RAGE in inflammation: a new therapeutic target?

High-molecular group box 1-protein, S100/calgranulins, advanced glycation end products (AGEs), amyloid-beta peptides and the family of beta-sheet fibrils contribute to a number of inflammatory conditions by promoting cellular dysfunction and breaking immune tolerance. The receptor of AGE (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules that acts as a pattern recognition receptor. Besides binding ligands actively participating in inflammation and immune responses, RAGE serves as an endothelial adhesion receptor for leukocyte integrins and promotes leukocyte recruitment and extravasation of infiltrating cells. Engagement of RAGE subsequently converts transient cellular stimulation into sustained cellular dysfunction driven by long-term activation of the proinflammatory nuclear factor-kappaB. Deletion of RAGE and pharmacological interventions targeting interruption of RAGE-ligand interaction suppresses inflammation and dampens tissue damage in experimental models of inflammatory disorders, thus delineating RAGE as a potential therapeutic target in inflammation.     

Cellular FLICE-inhibitory protein: an attractive therapeutic target?

Cellular FLIP (c-FLIP), also known as FLICE-inhibitory protein, has been identified as an inhibitor of apoptosis triggered by engagement of death receptors (DRs) such as Fas or TRAIL (TNF-related apoptosis-inducing ligand). cFLIP is recruited to DR signalling complexes, where it prevents caspase activation. Animal models have indicated that c-FLIP plays an important role in T cell proliferation and heart development. Abnormal c-FLIP expression has been identified in various diseases such as multiple sclerosis (MS), Alzheimer’s disease (AD), diabetes mellitus, rheumatoid arthritis (RA) and various cancers. This review focuses on recent insights into c-FLIP dysregulation associated with human diseases and addresses the possibilities of using c-FLIP as a therapeutic target.     

Cellular FLICE-inhibitory protein: an attractive therapeutic target?

Cellular FLIP (c-FLIP), also known as FLICE-inhibitory protein, has been identified as an inhibitor of apoptosis triggered by engagement of death receptors (DRs) such as Fas or TRAIL (TNF-related apoptosis-inducing ligand). cFLIP is recruited to DR signalling complexes, where it prevents caspase activation. Animal models have indicated that c-FLIP plays an important role in T cell proliferation and heart development. Abnormal c-FLIP expression has been identified in various diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), diabetes mellitus, rheumatoid arthritis (RA) and various cancers. This review focuses on recent insights into c-FLIP dysregulation associated with human diseases and addresses the possibilities of using c-FLIP as a therapeutic target.     

Imidazoline I2 receptors: target for new analgesics?

Pain remains a major clinical challenge because there are no effective analgesics for some pain conditions and the mainstay analgesics for severe pain, opioids, have serious unwanted effects. There is a dire need for novel analgesics in the clinic. Imidazoline receptors are a family of three receptors (I(1), I(2) and I(3)) that all can recognize compounds with an imidazoline structure. Accumulating evidence suggests that I(2) receptors are involved in pain modulation. Ligands acting at I(2) receptors are effective for tonic inflammatory and neuropathic pain but are much less effective for acute phasic pain. When studied in combination, I(2) receptor ligands enhance the analgesic effects of opioids in both acute phasic and chronic tonic pain. During chronic use, patients can develop tolerance to and dependence on opioids. Imidazoline I(2) receptor ligands can attenuate the development of tolerance to opioid analgesia and inhibit drug withdrawal or antagonist precipitation induced abstinence syndrome in animals. Taken together, drugs acting on I(2) receptors may be useful as a monotherapy or combined with opioids as an adjuvant for treating pain. Future studies should focus on understanding the relative efficacy of I(2) receptor ligands and developing new compounds to fill the gap in intrinsic efficacy continuum of I(2) receptors.     

Anti-inflammatory neuropeptide receptors: new therapeutic targets for immune disorders?

