Bioactive properties of the aromatic molecules of spearmint (Mentha spicata L.) essential oil: a review.

Spearmint belongs to the genus Mentha in the family Labiatae (Lamiaceae), which is cultivated worldwide for its remarkable aroma and commercial value. The aromatic molecules of spearmint essential oil, including carvone, carveol, dihydrocarvone, dihydrocarveol and dihydrocarvyl acetate, have been widely used in the flavors and fragrances industry. Besides their traditional use, these aromatic molecules have attracted great interest in other application fields (e.g., medicine, agriculture, food, and beverages) especially due to their antimicrobial, antioxidant, insecticidal, antitumor, anti-inflammatory and antidiabetic activities. This review presents the sources, properties, synthesis and application of spearmint aromatic molecules. Furthermore, this review focuses on the biological properties so far described for these compounds, their therapeutic effect on some diseases, and future directions of research. This review will, therefore, contribute to the rational and economic exploration of spearmint aromatic molecules as natural and safe alternative therapeutics.

Neuropharmacological potentials of ß-carboline alkaloids for neuropsychiatric disorders.

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. ß-Carboline (ßC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the ßC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that ßC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.

Neurotensins and their therapeutic potential: research field study.

The natural tridecapeptide neurotensin has been emerged as a promising therapeutic scaffold for the treatment of neurological diseases and cancer. In this work, we aimed to identify the top 100 most cited original research papers as well as recent key studies related to neurotensins. The Web of Science Core Collection database was searched and the retrieved research articles were analyzed by using the VOSviewer software. The most cited original articles were published between 1973 and 2013. The top-cited article was by Carraway and Leeman reporting the discovery of neurotensin in 1973. The highly cited terms were associated with hypotension and angiotensin-converting-enzyme. The conducted analysis reveals the therapeutic potentials of neurotensin, and further impactful research toward its clinical development is warrantied.

Vastly extended drug release from poly(pro-17ß-estradiol) materials facilitates in vitro neurotrophism and neuroprotection.

Central nervous system (CNS) injuries persist for years, and currently there are no therapeutics that can address the complex injury cascade that develops over this time-scale. 17ß-estradiol (E2) has broad tropism within the CNS, targeting and inducing beneficial phenotypic changes in myriad cells following injury. To address the unmet need for vastly prolonged E2 release, we report first-generation poly(pro-E2) biomaterial scaffolds that release E2 at nanomolar concentrations over the course of 1-10 years via slow hydrolysis in vitro. As a result of their finely tuned properties, these scaffolds demonstrate the ability to promote and guide neurite extension ex vivo and protect neurons from oxidative stress in vitro. The design and testing of these materials reported herein demonstrate the first step towards next-generation implantable biomaterials with prolonged release and excellent regenerative potential.

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives.

TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.

An Update of Erythrinan Alkaloids and Their Pharmacological Activities.

The period of the past 5 years has witnessed a remarkable increase in all of the number, structural variety, and complexity of erythrinan alkaloids reported. This structural diversity seems to be most pronounced in the alkaloids reported from the two species Erythrina arborescens and Erythrina variegata. Between them, work-up of these taxa yielded new polymeric (dimeric and trimeric) erythrinan alkaloids, a first example in one case where a normal 6,5,6,6-membered indoloisoquinoline spirocylic core has rearranged to a spiro-fused 6,5,7,6-skeleton. Furthermore, erythrinan alkaloids with a fifth ring containing a 2H-imidazole functionality were also reported for the first time, together with some new structures having an unusual substitution and with functionalities at positions C-3 and C-7 of the erythrinan core. This contribution has included 40 more erythrinan alkaloids that are either new or were omitted in the most recent major reviews on the same topic, leading to a total of 154 known erythrinan alkaloids to date. There are a few cases where the structures of the new alkaloids are contestable due to insufficient data having been obtained on isolation. To facilitate easier reference and identification, all structures having a common core have been placed in the same table or figure in this chapter.The reported pharmacological activities of the new and known erythrinan alkaloids documented have shown a considerable bias towards central nervous system and related activities. Other prominent activities that have been reported are antifeedant, insecticidal, cytotoxic, antiprotozoal, anti-inflammatory, antioxidant, antifungal, and antiviral effects. Erythrinan alkaloids generally seem to lack antibacterial activity. Several new polymeric alkaloids were found to lack cytotoxicity against a number of human cancer cell lines, although two of them showed moderate aphicidal activity and one exhibited weak to moderate acetylcholinesterase inhibition. The biological activity of erythrinan alkaloids seems to be influenced by basic substructural requirements, such as a conjugated diene (Δ1,2, Δ6,7) system and is modulated by the presence (or absence) of other groups in rings A, B, C, and D of the erythrinan core. The erythrinan core may provide potential leads to structures that eventually may be useful therapeutically.In recent years, a number of stereoselective chemical synthesis methods have been applied towards the erythinan alkaloids, and these are described in this contribution.

Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3ß and Tau-Aggregation Inhibitors.

Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3ß and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3ß, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 µM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.

Applications of Multi-Target Computer-Aided Methodologies in Molecular Design of CNS Drugs.

The discovery of drugs for diseases of the central nervous system (CNS) faces high attrition rates in clinical trials. Neural diseases are extremely complex in nature and typically associated with multiple drug targets. A conception of multi-target directed ligands (MTDL), widely applied to the discovery of cancer pharmaceuticals, may be a perspective solution for CNS diseases. Special bioinformatics approaches have been developed which can assist the medicinal chemists in identification and structural optimization of MTDL. In this review, we analyze the current status of the development of multitarget approaches in quantitative structure-activity relationships (mt-QSAR) for CNS drug discovery; and describes applications of multi-target approaches in molecular modelling (which can be called mt-MM), as well as perspectives for multi-target approaches in bioinformatics in relation to Alzheimer's disease.

Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease.

INTRODUCTION: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-ß aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. METHODS: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 EΔ9 mutations, 13 sporadic AD, and 14 control cases. RESULTS: 3H-PIB, 3H-florbetaben, 3H-AZD2184, and BTA-1 shared a high- and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The 3H-AZD2184 and 3H-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on 3H-AZD84 binding followed by 3H-florbetaben and minimal on 3H-PIB. DISCUSSION: This study implies amyloid tracers of different structures detect different sites on amyloid-ß fibrils or conformations.

Chemical Composition and in Vitro Antimicrobial, Cytotoxic, and Central Nervous System Activities of the Essential Oils of Citrus medica L. cv. 'Liscia' and C. medica cv. 'Rugosa' Cultivated in Southern Italy.

Citrus medica cv. 'liscia' and C. medica cv. 'rugosa' are two taxa of citron, belonging to the biodiversity of South Italy, in particular of Amalfi Coast, in the Campania region. The chemical composition of the essential oils (EOs) from fruit peels of both C. medica cultivars was studied by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) analyses. In all, 100 compounds were identified, 82 for C. medica cv. 'liscia', accounting for 91.4% of the total oil, and 88 for C. medica cv. 'rugosa', accounting for 92.0% of the total oil. Monoterpene hydrocarbons are the main constituents in both oils of C. medica cv. 'liscia' (79.1%) and C. medica cv. 'rugosa' (80.2%). In both oils, limonene (67.2%-62.8%) and camphene (8.5%-10.9%) are the main constituents. The antimicrobial activity of the EOs was assayed against some bacterial strains: Bacillus cereus (DSM 4313), Bacillus cereus (DSM 4384), Staphylococcus aureus (DSM 25693), Pseudomonas aeruginosa (ATCC 50071), and Escherichia coli (DSM 8579). Low concentrations of C. medica cv. 'rugosa' EO showed an inhibitory effect on P. aeruginosa and higher concentrations inhibited more B. cereus (4384) and E. coli than S. aureus. The cytotoxicity of the EO was evaluated against SH-SY5Y cell line. The influence of the EO on the expression of adenylate cyclase 1 (ADCY1) was also studied. The antimicrobial activity registered confirm their traditional uses as food preserving agents and led us to hypothesize the possible use of these oils as antimicrobials. The alterations in ADCY1 expression suggested a role for limonene in effects on the central nervous system.

Novel anionic polymer as a carrier for CNS delivery of anti-Alzheimer drug.

Natural and plant-based polymers could be used for control release of drugs and also helps in targeting drug to the site of action. The main objective of present work was to check the feasibility of plant-based, namely, mango gum polymeric nanoparticles (NPs) as a carrier for central nervous system (CNS) delivery using model drug donepezil (DZP). The NPs were prepared by modified ionic gelation method and emulsion cross-linking method. Zeta sizer results showed that the diameter of NPs was about 90-130 nm. The polymeric DZP-loaded NPs were almost spherical in shape, as revealed by transmission electron microscopy (TEM). On increasing concentration of NPs suspension from 50 µg/ml to 5000 µg/ml there was no significant increase in % hemolysis. In vivo studies showed that brain targeting was achieved. So on the basis of above results, the extracted water soluble fraction of mango gum is a suitable candidate for brain delivery in the form of nanoformulations.

Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

1, 2-Benzisoxazole: A Privileged Structure with a Potential for Polypharmacology.

BACKGROUND: Privileged structures are potentially able to bind to a diverse range of biologically important proteins with high affinities, thus benefiting the discovery of novel bioactive compounds. 1,2-Benxisoxazole derivatives can be such important types of "privileged structures" possessing a rich diversity of biological properties especially in the area of CNS disorders. METHODS: This review seeks to explore the most significant examples of 1,2-benzisoxazoles as privileged structures in terms of polypharmacology at the molecular level, specifically focusing on four 1,2-benzisoxazoles (zonisamide, risperidone, paliperidone, and iloperidone) which have been in clinical use and established as effective therapeutics. Furthermore, an updated and detailed account of the pharmacological properties of 1,2-benzisoxazole derivatives as therapeutics for CNS disorders is described. And finally, outlooks on current issues and future directions in this field are also provided. RESULTS: 1,2-Benzisoxazole was successfully employed in the discovery and development of zonisamide for the treatment of epilepsy and Parkinson's disease. 1,2- Benzisoxazole is also a significantly important structure for the development of atypical antipsychotics. CONCLUSION: It is very reasonable to say that 1,2-benzisoxazole is a good example of a privileged structure because it forms the centerpiece of small molecule chemical entities with a wide range of pharmacological properties, especially in the area of CNS disorders.

Challenges and new strategies for therapeutic peptide delivery to the CNS.

Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood-brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions.

Annona muricata (Annonaceae): A Review of Its Traditional Uses, Isolated Acetogenins and Biological Activities.

Annona muricata is a member of the Annonaceae family and is a fruit tree with a long history of traditional use. A. muricata, also known as soursop, graviola and guanabana, is an evergreen plant that is mostly distributed in tropical and subtropical regions of the world. The fruits of A. muricata are extensively used to prepare syrups, candies, beverages, ice creams and shakes. A wide array of ethnomedicinal activities is contributed to different parts of A. muricata, and indigenous communities in Africa and South America extensively use this plant in their folk medicine. Numerous investigations have substantiated these activities, including anticancer, anticonvulsant, anti-arthritic, antiparasitic, antimalarial, hepatoprotective and antidiabetic activities. Phytochemical studies reveal that annonaceous acetogenins are the major constituents of A. muricata. More than 100 annonaceous acetogenins have been isolated from leaves, barks, seeds, roots and fruits of A. muricata. In view of the immense studies on A. muricata, this review strives to unite available information regarding its phytochemistry, traditional uses and biological activities.

Recent advances in the chemistry and biology of pyridopyrimidines.

The interest in pyridopyrimidine cores for pharmaceutical products makes this scaffold a highly useful building block for organic chemistry. These derivatives have found applications in various areas of medicine such as anticancer, CNS, fungicidal, antiviral, anti-inflammatory, antimicrobial, and antibacterial therapies. This review mainly focuses on the progress achieved since 2004 in the chemistry and biological activity of pyridopyrimidines.

Iron catalysed cross-couplings of azetidines - application to the formal synthesis of a pharmacologically active molecule.

