Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 9, Issue 3, 2010

Neuroinflammation is believed to be the common pathological process in many neurodegenerative diseases, and what was believed to be a naive housekeeping process, as a result of neurodegeneration, can be a hostile contributor of the disease. Several primary neurological disorders are associated with inflammatory responses, in many cases they aggravate the initial problem and lead to acute symptoms and disability or permanent damage due to neuronal death. Most of the anti-inflammatory treatment strategies in neurological disorders aim to reduce the symptoms of the disease leading to a rapid recovery in many cases due to blocking the immune response by inhibiting the pro-inflammatory mediators. There are evidences that inflammatory mediators including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding [1]. Moreover, elevation of soluble tumor necrosis factor (TNF), a potent pro-inflammatory/ pro-apoptotic cytokine is one of the hallmarks of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and demyelinating disease such as multiple sclerosis (MS), as well as the ischemic stroke [2, 3]. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS) characterized by inflammation, demyelination and variable loss of axons [4-6]. The recurrent relapses of CNS inflammation in MS patients cause disability. The Th17 cell response has been indicated in experimental allergic encephalomyelitis (EAE, a model to study MS) [7]. Treatment strategies include the acute treatment of relapses, symptomatic relief, and immunomodulation by constraining the inflammation, stimulation of remyelination and neuroprotection. Relapses have long been treated with anti-inflammatory drugs including the steroids [8]. Interferon beta (IFNβ)-1b was the first immunomodulatory drug used for MS [9]. Several other anti-inflammatory or immunomodulatory drugs are currently used in the treatment of MS [10]. A new treatment approach to reduce or prevent the ROS by Dr. Michel Geffard in France and Dr. Rafael Covenas in Spain and colleagues suggests using fatty acids linked to poly-L-Lysine (PL), such as antioxidants linked to PL, free radical scavengers linked to PL, and amino acids linked to PL inhibits brain leukocyte infiltration in EAE, the animal model of MS, and abolishes the episodes of the disease and preserves myelin integrity [11, 12]. In this issue, the article: endotherapia, will discuss how fatty acids, anti-oxidants, amino acids and their derivatives linked to the polymer poly-L-lysine have a better efficiency as anti-inflammatory drugs, an approach that prevents metabolic degradation of the linked small molecules, improves the kinetics and increases the half-life of the product, as well as allowing it to reach the site of the lesion. The result of an open study in treatment of MS patient is presented using this new approach. Alzheimer's disease (AD) is a neurodegenerative disorder of the CNS associated with progressive cognitive and memory loss, and is characterized by senile plaques and deposition of amyloid beta peptide (Abeta), neurofibrilary tangles in brain tissue, degeneration of cholinergic pathways, and neuronal degeneration in brain including the cerebral cortex and the hippocampus [13]. Amyloid-beta and tau protein make up the plaques and tangles of Alzheimer's disease, where these normally soluble proteins assemble into amyloid-like filaments [14]. Inflammation also plays a role in AD and there are evidences for the convergence of the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators [15, 16]. Gliosis which is known to be induced by oxidative stress and is increased by aging, significantly contributes to the pathophysiology of AD. Several other factors including the genetic, biological and environmental factors play important role in the pathogenesis of AD. Most genes conferring susceptibility to AD are related to amyloid- beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) as well as the inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha) genes [17-21]. Amyloid-beta oligomers and fibrils and their cellular effects can activate the innate immunity defense and induce inflammatory and apoptotic responses in human brain. Several antiinflammatory drugs approved for other conditions, when used in AD counteract the inflammatory responses [22]. The cyclooxygenase (COX) inhibitors, such as aspirin and indomethacin, have been tested as potential therapeutics in AD [23, 24], but due to their side effects on stomach by interfering with production of eicosanoids such as prostaglandin (PGs, which have gastroprotective effects), as well as mediating to bronchoconstriction through other eicosanoids including the leukotriense (LTs), the COX-2 inhibitor drugs were proposed. However, the COX-2 inhibitors, which may reduce the production of prostaglandins, may increase the production of LTB4 which is one of the most potent endogenous chemotactic/inflammatory factors....

