Stretchable Sensor Materials Applicable to Radiofrequency Coil Design in Magnetic Resonance Imaging: A Review.

Wearable sensors are rapidly gaining influence in the diagnostics, monitoring, and treatment of disease, thereby improving patient outcomes. In this review, we aim to explore how these advances can be applied to magnetic resonance imaging (MRI). We begin by (i) introducing limitations in current flexible/stretchable RF coils and then move to the broader field of flexible sensor technology to identify translatable technologies. To this goal, we discuss (ii) emerging materials currently used for sensor substrates, (iii) stretchable conductive materials, (iv) pairing and matching of conductors with substrates, and (v) implementation of lumped elements such as capacitors. Applicable (vi) fabrication methods are presented, and the review concludes with a brief commentary on (vii) the implementation of the discussed sensor technologies in MRI coil applications. The main takeaway of our research is that a large body of work has led to exciting new sensor innovations allowing for stretchable wearables, but further exploration of materials and manufacturing techniques remains necessary, especially when applied to MRI diagnostics.

Integrating a quinone substructure into histone deacetylase inhibitors to cope with Alzheimer's disease and cancer.

Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds 1-8). Among the different compounds, compound 6 turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC50) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound 8 was nontoxic up to the concentration of 100 µM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment.

Phenolic and Antioxidant Characterization of Fruit By-Products for Their Nutraceuticals and Dietary Supplements Valorization under a Circular Bio-Economy Approach.

Agri-food by-products, obtained as waste from the food industry, negatively impact the global economy and the environment. In order to valorize waste materials from fruit juices and tomato sauces as upcycled materials rich in health-promoting compounds, they were characterized in terms of polyphenolic and protein content. The results obtained were compared with those collected for their final products. The recovery of polyphenols was performed via ultrasound-assisted extraction (UAE). A high-performance liquid chromatography-diode array detector (HPLC-DAD) method was developed and validated to depict the quali-quantitative polyphenolic profile of both the by-products and the final products. The antioxidant capacity of the resulting extracts was characterized by UV-Vis spectrophotometric assays in terms of total phenolic content (TPC) and total antioxidant status (TAS). Moreover, the protein content was assessed with the Kjeldahl method too. The results highlighted a significant quantity of polyphenols remaining in peach, apricot, and apple by-products, which were able to exert an antioxidant activity (in the range of 4.95 ± 5.69 × 10-1 to 7.06 ± 7.96 × 10-1 mmol Trolox 100 g-1 of dry weight (DW) sample). Conversely, the tomato by-products were highly rich in proteins (11.0 ± 2.00 to 14.4 ± 2.60 g of proteins 100 g-1 DW). The results proved that all by-products may potentially be sustainable ingredients with nutritional and functional value in a circular bio-economy prospect.

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3ß/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3ß (GSK-3ß). The synthesized compounds are highly potent GSK-3ß, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 µM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Anti-Inflammatory Activity of N'-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide Derivative via sGC-NO/Cytokine Pathway.

The N-acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound N'-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel N-acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent.

Dual-Channel Stretchable, Self-Tuning, Liquid Metal Coils and Their Fabrication Techniques.

Flexible and stretchable radiofrequency coils for magnetic resonance imaging represent an emerging and rapidly growing field. The main advantage of such coil designs is their conformal nature, enabling a closer anatomical fit, patient comfort, and freedom of movement. Previously, we demonstrated a proof-of-concept single element stretchable coil design with a self-tuning smart geometry. In this work, we evaluate the feasibility of scaling this coil concept to a multi-element coil array and the associated engineering and manufacturing challenges. To this goal, we study a dual-channel coil array using full-wave simulations, bench testing, in vitro, and in vivo imaging in a 3 T scanner. We use three fabrication techniques to manufacture dual-channel receive coil arrays: (1) single-layer casting, (2) double-layer casting, and (3) direct-ink-writing. All fabricated arrays perform equally well on the bench and produce similar sensitivity maps. The direct-ink-writing method is found to be the most advantageous fabrication technique for fabrication speed, accuracy, repeatability, and total coil array thickness (0.6 mm). Bench tests show excellent frequency stability of 128 ± 0.6 MHz (0% to 30% stretch). Compared to a commercial knee coil array, the stretchable coil array is more conformal to anatomy and provides 50% improved signal-to-noise ratio in the region of interest.

PROTAC-Induced Glycogen Synthase Kinase 3ß Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease.

