Current Pharmaceutical Design - Volume 18, Issue 1, 2012

The year 2012 will see the production of the 18th issue of Current Pharmaceutical Design. CPD was launched in 1996 and published 40 articles that year and 40 articles the next. In the last two years completed at the time of this writing (2009 and 2010), CPD published 766 articles, a nearly 10 fold increase. It is interesting to compare the world of CPD in 1996-7 to that of 2009-10 as a microcosm of the changes that have occurred in pharmacology and the pharmaceutical sciences at large. Only 8 countries were represented in the first two years of publication with 67% of articles coming from the US, 6.2 % from Canada, 11.2 % from England, France, Germany, and the Netherlands, and 2.5% from Japan and 2.5% from Korea. For 2009-20, authors were from 49 countries. Among the top 10 were the USA (22.8%), the EU countries of Italy, England, Germany, Spain, Greece, France, and The Netherlands (60.8%), Japan (4.6%) and Australia (4.2%). Peoples Republic of China was number 11 at 3.26%. The topics as based on the top 10 most cited papers from these two sets of years is also revealing about the new trends in the pharmaceutical literature. Purinergics are still with us as are antibiotics, anti-cancer drugs, and drugs related to metabolic syndrome. But a distinct shift from small molecules to probiotics and biologicals has occurred.

The incidence of neurodegenerative disease is increasing mostly in western countries due to the many cofactors involved. Among them, environmental factors (contaminants, pollution, climatic changes), antigenic pressure (microbial infections), life style disorders (smoke, alcohol, diet) as well as alteration of intestinal microbiota seem to represent the major etiopathogenic determinants of neurodegeneration. Nutraceuticals or functional foods have recently been object of intensive investigation for their capacity to prevent or attenuate the onset of many chronic diseases, even including neurodegenerative disease. Therefore, in the present special issue of Current Pharmaceutical Design, entitled “Nutraceuticals and Prevention of Neurodegeneration”, an update of the mechanisms of action of the major nutraceuticals active in the prevention of the neurodegenerative process will be provided. Andrade and Assuncao [1] will point out the beneficial effects of green tea (GT) whose polyphenols have been shown to be brainaccessible. In particular, in a model of aging rats the effects of GT on the glutathione system as well as the activation of cyclic AMP response element binding protein and the increase of brain-derived neurotrophic factor (BDNF) and of the anti-apoptotic protein B-cell lymphoma will be elucidated. Authors conclude that GT polyphenols seem to play an important role in reversal of loss of neuronal plasticity and recovery of neuronal damage in the elderly. Ho and associates [2] will adopt an integrative approach to introduce nutraceuticals able to prevent age-related neurodegeneration. Both small molecules such as polyphenols and big entities, e.g., oligosaccharides and polysaccharides seem to antagonize neurodegeneration in Alzheimer's disease (AD), Age-related Macular Degeneration and Parkinson's disease (PD). The indirect effects of these molecules on peripheral disease-related risk factors will also be discussed. Li and associates [3] will illustrate the effects of resveratrol (RSV), a non-flavonoid polyphenol, on AD. RSV has been shown to promote non-amyloidogenic cleavage of the amyloid precursor protein, enhance the clearance of amyloid beta-peptides, thus reducing the degree of neuronal damage. Some concerns related to bioavailability, biotransformation, synergism with other dietary factors as well as noxious effects due to RSV pro-oxidant capacity will also be taken into consideration. Magrone and associates [4] will emphasize the common pathogenic denominator which characterizes both PD and AD. Exaggerated activation of the systemic and cerebral immune system exerted by bacterial lipopolysaccharides and amyloid beta may account for the release of reactive oxygen species and proinflammatory cytokines. In this scenario, authors point out the properties of certain nutraceuticals such as vitamin D and polyphenols to prevent or attenuate neuroinflammation in both PD and AD. Marzulli and associates [5] will clarify the mechanisms of action of polyphenols from fermented grape marc (FGM). FGM from Koshu and Negroamaro grape Vitis vinifera when tested on peripheral blood mononuclear cells from normal donors generate two major effects: i. the induction of FoxP3 (a biomarker of T regulatory cells); ii the reduction of Granzyme B. Because of these anti-inflammatory effects FGM may represent a valid therapeutic measure to mitigating neuroinflammation in both AD and PD. Ozawa and associates [6] will provide evidence for the neuroprotective effects of lutein in the retina. Lutein is a carotenoid not synthesized in mammals and, therefore, must be obtained from the diet. In lutein-treated murine ocular disease models, oxidative stress is dramatically reduced. Furthermore, degradation of rhodopsin and synaptophysin, depletion of BDNF and DNA damage are also prevented by lutein treatment. Kim and Oh [7] will discuss on the use of traditional herb medicines to prevent or treat neurological disorders. In particular, they have the potential to be developed into optimal pharmaceuticals and nutraceuticals for their multifunction and multi target characteristics. In particular, inhibition of acethylcolinesterase activity, antioxidant and anti-inflammatory capacities seem to represent a common denominator among the biologic properties of many plants. Gadad and associates [8] will present the effects of a novel synthesized compound, Curcumin-glucoside (Curc-gluc). In particular, Curcgluc can inhibit alpha-synuclein aggregation which is centrally involved in PD. Then, Curc-gluc is able to solubilize the oligomeric form disintegrating preformed fibrils, thus preventing further fibrillization of alpha-synuclein. Its exploitation in the course of PD is discussed. Peluso and associates [9] will point out the emerging role of interleukin (IL)-17 in the pathogenesis of neurodegeneration. In particular, they have studied the circulating levels of IL-17 after ingestion of a High Fat Meal (HFM) in healthy overweight individuals. The association of the HFM to fruit juice drink in comparison with placebo reduced the secretion of IL-17. Therefore, this dietary supplementation for its capacity to reduce serum IL-17 may represent a preventive measure for diet-related disease such as AD and PD. Mythri and Srinivas Bharath [10] will describe the neuroprotective potential of curcumin, a polyphenol present in turmeric (Curcuma longa). This compound is able to cross the blood-brain-barrier, thus exerting antioxidant and anti-inflammatory activities at the central nervous system level. The therapeutic potential of curcumin in PD is discussed.

