the extracellular matrix. Although recent studies on genomic regulation and apoptosis have identified particularly important molecular targets, more is necessary to achieve long-term regeneration. A combination of the approaches targeting various aspects in the regenerating environment would be more effective than a single strategy. Overall, insights arising from the experimental results may eventually lead to better therapeutic intervention so as to lessen the functional disability and enhance the quality of life in patients with SCI.

The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1β, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the “Expanded Self-Non-Self” and the “Danger” theories of immune activation).

Hypertension and proteinuria are risk factors for renal disease progression. There is clear evidence that pharmacological blockade of the RAS with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows down the progression of renal disease in diabetic and non diabetic nephropathies, a beneficial effect not related to blood pressure control. However, not all patients respond similarly to these treatments. Some patients exhibit a significant beneficial response while others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI, which are unable to block completely the formation of AII, some generation of AII is produced via other non ACE pathways. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove to be useful. ARB produces a complete blockade of the RAS and stimulates the vasodilating and non-proliferative actions of AII via the AT-2 receptor. Furthermore, ACE inhibitors but not ARB; inhibit the metabolism of kinins, which increases the level of bradykinin, a potent vasodilator. Recently, several authors have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone in spite of a similar effect on blood pressure. A recent study also has demonstrated that this more marked antiproteinuric effect is associated with a less progression of renal disease in primary, non diabetic nephropathies. Furthermore, at least two studies have shown that, treatment with ARB postpones end-stage renal disease and reduces the rate of decline in renal function in patients with type 2 diabetes and nephropathy, but until now, there is not any clear evidence of a superior beneficial effect of dual blockade versus maximal recommended dose of ARB regarding renal progression in type 2 diabetic nephropathy, which is the most frequent cause of end stage renal disease. Long-term clinical trials are needed and encouraged to further establish the significant role of dual blockade in renal protection particularly in diabetic nephropathy.

Phospholipase A2 (PLA2)-catalyzed hydrolysis of membrane phospholipids results in the stoichiometric production of a free fatty acid, most importantly arachidonic acid, and a lysophospholipid. Both of these phospholipid metabolites serve as precursors for inflammatory mediators such as eicosanoids or platelet-activating factor (PAF). Since it was initially discovered that non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis, a vast amount of drug development has been performed to selectively inhibit the production of the inflammatory metabolites of arachidonic acid while preserving their protective role. This research has culminated in the development of selective cyclooxygenase-2 (COX-2) inhibitors that act on the inducible, inflammatory COX enzyme, but do not affect the constitutive prostaglandin synthesis in cells that is mediated via COX-1. The development of PLA2 inhibitors as potential anti-inflammatory agents has also been extensively pursued since the release of arachidonic acid from membrane phospholipids by PLA2 is one of the rate-limiting factors for eicosanoid production. In addition to the production of eicosanoids, PLA2-catalyzed membrane phospholipid hydrolysis is also the initiating step in the generation of PAF, a potent inflammatory agent. Thus, inhibition of PLA2 activity should, in theory, be a more effective anti-inflammatory approach. However, developing an inhibitor that would be selective for the production of inflammatory metabolites and not inhibit the beneficial properties of PLA2 has so far proved to be elusive. This review will focus on agents used currently to inhibit PLA2 activity and will explore their possible therapeutic use.

Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B1 receptor antagonists as antiepileptic agents, and for B2 receptor antagonists (and/or B1 agonists) in the treatment of stroke. Functional B1 receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.

The diabetic pathology induces reproductive abnormalities that enhance spontaneous abortion, congenital anomalies and neonatal morbidity/mortality rates, abnormalities that begin with an altered female gamete. In this review we focus on the damage induced by maternal hyperglycemia during ovulation, early embryo development, implantation and embryo organogenesis in experimental rat models of diabetes. Hyperglycemia can induce cellular damage by enhancing the production of reactive oxygen species (ROS), by altering arachidonic acid metabolism (thus leading to altered production of prostaglandins such us PGE2 and 15deoxydelta12- 14PGJ2, involved in signalling and developmental pathways), and by enhancing the generation of nitric oxide (a mediator of many cell functions including apoptotic cell death). In maternal diabetes all of these abnormalities are present from the oocyte stage, during embryonic implantation, and during embryo organogenesis. The involvement of these alterations in embryo loss and congenital malformations due to diabetes and the cross-talk among these metabolic pathways are discussed. As maternal hyperglycemia induces damage from the oocyte stage and throughout embryo development the data reviewed suggests the need of strict preconceptional metabolic control. The importance of the molecules involved in hyperglycemia-induced damage as future pharmacological targets for intervention is discussed.

Opioids are commonly used analgesics in clinical practice. Three opioid receptors (μ, δ and κ) that mediate opioid effects have been identified by molecular cloning. Each type of opioid receptors consists of subtypes of receptors as suggested by pharmacological studies. Although μ opioid receptors are the major receptor to mediate the analgesic effects of opioids, δ and κ receptors are also important in anti-nociception (for example, δ and κ receptors can mediate spinal analgesia). Recently, the cytoprotective effects of opioids have been recognized. The presence of opioids during harmful events such as ischemia reduces cell injury in multiple organs including heart and brain. These effects appear to be mediated by δ receptors in most studies. A new form of cytoprotection in which a prior exposure to opioids renders protection against cell ischemia (opioid preconditioning) has been identified. In the heart, this opioid preconditioning-induced protection has been well documented by multiple studies and may be mediated by δ' receptors, Gi/o proteins, protein kinase C, ATPsensitive potassium channels and free radicals. Our initial study suggests that opioid preconditioning also induces neuroprotection. This neuroprotection involves δ1 receptors, mitochondrial ATP-sensitive potassium channels and free radical production. In this review, we will briefly describe the analgesic effects of opioids. We will focus our discussion on opioid preconditioning-induced protection and its mechanisms. Opioids and agents that specifically work on the signaling molecules for opioid preconditioning-induced protection may prove to be useful in inducing protection against ischemia in clinical practice.