Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 14, 2008


Contents

Prebiotics and Probiotics Delivering Therapeutics as Dietary Components
Executive Editor: Colum Dunne


Non-Invasive Tests in Animal Models and Humans: A New Paradigm for Assessing Efficacy of Biologics Including Prebiotics and Probiotics Pp. 1341-1350
R.N. Butler
[Abstract]


Probiotics in Intestinal and Non-Intestinal Infectious Diseases - Clinical Evidence Pp. 1351-1367
K. Hatakka and M. Saxelin
[Abstract]


Modulation of the Maturing Gut Barrier and Microbiota: A Novel Target in Allergic Disease Pp. 1368-1375
E. Isolauri, M. Kalliomäki, K. Laitinen and S. Salminen
[Abstract]


Genomics can Advance the Potential for Probiotic Cultures to Improve Liver and Overall Health Pp. 1376-1381
D.J. O’Sullivan
[Abstract]


Life Under Stress: The Probiotic Stress Response and How it may be Manipulated Pp. 1382-1399
B.M. Corcoran, C. Stanton, G. Fitzgerald and R.P. Ross
[Abstract]


Cyclooxygenases and Cyclooxygenase Inhibitors inNeurological and Psychiatric Diseases
Executive Editor: Luisa Minghetti


Editorial : Pp. 1400


Cyclooxygenase Inhibition in Ischemic Brain Injury Pp. 1401-1418
E. Candelario-Jalil and B.L. Fiebich
[Abstract]


Cyclooxygenase-1 and -2 in the Different Stages Alzheimer’ Disease Pathology Pp. 1419-1427
J.J.M. Hoozemans, J.M. Rozemuller, E.S. van Haastert, R. Veerhuis and P. Eikelenboom
[Abstract]


Nonsteroidal Anti-Inflammatory Drugs in Experimental Parkinsonian Models and Parkinson’s Disease Pp. 1428-1434
M. Asanuma and I. Miyazaki
[Abstract]


Non Steroidal Anti-Inflammatory Drugs and Neurogenesis in the Adult Mammalian Brain Pp. 1435-1442
M.A. Ajmone-Cat, E. Cacci and L. Minghetti
[Abstract]


Cyclooxygenase-2 in Synaptic Signaling Pp. 1443-1451
H. Yang and C. Chen
[Abstract]


COX-2 Inhibition in Schizophrenia and Major Depression Pp. 1452-1465
N. Müller and M.J. Schwarz
[Abstract]




Abstracts


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Non-Invasive Tests in Animal Models and Humans: A New Paradigm for Assessing Efficacy of Biologics Including Prebiotics and Probiotics
R.N. Butler

Newer biological agents that are designed to have multiple effects on a host require better ways to determine both their safety and toxicity. Indeed ecologically potent factors such as agents that can alter the gut milieu and change host responses are now being realized as a viable alternative to more focused pharmaceuticals. Even in the pharmaceutical arena there is a growing awareness of the preventative and therapeutic potential of alternative agents. Probiotics and prebiotics amongst other agents fall into this category and can have both direct and indirect effects on the pathogenesis and progress of disease. This review details some of the new approaches using non-invasive tests to enable firstly a better definition of a stressed through to a damaged gastrointestinal mucosa. They constitute ways to apply dynamic function testing in animal models and humans to provide reference points to which other measurements can be related e.g. altered circulating cytokines, altered gene expression. As such this phenotypic scaffold, alone and combined with newer molecular parameters, will improve our understanding of the interaction of luminal factors within the alimentary tract and the impact that these have on physiologically challenged mucosa and in disease both at the gastrointestinal level and also in remote organs. Practically, the dynamic function tests, primarily breath tests, can now be used as diagnostic and prognostic indicators of the efficacy of new biologics such as probiotics and prebiotics that in part elicit their effects by altering the ecology of particular regions of the intestine.


