Current Drug Targets - Inflammation & Allergy - Volume 1, Issue 2, 2002

Synthetic glucocorticoids are among the most effective anti-inflammatory drugs available. The activity of this drug class is mediated by the glucocorticoid receptor, a nuclear steroid receptor whose endogenous ligand is the adrenal hormone cortisol. Chronic glucocorticoid treatment is accompanied by serious side-effects, reflecting the symptoms of cortisol excess seen in Cushing's syndrome patients. During the past 50 years advances to this drug class have been limited largely to reducing systemic exposure through inhaled delivery and increasing glucocorticoid receptor selectivity. However, a safer oral drug for the treatment of conditions such as rheumatoid arthritis, inflammatory bowel disease, and transplant rejection, still represents a major unmet medical need. Over the past 20 years, mechanisms of glucocorticoid receptor action have been elucidated. Before the gene was even cloned, the glucocorticoid receptor was known to be a ligand-induced DNA binding protein. Identification of hormone response elements in the promoters of metabolic target genes in the liver provided a model for its broad activities. It was since revealed that much of its anti-inflammatory activity is not DNAdependent after all, but instead is the result of a complex set of protein-protein interactions which lead to transcriptional inhibition of pro-inflammatory targets. Thus, a glucocorticoid receptor ligand that dissociates the DNA binding and protein interaction mediated activities is expected to show improved safety. This review will focus on the scientific advances, which impact the development of this hypothesis and will present a survey of current preclinical drug candidates employing this strategy.

NF-κB is a transcription factor governing the expression of genes involved in the immune response, embryo or cell lineage development, cell apoptosis, cell cycle progression, inflammation, and oncogenesis. During the past few years, considerable attention has been paid to the upstream signaling pathways that lead to the activation of NF-κB. Many of these signaling molecules can serve as potential pharmaceutical targets for the specific inhibition of NF-κB activation leading to interruption of disease processes. How these molecules interact with each other is however, still a debatable issue. Since many of the signal molecules in this pathway relay more than one of the upstream signals to downstream targets, it has been suggested that the transmission of signals involves a network, rather than a linear sequence in the activation of NF-κB. Thus, the detailed elucidation of the upstream signaling molecules involved with NF-κB activation will be important to the development of pharmaceutical inhibitors that specifically inhibit the activation of NF-κB. Such inhibitors would be predicted to have potent anti-inflammatory and / or anti-carcinogenic effects.

Experimentally and clinically, stroke is followed by both acute and prolonged inflammatory responses characterized by the production of inflammatory cytokines and leukocyte infiltration into the brain. A debate on whether inflammation after stroke is neurotoxic or participates in brain repair remains unresolved. However, the need to pharmacologically control inflammatory amplification has been commonly acknowledged. The principal challenge of devising successful anti-inflammatory strategies for stroke is to understand molecular and temporal interplay of inflammatory and cell-death-inducing processes triggered by cerebral ischemia in both parenchymal and vascular brain cells.This article will review a number of experimental and clinically tested approaches to reduce brain inflammation and damage after stroke (e.g., anti-neutrophil, anti-ICAM-1, anti-cytokine strategies) and will suggest potential pathways where novel therapeutic targets may emerge, including transcriptional regulators of inflammatory gene expression (e.g., NF-κB, proteasome) and signaling pathways (e.g., ICE-cascade, MAPK / MKK / ERK cascade) linked to both inflammation and neuronal cell death. Finally, we will discuss applications of functional genomics technologies in the discovery of stroke diagnostics and therapies.

Mast cells play a central role in allergic reactions and inflammation. Successful anti-allergic therapies have typically targeted mast cell mediators, particularly histamine. Antihistaminic compounds interact with the various histamine receptors found on many cells, whereas other compounds such as disodium cromoglycate, are referred to as mast cell stabilizers, as they inhibit degranulation. Some of the most successful compounds developed recently are dual-action, in that they have both anti-histaminic and mast cell stabilizing activities. Recent trends in pharmaceutical intervention, however, have been focused on the secondary effects of mast cell mediators on epithelial cell adhesion molecule expression and mediator release in the process of allergic inflammation. Since, the ocular mucosa is highly exposed to environmental allergens it is commonly involved in allergic reactions and, as such, has been a useful and accessible model in which to test new therapies in vivo. These ocular allergen provocation studies permit analysis of ocular surface cells and evaluation of tear film mediators. Furthermore, techniques to purify conjunctival mast cells have facilitated the study of the effects of mast cell stabilizing compounds on other mast cell mediators, such as cytokines, and the direct effects of mast cell mediators on epithelial cells in vitro. This review will discuss current understanding of how anti-histamines and mast cell stabilizers work, particularly in the context of molecular mechanisms of ocular allergic inflammation.

The innate immune system recognizes “non-self” by employing a set of germline-encoded receptors called Toll-like receptors (TLRs), originally characterized in Drosophila. TLRs are involved in the recognition of various microbial-derived molecules, including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN), as well as unmethylated bacterial DNA. The TLR-mediated intracellular signaling pathways converge to activate nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinases (JNKs), which induce the transcription of a series of cytokine / chemokine genes that are involved in the initiation or regulation of the inflammatory response. It is now known that, like other peripheral organs, the central nervous system (CNS) is also under constitutive immune surveillance by CNS-resident glial cells (microglia and astrocytes) and CNSinfiltrating immune cells. The recent progress in our understanding of TLR functions in the innate immune response sheds new light on how inflammatory immune responses are initiated within the CNS. In this review, we discuss recent studies on TLRs and their ligands, signal transduction pathways activated by TLRs, and the mechanisms through which these various activation events occur. Finally, we discuss how TLRs might play similar important roles in CNS inflammation.

Knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and in vascular dementia (VAD) remains scarce. Recently, we have demonstrated the presence of inflammatory components, such as cytokines, in the CSF of demented patients. Although the initial events triggering the neurodegenerative processes in AD versus VAD may be different and thus lead to different neuropathological outcome, they may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the CNS may in turn, act in a similar manner in both diseases, amplifying certain pathological changes such as amyloidogenesis and amyloid accumulation in the blood vessels, white matter lesions and angiogenesis. This hypothesis is supported by clinical studies demonstrating the presence of white matter infarcts and cerebrovascular pathology in patients with AD as well as the presence of senile plaques in patients with VAD. This review will focus on the production of pro-inflammatory and anti-inflammatory cytokines in dementia, and their putative role for glia cell activation, amyloidogenesis, vascular changes, white matter damage and neurodegeneration.

A range of low molecular weight chemicals have been developed to antagonise the eotaxin receptor, cysteine-cysteine chemokine receptor-3 (CCR3), with the aim of selectively inhibiting eosinophil recruitment into tissue sites. However, the results of recent clinical trials with monoclonal antibodies directed against interleukin-5 (IL-5) question the role of eosinophils in mediating the symptoms of asthma and allergic disease. For this reason, the plans for clinical development of certain CCR3 antagonists have been halted. However, eotaxin 1-3 and a variety of other chemokines interact with CCR3 and this receptor is expressed not only on eosinophils but also on basophils, mast cell subpopulations, activated Th2 cells, macrophages, and airway epithelial cells. Hence, CCR3 is closely associated with asthma and allergy and blockade of this receptor may have pronounced beneficial effects in these diseases. We consider the chemical structures of CCR3 antagonist molecules from a range of pharmaceutical companies, and present an early clinical development plan for a hypothetical CCR3 antagonist. CCR3 antagonists are likely to be safe and effective therapies for allergic diseases, and their clinical pharmacology can readily be defined within phase I / II studies in patients with allergy and asthma.