Primary headaches including the migraine, cluster, and tension headaches are common neurological disorders which cause pain and disability to the patients. The pathomechanism of migraine is not very well understood however, current clinical findings indicate a possible primary brain disorder due to activation of the brain and brainstem as triggers for migraine. The headache phase of migraine may be due to activation of the peripheral nerves including the trigeminal nerve and others innervating the cranial blood vessels and release of vasoactive substances including the calcitonin generelated peptides (CGRP), possibly leading to vasodilation and brainstem activation. Several of our studies in an experimental model of pain using electrical stimulation of the trigeminal ganglion in rats focused on various neuropeptides release from the peripheral and central trigeminal nerve terminals, however, clinically only the CGRP in migraine and CGRP and vasoactive intestinal peptide (VIP) in cluster headache were found in patient's blood. Although several drugs are used in the treatment of migraine, the non-steroid anti-inflammatory drugs (NSAIDs) and the triptan family of drugs are the first choice drugs recommended for the treatment of acute migraine headache. Although clinically very few studies detected other vasoactive/inflammatory molecules in the blood of migraine patients, sensitization of peripheral axons can involve many inflammatory mediators affecting the peripheral tissue substrates of pain. Moreover, central sensitization in the trigeminal nucleus can also contribute to additional pain responses. This article reviews neuropeptides and other molecules involved in primary headaches and major drugs proposed for their treatment in recent years.

While the exact causes or mechanisms of Alzheimer's disease (AD) are still not known, the most critical risk factor is aging. Cellular oxidative stress is known to occur in the brain during aging and some pathology of AD could be explained by the oxidative stress, including senile plaques, deposition of amyloid peptide (Aβ) and tangles (deposition of an abnormally phosphorylated tau). Also gliosis, which may release inflammatory molecules and cause oxidative stress, is a feature of aging and AD. Epidemiological analysis indicates that people with severe arthritis and who are subjected to leprosy therapy have significantly lower rates of AD. Since both arthritis and leprosy therapy involves high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), and the fact that inflammation is involved in AD pathology, NSAID-therapy might prevent or delay the onset of AD. More recently NSAIDs were found to reduce production of Aβ peptide. Therefore, we should revisit NSAIDs as potential treatment for AD therapy. There are clinical studies showing the beneficial effects of NSAIDs treatments in AD patients, in contrast, other studies show a lack of benefit. This article discusses the role of inflammation and oxidative stress in AD and the role of drugs preventing them.

Endotherapia is a new therapeutic approach against chronic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and rheumatoid arthritis. It combines the evaluation of circulating antibodies directed against specific self-antigens and self-antigens modified by free radicals. Here, we review the literature concerning this topic. In addition, our biological assays have allowed us to follow up the evolution of chronic diseases along time, checking remission phases. For more than 25 years, our scientific group has suggested that the chronicity of diseases may be due to nonpathological bacteria living in different biotopes. Endotherapia is the result of immunopathologic work addressing chronic incurable diseases with a multifactorial etiology. Several genes are susceptible to toxic environmental immunologic agents. Thus, the intestinal ecosystem plays an important role in these mechanisms. Therapy is a “tailor-made” combination (MG1/RA, GEMSP) of the small molecules (e.g., vitamins…) linked to poly-L-lysine (PLL). Each individual linkage to PLL offers great advantages owing to the chemical characteristics of PLL (e.g., non-immunogenic), increasing the half-life of the active PLL derivatives. Clinical trials have enabled us to confirm very good safety. Our results confirm the efficacy of the approach and we believe that it could be very promising for chronic diseases.

Increasing evidence suggests that activation of the innate immune system may play a seminal role in the pathophysiology of depression. Several lines of evidence support the association of inflammation and depression. Peripheral administration of cytokines, such as interferon-alpha, can induce many of the symptoms of the depressive syndrome. In addition, medically healthy patients with major depression exhibit elevated plasma levels of proinflammatory cytokines. Moreover, cytokines produce effects on a variety of neurobiological substrates previously implicated in the pathogenesis of depression. Thus, proinflammatory cytokines alter neuroendocrine function, several neurotransmitter systems including dopamine and glutamate, neural plasticity, and neuronal activity in limbic regions. The burgeoning evidence that depression is an inflammatory disease is reviewed.

Vasogenic edema resultant from malignant brain and spine tumors can impart neurological disability and life threatening compression of the central nervous system. Clinical management of edema requires a working understanding of the blood brain barrier, blood cerebrospinal fluid barrier, and the major mechanisms that tumors utilize to disrupt the normal function of these barriers. Corticosteroids and anti-angiogenic agents allay vasogenic edema and serve as fundamental treatment strategies for brain and spine tumor patients. This section reviews relevant microscopic anatomy, pathologic processes and inflammatory mediators important in the production of vasogenic cerebrospinal edema, and the rationale behind management strategies of edema in this patient population.

The immune system is a sophisticated and complex system that is influenced by various exogenous insults such as surgical stress and endogenous factors like the sympathetic nervous system. It has been demonstrated that sedative agents used in clinical practice alter the balance of pro- and anti-inflammatory cytokines. These effects may be reversible following short exposure to anaesthetic agents and sedative drugs. However, many critically ill patients are sedated for prolonged periods of time, which raises concerns about the risks of immunological interference by sedative agents. When one considers that sepsis accounts for significant morbidity in intensive care, it is imperative that anything modifiable which causes immunosuppression is identified. The systemic inflammatory response syndrome is known to feature an increase in pro-inflammatory mediators, something which could be influenced by sedative agents. We propose to outline the details surrounding this area, focusing on sedative agents commonly used in the intensive care setting. A more detailed understanding of this area could lead to improved patient outcomes and have far-reaching influence on clinical practice in critical care.

Algae are eaten as healthy foods in Asian countries. We summarize our recent results on the immunoregulatory role of polysaccharide fractions from edible algae on immediate hypersensitivity, delayed-type hypersensitivity, and antitumor immune responses. They are divided into two types. One is to manipulate immune response through toll-like receptor 4 (TLR 4). The other uses different receptors to modify the immune response. Petalonia binghamiae polysaccharide fraction and Spirulina pacifica complex polysaccharide attenuate the delayed-type hypersensitivity and tumor growth by reducing the production of inflammatory cytokine, IL-17 through TLR4. This is suggested from the results that these polysaccharide fractions could suppress the delayed-type hypersensitivity and tumor growth in C3H/HeN but not in tolllike receptor 4 mutant, C3H/HeJ mice. Alginic acid, the polysaccharide from brown algae suppressed tumor growth in both C3H/HeN and C3H/HeJ mice and did not suppress delayed-type hypersensitivity response significantly, when administered intraperitoneally. We propose the potential usefulness of edible algae as the fine tuning reagents of the immune response. We also summarize the recent advancement in the area of regulation of immune responses in relation to these polysaccharides.

RNA interference (RNAi) is an endogenous process initiated by short double stranded RNAs, which results in sequence-specific posttranscriptional gene silencing. Since its discovery RNAi has become the most widely used experimental tool providing powerful and sequence-specific knockdown of protein expression to elucidate the function of genes. The possibility of blocking the expression of any protein carries huge expectations for potential therapeutic applications in a wide range of diseases. For clinical development, however, the use of RNAi-based therapeutics has to overcome major drawbacks and disadvantages, mainly targeted delivery and safety issues. This review summarizes the current status of progress made in the development of efficient in vivo silencing; focusing on both viral and non viral delivery strategies, and provides an overview of specifications for anti-inflammatory RNAi-based gene therapy in preclinical models of immune- mediated inflammatory disorders such as rheumatoid arthritis, skin disorders and inflammatory bowel diseases.

Asthma is a chronic airway disease with a relatively high prevalence. Although the etiology of asthma is still not fully clear, there are effective treatments available. The treatment strategy for asthma consists of two steps: maintenance therapy with anti-inflammatory agents (inhaled corticosteroids and/or leukotriene antagonists) to reduce airway inflammation and retain proper lung function and secondly, the use of beta-agonists for quick symptomatic relief. Furthermore, oral steroids are used to treat acute exacerbations. There are large differences in response to drug therapy. This may be due to many factors, such as severity and type of disease, compliance, co-morbidity, co-medication (drug-drug interactions), environmental exposures and age. However, calculations of repeatability of treatment response suggest that part of this variance in response to pharmacotherapy could be due to genetic factors. Pharmacogenetics may explain the inter-individual variability in drug response due to genetic variation. Pharmacogenetics is a relatively new emerging research field that provides the opportunity to discover associations between genetic variation and response to a variety of drugs. This review will discuss the pharmacogenetics of antiinflammatory agents (corticosteroids and leukotriene antagonists) used in the treatment of asthma.