Dietary antioxidant compounds, due to their pivotal role in the modulation of cellular redox mechanisms, are gaining attention of researchers in the field of brain aging and related degenerative diseases. In this perspective, green tea (GT) can be an excellent resource, as it contains large amounts of brain-accessible polyphenols. Many of these compounds are monomeric catechins, which have been shown to exert antioxidant effects, acting directly as radical scavengers or metal-chelators. In the current article, we review the general properties of GT, the direct antioxidant action of its polyphenols and the fine modulation of signaling systems related to survival and antioxidant defenses in the central nervous system of aging rats. The effects in the glutathione system and the activation of several transcription factors including cyclic AMP response element-binding (CREB) protein, levels of the brain-derived neurotrophic factor (BDNF) and the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) are given in detail. We discuss also the beneficial action of catechins in learning and memory with a particular focus on the hippocampal formation. We conclude that GT polyphenols can have a promising role in the reversal of age-related loss of neuronal plasticity and recovery after neuronal lesions associated with aging.

Age-related neurodegeneration in the brain and retina is complicated. It comprises a series of events encompassing different modes of degeneration in neurons, as well as inflammation mediated by glial cells. Systemic inflammation and risk factors can contribute to disease progression. Age-related conditions such as Alzheimer's disease (AD), Parkinson's disease (PD) and Age-related Macular Degeneration (AMD) affect patients for 5 to 20 years and are highly associated with risk factors such as hyperhomocysteinæmia, hypercholesterolæmia, hypertension, and symptoms of mood disorder. The long duration of the degeneration and the wide array of systemic factors provide the opportunity for nutraceutical intervention to prevent or delay disease progression. Small molecules such as phenolic compounds are candidates for neuroprotection because they have anti-oxidant activities and can modulate intracellular signaling pathways. Bigger entities such as oligosaccharides and polysaccharides have often been neglected because of their complex structure. However, certain big molecules can provide neuroprotective effects. They may also have a wide spectrum of action against risk factors. In this review we use an integrative approach to the potential uses of nutraceutical products to prevent age-related neurodegeneration. These include direct effects of phenolic compounds and polysaccharides on neurons to antagonize various neurodegenerative mechanisms in AD, PD and AMD, and indirect effects of these compounds on peripheral disease-related risk factors.