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Probiotics in Intestinal and Non-Intestinal Infectious Diseases - Clinical Evidence
K. Hatakka and M. Saxelin

There is increasing evidence that certain probiotic strains can be useful in improving human health. The use of probiotics has received attention as a natural way of restoring body’s normal microbiota, and an alternative and inexpensive way of preventing or treating infectious diseases without side effects. The best-documented clinical application of probiotics comes from trials on the treatment of gastrointestinal infections, mainly infectious diarrhoea. The enhancement of local as well as systemic immune responses by probiotics also offers new opportunities for probiotics in preventing infections at distal mucosal surfaces, such as those in the oral cavity, respiratory and urogenital tracts. The underlying mechanisms of probiotics are still unclear, but may include strengthening of the non-immunological gut barrier, interference with pathogen adhesion and growth inhibition, and the enhancement of the local mucosal immune system in the gut, as well as of the systemic immune response.


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Modulation of the Maturing Gut Barrier and Microbiota: A Novel Target in Allergic Disease
E. Isolauri, M. Kalliomäki, K. Laitinen and S. Salminen

The underlying denominators and treatment targets in atopic disease may be outlined as aberrant barrier functions of the skin epithelium and gut mucosa, and dysregulation of the immune response to ubiquitous environmental antigens. The route of sensitization varies with age, dietary antigens predominating in infancy. The immaturity of the immune system and the gastrointestinal barrier may explain the peak prevalence of food allergies at an early age. Dietary methods to control symptoms and reduce the risk of allergic disease have hitherto focused on elimination diets, alone or in combination with other environmental measures. The results have not been satisfactory regarding long-term prevention, primary or secondary. In view of the increasing burden of the abnormalities, new approaches are urgently needed for the management of allergic diseases and their prevention in at-risk infants. Novel methods here may include probiotics to counteract the immunological and gut mucosal barrier dysfunction associated with allergic disease, and thereby to strengthen endogenous defence mechanisms. Notwithstanding the demonstrations of important immunoregulatory potential of the well-balanced gut microbiota, the major objective health benefits of specific strains in allergic infants have only recently been clinically proven. Advances here have prompted enthusiasm in the scientific community and food industry and have fuelled research activities currently focusing firstly on identification of specific strains with anti-allergenic potential, and secondly on the question how food matrix and dietary content interact with the most efficacious probiotic strains.


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Genomics can Advance the Potential for Probiotic Cultures to Improve Liver and Overall Health
D.J. O’Sullivan

The concept of probiotics has evolved immensely since it was first proposed a century ago. There are numerous potential health benefits attributed to certain probiotic bacteria, from preventing gastrointestinal (GI) infections to stimulating the immune system. Recent evidence is now quite compelling for a role of probiotics in enhancing liver health. Liver injury is on the rise worldwide with non-alcohol fatty liver disease (NAFLD) the fastest rising liver problem, due largely to the rise in obesity and type II diabetes. A damaged liver can progress to more serious conditions such as steatohepatitis and cirrhosis, and the intestinal microflora are believed to play a large role in this progression. When the intestinal microbial flora is high in facultative microbes, particularly the Enterobacteriaceae, and low in anaerobes such as bifidobacteria, higher levels of ammonia, endotoxins and other compounds enter the blood stream. This results in direct liver damage and also indirectly from pro-inflammatory cytokines such as TNF-α. Probiotics have been shown to modulate the intestinal microflora and decrease the urease producing gram negatives and increase the anaerobic population. While results have been obtained with current probiotic strains, more effective strains could be obtained if all the characteristics bacteria use to survive and compete successfully in the intestine were known. The genomics era is now providing the tools to more effectively understand probiotic interactions in the intestine. This will lead to a new generation of exciting probiotics in the future.


