Current Medicinal Chemistry - Volume 15, Issue 23, 2008

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of α-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, α-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of α-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.

The research on high hydrostatic pressure in medicine and life sciences is multifaceted. According to the used pressure head the research has to be divided into two different parts. To study physiological aspects of pressure on eukaryotic cells physiological pressure (pHHP; < 100 MPa) is used. pHHP induces morphological alterations in the cellular organelles and evokes a reversible stress response similar to the well known heat shock response. pHHP induces highly reversible alterations and normally does not affect cellular viability. The treatment of eukaryotic cells with nonphysiological pressure (HHP; ≥ 100 MPa) reveals different outcomes. Treatment with HHP < 150 MPa does not markedly affect viability of human cells, but induces apoptosis in murine cells. In human cells apoptosis is observed after treatment with ≥ 200 MPa. Moreover, HHP treatment with > 300 MPa leads to necrosis. Therefore, HHP plays a role for the sterilisation of human transplants, of food stuff, and pharmaceuticals. Human tumour cells subjected to HHP > 300 MPa display a necrotic phenotype along with a gelificated cytoplasm, preserve their shape, and retain their immunogenicity. These observations favour the use of HHP to produce whole cell based tumour vaccines. Further experiments revealed that the increment of pressure as well as the pressure holding time influences the cell death of tumour cells. We conclude that high hydrostatic pressure offers both, an economic, easy to apply, clean, and fast technique for the generation of vaccines, and a promising tool to study physiological aspects.

Invariant natural killer T (iNKT) cells are an attractive therapeutic target in autoimmune diseases, since they play a major role in immune regulation. iNKT cells recognize glycolipid antigens presented by CD1d molecules that resemble the non-polymorphic MHC class I protein. α-galactosylceramide (α-GalCer) isolated from marine sponge has long been used as a prototype iNKT cell ligand in the laboratory. As α-GalCer is the most efficacious ligand for iNKT cells, its potential to treat autoimmune disease has been evaluated in animal models. Previous studies showed that α- GalCer effectively suppressed disease in some autoimmunity models, but not in others. This inconsistency may be attributed to the ability of α-GalCer to induce the production of both proinflammatory Th1 and anti-inflammatory Th2 cytokines by iNKT cells. To overcome this issue, we and other groups have synthesized new, unnatural glycolipids by modifying the structure of α-GalCer. These efforts have led to an identification of glycolipid compounds that provoke the production of Th2 (but not Th1) cytokines by iNKT cells. Among these novel ligands, an α-GalCer analogue named OCH, which contains a truncated sphingosine chain, induces a Th2 biased response by murine iNKT cells. Here we describe that OCH also polarizes human iNKT cells towards Th2, which opens up a new avenue for the clinical application of glycolipid compounds in treating of autoimmune diseases such as multiple sclerosis. The pursuit of synthetic glycolipid antigens has the great potential to lead to a better understanding of the regulatory effects of human iNKT cells and development of a new therapeutic agent for autoimmune diseases.

Cytochrome P450 (CYP) enzymes are a superfamily of heme containing proteins that catalyze xenobiotic metabolism phase I reactions. Oxidation reactions are the most common CYP-catalyzed reactions for both endogenous substrates and exogenous compounds, including drugs, although CYP enzymes are capable also to catalyze reduction reactions. Whereas the majority of clinically used drugs are inactivated by CYPs, several prodrugs are bioconverted to their active species by these enzymes. Therefore, this mechanism could be exploited to a greater extend, e.g. by taking advantage of the different CYP enzymes to achieve targeted drug delivery, to improve efficacy or to decrease the unwanted adverse effects of existing and novel drug molecules. This review describes the potential of CYP enzymes in prodrug design and summarizes a wide variety of CYP-activated prodrug structures, which are on the market or under the development. The bioactivation mechanisms of each CYP-activated prodrug structure are described and the specificity for the different forms of CYP enzymes is discussed.

