Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (v.12, #2)

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 parasympatheticnervous fibers but also in non neuronal cells. This knowledge led to expand the role of ACh as a neurotransmitterand to consider it as a "cytotransmitter" and also to evaluate the existence of a non-neuronal cholinergic system comprisingACh, ChAT, acetylcholinesterase, and the nicotinic and muscarinic ACh receptors, outside the nervous system. Thisreview analyzes the participation of cholinergic system in inflammation and discusses the role of different muscarinic andnicotinic drugs that are being used to treat skin inflammatory disorders, asthma, and chronic obstructive pulmonary diseaseas well as, intestinal inflammation and systemic inflammatory diseases, among others, to assess the potential applicationof these compounds as therapeutic tools.

Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, α -Synuclein Synthesis, Interleukin-1β Release, and Cholinergic Action. by Qian-sheng Yu, Marcella Reale, Mohammad A. Kamal, Harold W. Holloway, Weiming Luo, Kumar Sambamurti, Balmiki Ray, Debomoy K. Lahiri, Jack T. Rogers, Nigel H. Greig (117-128).
A major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques thatare 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 Aβ levels by lowering the rate ofAPP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its threemajor metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), wererequired 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, theAD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All thecompounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compoundsbound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinicaltrial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclearcells was evaluated, and found to be potently inhibited by both agents.

Molecular Interaction Study of N1-p-fluorobenzyl-cymserine with TNF-α , p38 Kinase and JNK Kinase by Sidra Batool, Muhammad Sulaman Nawaz, Nigel H. Greig, Mohd Rehan, Mohammad A. Kamal (129-135).
Alzheimer's disease (AD) is an age-related neurodegenerative disease distinguished by progressive memoryloss 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 clustersof activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesisof AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied byan elevated expression of inflammatory mediators that further drives Aβ and p-tau generation. Although epidemiologicaland experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen ADrisk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevatedsystemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, andBuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevatesacetylcholine (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 developedto test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the currentstudy was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interactionbetween inflammation,Aβ and 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-α with respect to putative binding free energy and IC50 values. Our in-silico studies support the abilityof FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamicsand physiochemical studies for auxiliary confirmation.

MicroRNA: Novel Modulators of the Cholinergic Anti-Inflammatory Pathway by Medha Priyadarshini, N.A. Arivarasu, Aaliya Shah, Shams Tabrez, Shubha Priyamvada, Mohd. Aatif (136-140).
MicroRNAs (miRNAs) have emerged as key gene regulators controlling the expression of many targetmRNAs. 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 tuningof the immune responses. Besides controlling the maturation, proliferation and differentiation of myeloid and lymphoidlineages they participate directly by modulating the signaling pathways through the Toll-like receptors and thus thecytokine response. The miRNAs commuting between the nervous and immune systems and affecting the neuro-immunedialogue are emerging.

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

Anti-Inflammatory, Antibacterial and Analgesic Potential of Cocos Nucifera Linn.: A Review by Kamal Dua, Ravi Sheshala, Teck Ying Ling, Shiau Hui Ling, Adinarayana Gorajana (158-164).
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 onthe 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 andparticularly as an anti-inflammatory, antimicrobial and analgesic agent. This review emphasizes on the recent literatureand 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 apivotal role in Familial Mediterranean Fever (FMF) pathogenesis. We investigated neutrophil F-actin, phagocytosis andmacropinocytosis dynamics during neutrophil chemoattractant-dependent activation in FMF patients carrying mutations inthe MEFV locus. We found that while a non-stimulated neutrophil shows an increased overall F-actin content in patientswith 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 doubledoses 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 maycontribute to the decreasing of plasticity of the cellular cytoskeleton during FMF. Colchicine causes reduction of overallF-actin content and shows a distinctively unequal effect on chemoattractant-activated neutrophil F-actin dynamics in FMFpatients compared with healthy donors. These data suggested that mutations in MEFV cause the dissolution of cellular adaptationto chemoattractant stimuli due to alterations in neutrophil F-actin and phagocytosis dynamics, which could serveas a major target for FMF treatment.

Previously, we have meticulously examined the efficacy of the measurable antimicrobial activity of sweetcherry (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 varietyof extracts of sweet cherries, antioxidant compounds of immunological significance, including L-ascorbic acid (vitaminC), phenols, flavonoids, and anthocyanins, and the total antioxidant (free radical scavenging) activity were simultaneouslymeasured under varying and versatile extraction conditions (mild heating [5, 10 and 20 min.], and brief microwaveexposure [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 versatileextraction 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 contentwas not affected with mild to prolonged heating or microwave exposure, except tangibly with dPOM and mPOM. The totalphenols content assessed showed no significant variations, as compared with control extracts. In a manner similar toascorbic acid, total flavonoids were mildly reduced under varying conditions, an effect mimicked to a certain extent withanthocyanins. Assessment of extraction means as compared with WJE revealed sharp decrease in the antioxidant activityfor dPOM and mPOM, significant increase in L-ascorbic acid, total phenol, and flavonoid contents for MEJ, dPOM, andmPOM, and mild decrease in anthocyanin contents for dPOM and mPOM. These results confirm the measurable antioxidantactivities and contents of P. avium extracts under versatile conditions of mild exposure, an effect bearing significantbiochemical properties of a variety of extraction methods. Further studies are currently investigating the effect of specificantioxidants of P. avium on microbial growth in vitro per se. Since many of the aforementioned molecules hold immunobiochemicalconstituencies, antioxidant compounds in sweet cherries may have putative anti-inflammatory potential inmedicinal chemistry, corroborating the observation of regulating/attenuating the growth of microorganisms of medicalimportance in vitro.