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Life Under Stress: The Probiotic Stress Response and How it may be Manipulated
B.M. Corcoran, C. Stanton, G. Fitzgerald and R.P. Ross

The continuing expansion of interest in probiotic bacteria has led to an increase in manufactured Functional Foods and medicines containing these bacteria. Given the intestinal origin of these microorganisms, the challenges these sensitive bacteria face in order to be in a highly viable state throughout processing, storage and gastrointestinal transit to the site of action in the human gut are enormous. These bacteria encounter stresses including temperature, acid, bile, exposure and osmotic and oxidative stress in both product matrices and during gastrointestinal transit. However, like all bacteria, probiotic bacteria retain a broad arsenal of molecular mechanisms to combat the often lethal environmental stresses encountered during processing and following ingestion. A comprehensive appreciation of these mechanisms should inevitably lead to the design and manufacture of probiotic cultures, which retain greater viability through to the target site in the intestine. This review attempts to catalogue the cellular processes available to probiotic bacteria to facilitate survival in stressful conditions, and to speculate on how manipulation of these cellular systems can lead to production of designer strains with enhanced viability in food systems and efficacy following ingestion.


Cyclooxygenases and Cyclooxygenase Inhibitors inNeurological and Psychiatric Diseases
Executive Editor: Luisa Minghetti


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Editorial: Cyclooxygenases and Cyclooxygenase Inhibitors inNeurological and Psychiatric Diseases

In the last decade, the potential role of cyclooxygenase (COX) activity in brain diseases has been extensively studied. In particular, the association between the COX-2 isoform and neurotoxic processes has been proposed for several neurological conditions, including acute and chronic diseases. The beneficial effects of COX inhibitors observed in several experimental models and in retrospective epidemiological studies have further, albeit indirectly, supported COX-2 as a major therapeutic target to treat brain diseases. Nonetheless, the role played by each COX isoform in neurodegenerative diseases is still controversial and the emerging role of COX-2 in behavioural and cognitive functions strongly indicates that studies aimed at improving our knowledge of physiological role of COX-2 in the central nervous system are crucial to fully understand the pros and cons of COX-2 manipulation in disabling neurological and psychiatric diseases. The purpose of this issue of Current Pharmaceutical Design is to provide a comprehensive overview of the role of COX activity in the pathogenesis of neurodegenerative diseases and therapeutic potential of its inhibition. In addition, the issue is intended to highlight novel aspects of the physiological and pathological function of COXs, and particularly of the COX-2 isoform.

The first three articles concern three major neurological conditions, such as cerebral ischemia, Alzheimer’s disease (AD) and Parkinson’s disease (PD). Candelario-Jalil and Fiebich [1], review current knowledge of the relative contribution of COX isoforms to the brain ischemic pathology and offer a critical evaluation of the therapeutic potential of COX inhibitors in cerebral ischemia, highlighting the new targets identified downstream of COX with potential neuroprotective ability. Hoozemans and colleagues [2], provide a critical overview of the controversial role of COX isoforms in the pathogenesis of AD. The authors discuss of the diverse roles of COX-1 and COX-2 in the different stages of AD pathology and their involvement in inflammatory and regenerating pathways. Asanuma and Miyazaki [3] emphasize the heterogeneous pharmacological properties of non steroidal anti-inflammatory drugs (NSAIDs), which are likely to contribute to the protection of dopaminergic neurons in number of experimental studies using parkinsonian models, and discuss the discrepancy of effects of NSAIDs in experimental and epidemiological studies.

The fourth article focuses on the recent interest in anti-inflammatory treatments as tools to foster endogenous neurogenesis in the attempt to re-establish the lost tissue integrity in major brain diseases. Ajmone-Cat and colleagues [4] point out the complexity of inflammation and glial responses to acute or chronic injuries and the likelihood to generate either harmful or beneficial effects by interfering with them through NSAID treatment.

The last two articles cover the recent advancements on the role of COX-2 in neurotransmission and psychiatric disturbances. Yang and Chen [5] discuss the involvement of COX-2 activity in excitatory glutamatergic and long-term potentiation (LTP) and the recent evidence proving that endogenous cannabinoids are substrates for COX-2 and precursors of new classes of prostaglandins that could modulate synaptic transmission and plasticity. Mueller and Schwarz [6] report on the recent involvement COX-2 and prostaglandin E2 in the immunological imbalance observed in schizophrenia and in depression and on the experimental and clinical evidence supporting beneficial effects of anti-inflammatory therapies in these psychiatric disorders.