GnRH (gonadotropin-releasing hormone), a decapeptide produced by the hypothalamus, plays an important role in the reproduction by regulating the pituitary-gonadal axis. Continuous high doses of GnRH or its superactive agonists result in desensitization of the pituitary gonadotropes and a suppression of sex steroid production by the gonads (chemical castration). Based on these effects, the treatment with GnRH agonists has become a widely used hormonal therapy of the sex-steroid dependent tumors. It was also demonstrated that most tumor cells contain GnRH receptors, and the direct antiproliferative effect of GnRH analogs on cancer cells might be mediated by these receptors. Development of new GnRH derivatives is focused on the decrease of their hormonal potency resulting in higher selectivity of the antitumor activity. One of the most promising natural GnRH analogs, lamprey (l) lGnRH-III, was isolated from see lamprey. This variant of GnRH binds to GnRH receptors and inhibits proliferation of various cancer cells. However, its endocrine effect is insignificant in mammals. lGnRH-III dimers and conjugates were prepared and were shown to have increased antiproliferative effects on various cancer cells, while their hormonal activity was lower than that of the native hormone. lGnRH-III was applied as targeting moiety to deliver anticancer agents to tumor cells. Research data concerning lGnRH-III and its analogs represent a new outlook for research trends of the application of GnRH compounds in cancer chemotherapy. Studies on the effects of lGnRH-III derivatives including antiproliferative effects, cytotoxicity, hormonal actions, and enzymatic stability are reviewed in this article.

Pharmacological studies highlighted pleiotropic effects of statins, that seem to influence atherogenesis not only by increasing atherosclerotic plaque stability but also by modulating endothelial function and inflammation and acting on platelet aggregation and thrombosis. Despite a strong association between increased levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of coronary heart disease (CHD) has been well proven, it not yet established whether serum LDL-C levels are related to stroke incidence. The major aim of this paper is to perform a comprehensive up-to-date review of research papers, meta-analyses and randomized controlled clinical trials reporting the effects of statins in primary and secondary stroke prevention strategies. In addition, our work provides an overview on statin chemical structure, mechanism of action and pharmacological properties, investigating also most common adverse effects and relationship between statin therapy and haemorrhagic stroke risk, in order to assess drugs safety. Although studies are heterogeneous, our analysis shows that statins reduce the risk of stroke occurrence in high risk patients and seem also to reduce stroke recurrence. Moreover, the low incidence and reversibility of adverse effects, and the unclear association with hemorrhagic events, support the safe use of these drugs.

Cancer can be defined as a deviated protein network system toward dysregulated cellular proliferation. Alteration in the content and functional state of the proteins with many linkages may shift the equilibrium state of the protein signaling network to enhance a survival advantage of the affected cells. Searching for such hub proteins is the main purpose of the cancer proteomics. Although the progression in the vanguard proteomic technologies would largely contribute to cancer diagnosis and treatment in the future, the technology most frequently used for the analysis of clinical tissue samples is the two-dimensional gel electrophoresis (2DE) combined with matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). Accumulation of 2DE data has generated many candidate biomarkers with potential clinical value. The identified proteins are restricted to a subset of the predicted human proteome, and ubiquitously exist in all normal cells taking important roles in the basic biological functions. Although these proteins can be used as valuable prognostic markers, the low-abundance proteins which is tissue-specific and useful as diagnostic markers could not easily be found by the standard 2DE technology alone. None of the current proteomic technologies can identify the whole proteome by themselves. Adequate combinations of different approaches not only in proteomics but in immunological methods would be necessary for the tissue specific markers.

Pyridinium aldoximes are used as antidotes to organophosphorus cholinesterase inhibitors. All pyridinium aldoximes (oximes) are highly polar quaternary ammonium compounds showing low to minimal blood-brain-barrier (BBB) penetration. Oximes are separated using reversed-phase (RP) HPLC methods and/or thin-layer chromatography (TLC). The chemical structures, elementary compositions, molecular sizes and the calculated logP values of several mono- and bis-pyridinium aldoximes are given. Chromatographic and electrophoretic analyses of oximes are detailed, including the stationary and mobile phase composition and the mode of detection. Degradation pathways and products are also discussed. To characterize oximes lipophilicity/hydrophilicity an in silico method was used and expanded as to describe organophosphorus compound adducts with several pyridinium aldoximes.