The loss of immune tolerance results in the breakdown of immune homeostasis and the appearance of exacerbated inflammatory conditions. Some anti-inflammatory neuropeptides have recently emerged as endogenous factors participating in the maintenance of immune tolerance. The effects of these neuropeptides in self-tolerance primarily depend on the activation of cAMP-protein kinase A signaling and the regulation of various transduction pathways involved in the expression of many immune factors. Understanding of the structure-function relationship of anti-inflammatory neuropeptides and their receptors will facilitate the development of novel pharmacological agents for the treatment of immune disorders.     

The cardiac persistent sodium current: an appealing therapeutic target?

The sodium current in the heart is not a single current with a mono-exponential decay but rather a mixture of currents with different kinetics. It is not clear whether these arise from distinct populations of channels, or from modulation of a single population. A very slowly inactivating component, [(INa(P))] I(Na(P)) is usually about 1% of the size of the peak transient current [I(Na(T))], but is enhanced by hypoxia. It contributes to Na(+) loading and cellular damage in ischaemia and re-perfusion, and perhaps to ischaemic arrhythmias. Class I antiarrhythmic agents such as flecainide, lidocaine and mexiletine generally block I(NA(P)) more potently than block of I(Na(T)) and have been used clinically to treat LQT3 syndrome, which arises because mutations in SCN5A produce defective inactivation of the cardiac sodium channel. The same approach may be useful in some pathological situations, such as ischaemic arrhythmias or diastolic dysfunction, and newer agents are being developed with this goal. For example, ranolazine blocks I(Na(P)) about 10 times more potently than I(Na(T)) and has shown promise in the treatment of angina. Alternatively, the combination of I(Na(P)) block with K(+) channel block may provide protection from the induction of Torsades de Pointe when these agents are used to treat atrial arrhythmias (eg Vernakalant). In all of these scenarios, an understanding of the role of I(Na(P)) in cardiac pathophysiology, the mechanisms by which it may affect cardiac electrophysiology and the potential side effects of blocking I(Na(P)) in the heart and elsewhere will become increasingly important.     

Monocyte cyclooxygenase-2 activity: a new therapeutic target for atherosclerosis?

It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases of leukocyte recruitment to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. COX-2 has been detected in macrophages, smooth muscle cells and endothelial cells in human atherosclerotic lesions. Several studies have also reported the presence of COX-2 in the shoulder region of atherosclerotic plaques, mainly colocalizing with macrophages and MMPs, enzymes that are involved in the destabilization of atherosclerotic plaques, leading to rupture and atherothrombotic syndromes (i.e. acute myocardial infarction). We have recently assessed monocyte COX-2 activity and the production of PGE(2) in a population of apparently healthy subjects free from clinically overt atherosclerosis. We found an association between increased PGE(2) and increasing number of cardiovascular risk factors and carotid intima-media thickness, a noninvasive surrogate marker of atherosclerosis, independently of traditional and non traditional cardiovascular risk factors. Our findings support the notion that the COX-2/PGE(2)axis may have a role in atherosclerosis, and this might be an attractive therapeutic target. COX-2 inhibitors, collectively called coxibs (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise of improved treatment of arthritis without the gastrointestinal side effects associated with aspirin and other nonsteroidal anti-inflammatory drugs. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk. Only well designed large scale clinical trials can provide the answer as to the net effect of selective COX-2 inhibition on cardiovascular events before this new class of anti-inflammatory drugs can be incorporated into the armamentarium of atherosclerosis.     

Role of serotonin in Alzheimer's disease: a new therapeutic target?

Mounting evidence accumulated over the past few years indicates that the neurotransmitter serotonin plays a significant role in cognition. As a drug target, serotonin receptors have received notable attention due in particular to the role of several serotonin-receptor subclasses in cognition and memory. The intimate anatomical and neurochemical association of the serotonergic system with brain areas that regulate memory and learning has directed current drug discovery programmes to focus on this system as a major therapeutic drug target. Thus far, none of these programmes has yielded unambiguous data that suggest that any of the new drug entities possesses disease-modifying properties, and significantly more research in this promising area of investigation is required. Compounds are currently being investigated for activity against serotonin 5-HT(1), 5-HT(4) and 5-HT(6) receptors. This review concludes that most work done in the development of selective serotonin receptor ligands is in the pre-clinical or early clinical phase. Also, while many of these compounds will likely find application as adjuvant therapy in the symptomatic treatment of Alzheimer's disease, there are currently only a few drug entities with activity against serotonin receptors that may offer the potential to alter the progression of the disease.     