The polyphenolic compound resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical which has been found in more than 70 plant species, including herbs and human food products such as grapes, berries, and peanuts. Resveratrol was first isolated in 1940; however, little attention was paid to it until its benefits in coronary heart disease were studied in 1992. Since then, increasing evidence has indicated that resveratrol may be useful in treating cardiovascular diseases, cancers, pain, inflammation, tissue injury, and in reducing the risk of neurodegenerative disorders, especially Alzheimer's disease (AD). AD is characterized by a progressive dementia, and is one of the most common neurodegenerative disorders in the elderly. It has been reported that resveratrol exhibits neuroprotective benefits in animal models of AD. Resveratrol promotes the non-amyloidogenic cleavage of the amyloid precursor protein, enhances clearance of amyloid beta-peptides, and reduces neuronal damage. Despite the effort spent trying to understand the mechanisms by which resveratrol functions, the research work in this field is still incomplete. Many concerns such as bioavailability, biotransformation, synergism with other dietary factors, and risks inherent to its possible pro-oxidant activities still need to be addressed. This review summarizes and discusses the neuroprotective effects of resveratrol on AD, and their potential mechanisms.

Parkinson disease (PD) and Alzheimer disease (AD) are neurodegenerative processes whose frequency is dramatically increasing in the western world. Both diseases share a common pathogenic denominator characterized by an exaggerated activation of the systemic and cerebral immune system, respectively. For instance, lipopolysaccharides in PD and amyloid beta in AD trigger microglia and astrocytes to release reactive oxygen species (ROS) and proinflammatory cytokines. Infiltrating peripheral T cells once activated in the central nervous system also contribute to the neurodegenerative process. Besides innovative biotherapy, nutraceuticals or functional foods are currently investigated for their neuroprotective activities. Especially, vitamin D and polyphenols, seem to be promising therapeutic tools for inhibiting ROS formation and arresting cytokine-mediated neuroinflammation in PD and AD.

The onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM-induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease.

Although a large variety of pharmaceutical therapies for treating disease have been developed in recent years, there has been little progress in disease prevention. In particular, the protection of neural tissue is essential, because it is hardly regenerated. The use of nutraceuticals for maintaining the health has been supported by several clinical studies, including cross-sectional and interventional studies for age-related macular disease. However, mechanistic evidence for their effects at the molecular level has been very limited. In this review, we focus on lutein, which is a xanthophyll type of carotenoid. Lutein is not synthesized in mammals, and must be obtained from the diet. It is delivered to the retina, and in humans, it is concentrated in the macula. Here, we describe the neuroprotective effects of lutein and their underlying molecular mechanisms in animal models of vision-threatening diseases, such as innate retinal inflammation, diabetic retinopathy, and light-induced retinal degeneration. In lutein-treated mouse ocular disease models, oxidative stress in the retina is reduced, and its downstream pathological signals are inhibited. Furthermore, degradation of the functional proteins, rhodopsin (a visual substance) and synaptophysin (a synaptic vesicle protein also influenced in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease), the depletion of brain-derived neurotrophic factor (BDNF), and DNA damage are prevented by lutein, which preserves visual function. We discuss the possibility of using lutein, an antioxidant, as a neuroprotective treatment for humans.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of progressive dementia in aging. Research on AD therapy has been partly successful in terms of developing symptomatic treatments, but there have been a number of failures with regard to developing disease-modifying therapies. The pathogenesis of AD remains unclear and the present one-drug, one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. This review briefly introduces progress in the development of anti-AD treatments and then focuses on recent advances in the research, characteristics, and development of herbal medicines. Because AD arises via multiple pathological or neurotoxic pathways, herbal medicines have the potential to be developed into optimum pharmaceuticals and nutraceuticals for AD because of their multi-function, multi-target characteristics.