A protocol for the coupling of 3-iodoazetidines with Grignard reagents in the presence of an iron catalyst has been developed. A variety of aryl, heteroaryl, vinyl and alkyl Grignards were shown to participate in the coupling process to give the products in good to excellent yields. Furthermore, a short formal synthesis towards a pharmacologically active molecule was shown.

Central-stimulating and analgesic activity of the ethanolic extract of Alternanthera sessilis in mice.

BACKGROUND: Alternanthera sessilis is a popular vegetable and used in traditional medicinal practice of Bangladesh and other parts of Asia to relive tiredness, laziness, and sleeps as well as pain and inflammation. However, no report was found on the neuropharmacological and analgesic activity of this plant to-date. Present study was undertaken to evaluate the neuropharmacological and analgesic activity of the ethanol extract of A. sessilis whole plant (ETAS) in mice models. METHODS: Central stimulating activity was investigated by pentobarbitone induced sleeping time, open field, and hole cross tests. Analgesic activity was evaluated by acetic acid induced writhing and hot-plate methods. The tests were performed at 250 and 500 mg/kg body weight dose levels. RESULTS: In sleeping time test, ETAS significantly (p < 0.001) increased the onset of sleep, and decreased the duration of sleep. In open field and hole cross tests, ETAS significantly (p < 0.001) increased the movements of mice which persisted throughout the study period. In writhing test, ETAS showed, significant (p < 0.001) inhibition of writhing reflex. In hot plate test, ETAS significantly (p < 0.001) raised the pain threshold. In HPLC analysis for polyphenols, (+)-catechin, rutin, ellagic acid, and quercetin were detected in ETAS (117.72, 490.74, 3007.26, and 13.85 mg/100 g of dry extract, respectively). CONCLUSION: Present study supported the traditional uses of A. sessilis and indicated that the plant can be a potential source of bioactive molecules.

5-HT(1A) receptor: an old target as a new attractive tool in drug discovery from central nervous system to cancer.

The serotonin receptor subtype 5-HT(1A) was one of the first serotonin receptor subtypes pharmacologically characterized. This receptor subtype has long been object of intense research and is implicated in the pathogenesis and treatment of anxiety and depressive disorders. In recent years, new chemical entities targeting the 5-HT(1A) receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic uses in neuroprotection, cognitive impairment, Parkinson's disease, pain treatment, malignant carcinoid syndrome, and prostate cancer. This Perspective compares existing data on expression and signaling activity of the 5-HT(1A) receptor to a ligand with an intrinsic agonist or antagonist profile. Our purpose is also to make a complete overview, useful for underlining the features needed to select a specific pharmacological profile rather than another one. This aspect could be really interesting to consider and justify the 5-HT(1A) receptor as a new attractive target for drug discovery.

Exposure to inhaled particulate matter activates early markers of oxidative stress, inflammation and unfolded protein response in rat striatum.

To study central nervous system airborne PM related subchronic toxicity, SD male rats were exposed for eight weeks to either coarse (32 µg/m³), fine (178 µg/m³) or ultrafine (107 µg/m³) concentrated PM or filtered air. Different brain regions (olfactory bulb, frontal cortex, striatum and hippocampus), were harvested from the rats following exposure to airborne PM. Subsequently, prooxidant (HO-1 and SOD-2), and inflammatory markers (IL-1ß and TNFα), apoptotic (caspase 3), and unfolded protein response (UPR) markers (XBP-1S and BiP), were also measured using real-time PCR. Activation of nuclear transcription factors Nrf-2 and NF-κB, associated with antioxidant and inflammation processes, respectively, were also analyzed by GSMA. Ultrafine PM increased HO-1 and SOD-2 mRNA levels in the striatum and hippocampus, in the presence of Nrf-2 activation. Also, ultrafine PM activated NF-κB and increased IL-1ß and TNFα in the striatum. Activation of UPR was observed after exposure to coarse PM through the increment of XBP-1S and BiP in the striatum, accompanied by an increase in antioxidant response markers HO-1 and SOD-2. Our results indicate that exposure to different size fractions of PM may induce physiological changes (in a neuroanatomical manner) in the central nervous system (CNS), specifically within the striatum, where inflammation, oxidative stress and UPR signals were effectively activated.