Is YKL-40 a new therapeutic target in cancer?

YKL-40 is produced by cancer cells and tumour-associated macrophages. YKL-40 may play a role in cancer cell proliferation, differentiation, survival, invasiveness, metastasis, in angiogenesis and the inflammation and remodelling of the extracellular matrix surrounding the tumour. Serum YKL-40 is a biomarker of prognosis, confirmed in 13 different types of cancer including > 2500 patients. Highest serum YKL-40 is found in patients with metastatic cancer with the shortest recurrence-free interval and shortest overall survival. Serum YKL-40 provides independent information compared with clinical characteristics and biomarkers, such as HER2, carcinoembryonic antigen, CA-125, prostate-specific antigen and lactate dehydrogenase. The authors hypothesise that inhibition of YKL-40 by monoclonal antibodies either directly or towards its receptor may be as efficient a cancer therapeutic as the monoclonal antibodies against HER2, HER1, vascular endothelial growth factor and CD20. Drugs inhibiting YKL-40 should be explored as new cancer therapeutics.     

Endothelial ATP-sensitive potassium channels: a new therapeutic target in cardiovascular medicine?

Recent electrophysiological studies have demonstrated convincingly that ATP-sensitive potassium channels (K(ATP)) are expressed in macro- and microvascular endothelial cells from heart and brain. Several reports have indirectly demonstrated the contribution of endothelial K(ATP) to the regulation of vascular tone, eg, during hypoxia. Experimentally, endothelial K(ATP) can be activated by energy depletion of cells or by adding synthetic potassium channel openers (PCOs). In endothelial cells, in contrast to vascular smooth muscle cells (VSMC), hyperpolarization induced by K(ATP) opening can result in an increase of [Ca(2+)](i) and, further, to enhanced NO and prostanoid synthesis. Although this mechanism is highly speculative, synthetic PCOs, directed against endothelial K(ATP), may counteract atherogenic stimuli (hypercholesterolemia and hypertension) and/or even suppress symptoms occurring in atherosclerosis (proliferation of VSMC, thrombogenesis). Further-more, the cardioprotective effects of PCOs may be mediated, at least in part, by an activation of endothelial K(ATP).     

Phosphodiesterase 7A: a new therapeutic target for alleviating chronic inflammation?

Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.     

Functional chemokine receptors in allergic diseases: is CCR8 a novel therapeutic target?

CC chemokine receptor (CCR) 8, which is expressed on Th2 cells and eosinophils, has been implicated in allergic diseases. This review represents an overview of the functional roles of CCR8 in the pathogenesis of eosinophilic inflammation and debates the potential of recently developed CCR8 antagonists to treat allergic disorders.     

α7 nicotinic acetylcholine receptors: a therapeutic target in the structure era

The nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels involved in cognitive processes and are associated with brain disorders which makes them interesting drug targets. This article presents a general overview of the receptor to introduce the α7 nAChR as a drug target. The advances in understanding of the structure/function properties of the nAChR produced during the last decade are detailed as they are crucial for rational drug design. The allosteric properties of the nAChR will also be described because they also have important consequences for drug design.     

Calreticulin,a therapeutic target?

Introduction: Calreticulin is an endoplasmic reticulum (ER) resident protein critical for maintaining Ca²⁺ homeostasis and glycoprotein folding in the ER. The protein has also been identified on the cell surface of apoptotic and necrotic cells and implicated to play a role in immunogenic cell death and other extracellular functions. The molecular events that promote cell surface association of calreticulin are not clear. Under cell stress conditions (environmental, drug induced, hypoxia), calreticulin may be upregulated as it attempts to regulate cell survival, death or repair. The initial signaling mechanisms involved in these processes may be regulated by the unfolded protein response (UPR) and genome damage response (GDR) pathways.

Area covered: Here, the phenomenon of cell surface calreticulin and its extracellular functions are discussed, with a major emphasis on the process of immunogenic cell death. The evidence of how cell surface calreticulin may act as a damage associated molecular pattern molecule is evaluated, in addition to how these properties of the protein can be exploited for therapeutic vaccine development, cancer treatment and mediating other inflammatory processes. In addition, clarification of calreticulin functions from its intracellular, cell surface, and extracellular locations are provided.

Expert opinion: While the protein folding and immune-stimulatory properties of calreticulin can be exploited to develop therapies, the molecular pathways involved remain to be elucidated. Nevertheless, exploiting the multifaceted properties of calreticulin may in the future provide a means to treat a number of diseases.     

Opiate withdrawal during development: are NMDA receptors indispensable?

Despite decades of research, the mechanisms that underlie opiate tolerance, dependence and withdrawal remain elusive. Evidence accumulated over the past ten years suggests that the NMDA receptor plays a central role in mediating the neuroplasticity induced by chronic opiate administration in adult animals. Yet, during ontogeny, the NMDA receptor complex undergoes qualitative developmental changes, which renders some of the basic assumptions for a role of the NMDA receptor in opiate withdrawal invalid in infants. Recent data indicate that NMDA receptor antagonists are not effective in blocking morphine tolerance, dependence and withdrawal in the neonatal rat. Roles for other glutamate receptor types (e.g. metabotropic glutamate receptors) have also been proposed recently. In this article, the latest evidence that characterizes the dynamic roles of glutamate receptors in these phenomena during ontogeny will be discussed.     

Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future?

The predominant isoform of the endothelin peptide family. endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+/H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.     

LXRs: new therapeutic targets in atherosclerosis?

The liver X receptors (LXRs) are nuclear receptors activated by oxysterols that are now recognized to play an important role in the control of lipid homeostasis. LXRs have been implicated in the regulation of cholesterol and fatty acid metabolism in multiple tissues, including liver and intestine, as well as in macrophages. The importance of these receptors in physiological lipid metabolism suggests that they may also influence the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Strong support for this idea has been provided by recent studies that directly linked LXR activity to the pathogenesis of atherosclerosis. These observations identify the LXR pathway as an attractive target for intervention in cardiovascular disease.     

Toll-like receptors: a novel target for therapeutic intervention in intestinal and hepatic ischemia–reperfusion injury?

Importance of the field: Toll-like receptors (TLRs) are transmembrane proteins that act mainly as sensors of microbes, orchestrating an organism's defense against infections, while they sense also host tissue injury by recognizing products of dying cells. Ischemia–reperfusion injury (IRI) represents one of these tissue damage states in which TLR-mediated mechanisms might be implicated.

Areas covered in this review: The most recent data on TLR signaling and the latest knowledge regarding the involvement of TLRs in the pathogenesis and progression of intestinal and hepatic IRI are presented. The potential effectiveness of TLR-modulating therapy in intestinal and liver IRI is also analyzed.

What the reader will gain: A comprehensive summary of the data suggesting TLR involvement in intestinal and hepatic IRI. Knowledge required for developing TLR modulation strategies against intestinal and hepatic IRI.

Take home message: TLRs play a significant role in both intestinal and hepatic IRI pathophysiology. Better understanding of TLR involvement in such processes may enable the invention of novel TLR-based therapies for IRI in the intestine and liver.     

GABA-A receptors: a viable target for novel anxiolytics?

Benzodiazepine (BZ) anxiolytics mediate their clinical effects by enhancing the effect of gamma-aminobutyric acid (GABA) at the GABA-A receptor. Classical BZ full agonists such as diazepam, which maximally enhance the function of GABA-A receptors, are effective anxiolytics but carry unwanted side effects including sedation, dependence and abuse liability, limiting their utility. Although a second generation of 'partial agonist' BZs have been pursued, promising preclinical data, in terms of anxiolytic efficacy and decreased unwanted effects, have so far failed to translate to the clinic. Following the insights into GABA-A receptor subtypes mediating the effects of BZs, a third generation of 'receptor subtype-selective' BZ site ligands have been developed. However, it remains to be determined whether promising preclinical data are recapitulated in the clinic.