Finally, as an Executive Editor of Current Pharmaceutical Design, I would like to thank all the authors contributing to this issue, for their time and effort.

References

[1] Candelario-Jalil E, Fiebich BL. Cyclooxygenase inhibition in ischemic brain injury. Curr Pharm Des 2008; 1414): 1401-1418.

[2] Hoozemans JJ, Rozemuller JM, van Haastert ES, Veerhuis R, Eikelenboom P. Cyclooxygenase -1 and 2 in the different stages Alzheimer’s disease pathology. Curr Pharm Des 2008; 14(14): 1419-1427.

[3] Asanuma M, Miyazaki I. Nonsteroidal Anti-inflammatory Drugs in Experimental Parkinsonian Models and Parkinson’s Disease. Curr Pharm Des 2008; 14(14): 1428-1434.

[4] Ajmone-Cat MA, Cacci E, Minghetti L. Non Steroidal Anti-Inflammatory Drugs and Neurogenesis in the Adult Mammalian Brain. Curr Pharm Des 2008; 14(14): 1435-1442.

[5] Yang H, Chen C. Cyclooxygenase-2 in Synaptic Signaling. Curr Pharm Des 2008; 14(14): 1443-1451.

[6] Müller N, Schwarz MJ. Cox-2 Inhibition In Schizophrenia And Major Depression Curr Pharm Des 2008; 14(14): 1452-1465.


Luisa Minghetti
Department of Cell Biology and Neurosciences
Istituto Superiore di Sanità
Viale Regina Elena 299
00161Rome
Italy
E-mail: luisa.minghetti@iss.it


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Cyclooxygenase Inhibition in Ischemic Brain Injury
E. Candelario-Jalil and B.L. Fiebich

Neuroinflammation is one of the key pathological events involved in the progression of brain damage caused by cerebral ischemia. Metabolism of arachidonic acid through cyclooxygenase (COX) enzymes is known to be actively involved in the neuroinflammatory events leading to neuronal death after ischemia. Two isoforms of COX, termed COX-1 and COX-2, have been identified. Unlike COX-1, COX-2 expression is dramatically induced by ischemia and appears to be an effector of tissue damage. This review article will focus specifically on the involvement of COX isozymes in brain ischemia. We will discuss issues related to the biochemistry and selective pharmacological inhibition of COX enzymes, and further refer to their expression in the brain under normal conditions and following excitotoxicity and ischemic cerebral injury. We will review present knowledge of the relative contribution of each COX isoform to the brain ischemic pathology, based on data from investigations utilizing selective COX-1 / COX-2 inhibitors and genetic knockout mouse models. The mechanisms of neurotoxicity associated with increased COX activity after ischemia will also be examined. Finally, we will provide a critical evaluation of the therapeutic potential of COX inhibitors in cerebral ischemia and discuss new targets downstream of COX with potential neuroprotective ability.


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Cyclooxygenase-1 and -2 in the Different Stages Alzheimer’s Disease Pathology
J.J.M. Hoozemans, J.M. Rozemuller, E.S. van Haastert, R. Veerhuis and P. Eikelenboom

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Aβ) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD.

The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Aβ deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Aβ deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.


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Nonsteroidal Anti-Inflammatory Drugs in Experimental Parkinsonian Models and Parkinson’s Disease
M. Asanuma and I. Miyazaki

A number of experimental studies using parkinsonian models have revealed that nonsteroidal anti-inflammatory drugs (NSA-IDs) have neuroprotective properties against dopaminergic neurotoxicity not only by their cyclooxygenase-inhibiting effect but also by other specific properties or some unknown pharmacological effects. This article reviews heterogeneous pharmacological properties of NSAIDs including inhibitory effect against nitric oxide synthesis, agonistic action for peroxisome proliferator-activated receptor γ or possible suppressive effects against dopamine quinone generation, and also reviews their neuroprotective effects in the experimental parkinsonian models and pathogenesis of Parkinson's disease. Several epidemiological studies recently clarified that the use of nonaspirin NSAIDs but not aspirin was associated with a lower prevalence of Parkinson's disease, in contrast with neuroprotective effects of aspirin in the experimental studies. It also discusses the discrepancy between results in the experimental parkinsonian models and epidemiological data in prevalence of Parkinson's disease on the effects of NSAIDs.