α-Synuclein aggregation is centrally implicated in Parkinson's disease (PD). It involves multi-step nucleated polymerization process via the formation of dimers, soluble toxic oligomers and insoluble fibrils. In the present study, we synthesized a novel compound viz., Curcumin-glucoside (Curc-gluc), a modified form of curcumin and studied its anti-aggregating potential with α-synuclein. Under aggregating conditions in vitro, Curc-gluc prevents oligomer formation as well as inhibits fibril formation indicating favorable stoichiometry for inhibition. The binding efficacies of Curc-gluc to both α-synuclein monomeric and oligomeric forms were characterized by micro-calorimetry. It was observed that titration of Curc-gluc with α-synuclein monomer yielded very low heat values with low binding while, in case of oligomers, Curc-gluc showed significant binding. Addition of Curc-gluc inhibited aggregation in a dosedependent manner and enhanced α-synuclein solubility, which propose that Curc-gluc solubilizes the oligomeric form by disintegrating preformed fibrils and this is a novel observation. Overall, the data suggest that Curc-gluc binds to α-synuclein oligomeric form and prevents further fibrillization of α-synuclein; this might aid the development of disease modifying agents in preventing or treating PD.

An emerging role of IL-17 in the inflammatory response associated with pathogenesis of neurodegeneration has been recently suggested. However, though diet represents a key factor in the modulation of inflammatory processes, evidence is not currently available on the nutritional regulation of IL-17 in humans. In a double blind, randomized, placebo controlled, crossover study, we investigated the effect of High Fat Meal (HFM) on IL-17 circulating levels in presence of a placebo (HFM-P) or with a Fruit Juice Drink (HFM-FJD) composed of pineapple, blackcurrant and plum in fourteen healthy overweight humans. Fasting in the morning subjects ingested a test meal providing 1344 Kcal. Ingestion of HFM-P induced an inflammatory response mediated by TNF-α (p<0.001), IL-6 (p<0.001) and IL-17 (p<0.01). Plasma IL-17 concentration significantly increased at 1 h (+2.6 ± 1.1 pg/ml), remaining high at 4 h (+2.98 ± 1.2pg/ml), 6h (+2.38 ± 0.6pg/ml) and 8 h (+2.8 ± 0.9 pg/ml) (ANOVA for time-course p=0.009). When the HFM was consumed in the presence of the FJD a marked inhibition of IL-17 response to the HFM was observed (ANOVA between treatment p=0.037). We provided, for the first time, evidence on the role of diet in modulating IL-17 production in healthy overweight subjects.

Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD.

Currently the long-term usage of traditional anti-HIV drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), eventually leads to the emergence of drug resistance and severe side effects. Thus it is imperative to design and develop more promising HIV-1 inhibitors to overcome these drawbacks. Fortunately, with the identification of some fascinating targets in the entry process of viral life cycle, HIV-1 entry inhibitors (EIs) with low cytotoxicity and mild side effects turned out as novel and effective anti-HIV agents. Especially, of these potent EIs, small molecule CCR5 antagonist maraviroc was approved by US FDA in 2007, which significantly increased the therapeutic options for the clinical treatment of HIV-infected patients. Subsequently, as promising anti-HIV drug candidates, kinds of small molecule CCR5 antagonists have been synthesized and evaluated in clinical trials. In this article, current progress in the development of novel small molecule CCR5 antagonists will be reviewed on the basis of their chemical structures with a special attention to their discovery stories. Simultaneously, binding mode analysis based on molecular modeling studies will also be introduced.

In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: “liking,”“learning,” and “wanting” [1]. That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or “wanting” hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily selfadministered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens (NAC), and they stimulate the functioning of brain reward circuitry (producing the “high” that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions.