Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 12, Issue 2, 2013

Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) from acetylcoenzime A and choline. This reaction occurs not only in pre-ganglionic fibers of the autonomic nervous system and post-ganglionic parasympathetic nervous fibers but also in non neuronal cells. This knowledge led to expand the role of ACh as a neurotransmitter and to consider it as a “cytotransmitter” and also to evaluate the existence of a non-neuronal cholinergic system comprising ACh, ChAT, acetylcholinesterase, and the nicotinic and muscarinic ACh receptors, outside the nervous system. This review analyzes the participation of cholinergic system in inflammation and discusses the role of different muscarinic and nicotinic drugs that are being used to treat skin inflammatory disorders, asthma, and chronic obstructive pulmonary disease as well as, intestinal inflammation and systemic inflammatory diseases, among others, to assess the potential application of these compounds as therapeutic tools.

A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβlevels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.

Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid- beta peptide (Aβ)containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Aβand p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase- inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation,Aβand p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-αwith respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation.

MicroRNAs (miRNAs) have emerged as key gene regulators controlling the expression of many target mRNAs. The nervous system harbors highest number of miRNAs expressed in a spatially and temporally controlled manner. Neural miRNAs have been accredited with diverse roles like regulation of neural differentiation, synaptogenesis, inflammation, memory and cognition. Their aberrant expression and/or function has been linked to various neurodegenerative, neuroinflammatory and stress related disorders. Recent evidence indicates that miRNAs are essential to the fine tuning of the immune responses. Besides controlling the maturation, proliferation and differentiation of myeloid and lymphoid lineages they participate directly by modulating the signaling pathways through the Toll-like receptors and thus the cytokine response. The miRNAs commuting between the nervous and immune systems and affecting the neuro-immune dialogue are emerging.

Responses to oxidative stress are generally regulated by redox-responsive transcription factors (TFs). The abrupt variation in the partial pressure of oxygen (pO2) constitutes a regulatory mechanism. Such TFs forming an integral part of those putative pathways are hypoxia-inducible factor-1α(HIF)-1αand nuclear factor-κB (NF-κB), both are sufficiently tuned to govern such a specific response. Reactive species are produced during this transition and the antioxidant defense system controls their production. Oxidative stress occurs when there is imbalance between the production and removal of reactive species. Evidence exists showing that enhancement of the antioxidant defense system can reduce markers of oxidative stress. Recognition of reactive species and redox-mediated modifications as signals may open up a field of cell regulation via targeted control of TFs and hence can providea novel way of controlling diseases. This synopsis summates the major cutting-edge research work in the field of oxidative stress, and surgically identifies common and unique pathways involved with oxidative stress as means of regulatory elements governing TFs.

At present, approximately 25%of drugs in modern pharmacopoeia are derived from plant sources (phytomedicines) that can be developed for the treatment of diseases and disorders. Many other drugs are synthetic analogues built on the prototype compounds isolated from plants. Cocos nucifera Linn. (Arecaceae), which is commonly known as coconut, is a plant possessing a lot of potential as an ingredient in traditional medicines for the treatment of metabolic disorders and particularly as an anti-inflammatory, antimicrobial and analgesic agent. This review emphasizes on the recent literature and research findings that highlight the significant biological activities of C. nucifera Linn. such as its anti-inflammatory, antimicrobial and analgesic properties. This review can help researchers keen on exploiting the therapeutic potential of C. nucifera Linn. which may motivate them to further explore their commercial viability.

In the innate immune system, cellular adaptation regulates neutrophil activation and chemotaxis, which have a pivotal role in Familial Mediterranean Fever (FMF) pathogenesis. We investigated neutrophil F-actin, phagocytosis and macropinocytosis dynamics during neutrophil chemoattractant-dependent activation in FMF patients carrying mutations in the MEFV locus. We found that while a non-stimulated neutrophil shows an increased overall F-actin content in patients with FMF, the activation-dependent F-actin dynamics in the presence of chemoattractant peptide is significantly reduced. Neither overall F-actin content nor F-actin dynamics was changed in FMF patient’s neutrophils in the presence of double doses of chemoattractant, while in healthy donors it occurred with significant reduction of F-actin content and dynamics. The neutrophil shows increased phagocytosis and macropinocytosis dynamics for a relatively short period, which may contribute to the decreasing of plasticity of the cellular cytoskeleton during FMF. Colchicine causes reduction of overall F-actin content and shows a distinctively unequal effect on chemoattractant-activated neutrophil F-actin dynamics in FMF patients compared with healthy donors. These data suggested that mutations in MEFV cause the dissolution of cellular adaptation to chemoattractant stimuli due to alterations in neutrophil F-actin and phagocytosis dynamics, which could serve as a major target for FMF treatment.

Previously, we have meticulously examined the efficacy of the measurable antimicrobial activity of sweet cherry (Prunus avium) extracts on a wide spectrum of gram-positive and gram-negative bacteria, in addition to the fungus, Candida albicans, a priori. In order to further understand the biochemical constituents and antioxidant activities of a variety of extracts of sweet cherries, antioxidant compounds of immunological significance, including L-ascorbic acid (vitamin C), phenols, flavonoids, and anthocyanins, and the total antioxidant (free radical scavenging) activity were simultaneously measured under varying and versatile extraction conditions (mild heating [5, 10 and 20 min.], and brief microwave exposure [1, 2 and 5 min.]) for a variety of extracts: i) whole juice extracts (WJE), ii) methanol-extracted juice (MEJ), iii) ddH2O-extracted pomace (dPOM), and iv) methanol-extracted pomace (mPOM). The antioxidant activity under the versatile extraction conditions adopted in this study was conspicuously reduced, such that the %inhibition against 2,2- diphenyl-1-picrylhydrazyl (DPPH) followed an inverse, negative correlational trendline. Moreover, ascorbic acid content was not affected with mild to prolonged heating or microwave exposure, except tangibly with dPOM and mPOM. The total phenols content assessed showed no significant variations, as compared with control extracts. In a manner similar to ascorbic acid, total flavonoids were mildly reduced under varying conditions, an effect mimicked to a certain extent with anthocyanins. Assessment of extraction means as compared with WJE revealed sharp decrease in the antioxidant activity for dPOM and mPOM, significant increase in L-ascorbic acid, total phenol, and flavonoid contents for MEJ, dPOM, and mPOM, and mild decrease in anthocyanin contents for dPOM and mPOM. These results confirm the measurable antioxidant activities and contents of P. avium extracts under versatile conditions of mild exposure, an effect bearing significant biochemical properties of a variety of extraction methods. Further studies are currently investigating the effect of specific antioxidants of P. avium on microbial growth in vitro per se. Since many of the aforementioned molecules hold immunobiochemical constituencies, antioxidant compounds in sweet cherries may have putative anti-inflammatory potential in medicinal chemistry, corroborating the observation of regulating/attenuating the growth of microorganisms of medical importance in vitro.