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Non Steroidal Anti-Inflammatory Drugs and Neurogenesis in the Adult Mammalian Brain
M.A. Ajmone-Cat, E. Cacci and L. Minghetti

Non steroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents of first choice for the treatment of inflammation, pain, and fever. Neuroscience research of the last decades has pointed out the important role of inflammation in the pathogenesis of several brain disorders, and epidemiological and experimental evidence has suggested a beneficial role of NSAIDs in both chronic and acute neuropathologies. More recently NSAIDs have gained further attention as potential tools to enhance neuroregenerative processes in the adult mammalian brain. The rational behind their use arises from the notion that inflammatory processes that accompany brain damage would exert a major detrimental effect on endogenous neurogenesis. However, inflammation and glial responses to acute or chronic injuries constitute a complex and multifaceted process by which, besides potentially harmful and cytotoxic activities, beneficial responses can be initiated in the attempt to re-establish the lost tissue integrity. The individuation of optimal timing and type of pharmacological intervention able to potentiate the beneficial aspects of inflammation rather than to suppress it as a whole, would allow the achievement of enhanced and successful regenerative responses. In the present article, we will review the current literature on the effects of NSAIDs on neurogenesis and briefly discuss the cellular or molecular mechanisms by which these drugs can modulate brain restorative processes.


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Cyclooxygenase-2 in Synaptic Signaling
H. Yang and C. Chen

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme converting arachidonic acid to prostaglandins and a key player in neuroin-flammation, has been implicated in the pathogenesis of neurodegenerative diseases such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, and in traumatic brain injury- and ischemia-induced neuronal damage, and epileptogenesis. Accumulated information suggests that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic modification. Inhibition or elevation of COX-2 has been shown to suppress or enhance excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE₂ , the predominant reaction product of COX-2, and the PGE₂ subtype 2 receptor (EP₂)-protein kinase A pathway. Recent evidence shows that endogenous cannabinoids are substrates for COX-2 and can be oxygenated by COX-2 to form new classes of prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides). These COX-2 oxidative metabolites of endocannabinoids, as novel signaling mediators, modulate synaptic transmission and plasticity and cause neurodegeneration. The actions of these COX-2 metabolites are likely mediated by mitogen-activated protein kinase (MAPK) and inositol 1,4,5-trisphosphate (IP₃ ) signal transduction pathways. These discoveries suggest that the contributions of COX-2 to neurotransmission and brain malfunction result not only from its conversion of arachidonic acid to classic prostaglandins but also from its oxidative metabolism of endocannabinoids to novel prostaglandins. Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.


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COX-2 Inhibition in Schizophrenia and Major Depression
N. Müller and M.J. Schwarz

In schizophrenia and depression, opposite patterns of type-1 – type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia and decreased production of kynurenic acid in depression. These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D-aspartate (NMDA) agonism in depression and of NMDA antagonism in schizophrenia. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. The immunological imbalance results both in schizophrenia and in depression in an increased Prostaglandin E₂ (PGE₂) production and probably also in an increased Cyclo-oxygenase-2 (COX-2) expression. Although there is strong evidence for the view, that the interactions of the immune system, IDO, the serotonergic system, and the glutamatergic neuro-transmission play a key role in schizophrenia and in depression, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc. have to be bridged by intense further research. There are already hints that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression. COX-2 inhibititors have been tested in animal models of depression and in preliminary clinical trials, the latter showing favourable effects compared to placebo, both, in schizophrenia and in major depression. The effects of COX-2 inhibition in the central nervous system (CNS) as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further validation including clinical studies with sufficient sample size.