Glycogen synthase kinase 3ß (GSK-3ß) is a serine/threonine kinase and an attractive therapeutic target for Alzheimer's disease. Based on proteolysis-targeting chimera (PROTAC) technology, a small set of novel GSK-3ß degraders was designed and synthesized by linking two different GSK-3ß inhibitors, SB-216763 and tideglusib, to pomalidomide, as E3 recruiting element, through linkers of different lengths. Compound 1 emerged as the most effective PROTAC being nontoxic up to 20 µM to neuronal cells and already able to degrade GSK-3ß starting from 0.5 µM in a dose-dependent manner. PROTAC 1 significantly reduced the neurotoxicity induced by Aß25-35 peptide and CuSO4 in SH-SY5Y cells in a dose-dependent manner. Based on its encouraging features, PROTAC 1 may serve as a starting point to develop new GSK-3ß degraders as potential therapeutic agents.

Silicone-based materials with tailored MR relaxation characteristics for use in reduced coil visibility and in tissue-mimicking phantom design.

BACKGROUND: The development of materials with tailored signal intensity in MR imaging is critically important both for the reduction of signal from non-tissue hardware, as well as for the construction of tissue-mimicking phantoms. Silicone-based phantoms are becoming more popular due to their structural stability, stretchability, longer shelf life, and ease of handling, as well as for their application in dynamic imaging of physiology in motion. Moreover, silicone can be also used for the design of stretchable receive radio-frequency (RF) coils. PURPOSE: Fabrication of materials with tailored signal intensity for MRI requires knowledge of precise T1 and T2 relaxation times of the materials used. In order to increase the range of possible relaxation times, silicone materials can be doped with gadolinium (Gd). In this work, we aim to systematically evaluate relaxation properties of Gd-doped silicone material at a broad range of Gd concentrations and at three clinically relevant magnetic field strengths (1.5 T, 3 T, and 7 T). We apply the findings for rendering silicone substrates of stretchable receive RF coils less visible in MRI. Moreover, we demonstrate early stage proof-of-concept applicability in tissue-mimicking phantom development. MATERIALS AND METHODS: Ten samples of pure and Gd-doped Ecoflex silicone polymer samples were prepared with various Gd volume ratios ranging from 1:5000 to 1:10, and studied using 1.5 T and 3 T clinical and 7 T preclinical scanners. T1 and T2 relaxation times of each sample were derived by fitting the data to Bloch signal intensity equations. A receive coil made from Gd-doped Ecoflex silicone polymer was fabricated and evaluated in vitro at 3 T. RESULTS: With the addition of a Gd-based contrast agent, it is possible to significantly change T2 relaxation times of Ecoflex silicone polymer (from 213 ms to 20 ms at 1.5 T; from 135 ms to 17 ms at 3 T; and from 111.4 ms to 17.2 ms at 7 T). T1 relaxation time is less affected by the introduction of the contrast agent (changes from 608 ms to 579 ms; from 802.5 ms to 713 ms at 3 T; from 1276 ms to 979 ms at 7 T). First results also indicate that liver, pancreas, and white matter tissues can potentially be closely mimicked using this phantom preparation technique. Gd-doping reduces the appearance of the silicone-based coil substrate during the MR scan by up to 81%. CONCLUSIONS: Gd-based contrast agents can be effectively used to create Ecoflex silicone polymer-based phantoms with tailored T2 relaxation properties. The relative low cost, ease of preparation, stretchability, mechanical stability, and long shelf life of Ecoflex silicone polymer all make it a good candidate for "MR invisible" coil development and bears promise for tissue-mimicking phantom development applicability.

Overview of Methods for Noise and Heat Reduction in MRI Gradient Coils.

Magnetic resonance imaging (MRI) gradient coils produce acoustic noise due to coil conductor vibrations caused by large Lorentz forces. Accurate sound pressure levels and modeling of heating are essential for the assessment of gradient coil safety. This work reviews the state-of-the-art numerical methods used in accurate gradient coil modeling and prediction of sound pressure levels (SPLs) and temperature rise. We review several approaches proposed for noise level reduction of high-performance gradient coils, with a maximum noise reduction of 20 decibels (dB) demonstrated. An efficient gradient cooling technique is also presented.

Integrated analytical approaches for the characterization of Spirulina and Chlorella microalgae.

Microalgae are well-known for their content of bioactive molecules such as pigments, proteins, fatty acids, polysaccharides, vitamins and antioxidants, all of which are of great interest in the preparation of a wide range of products such as food, cosmetics and nutraceuticals. The purpose of this project was the analytical characterization of commercial dry microalgal biomass: four samples of Chlorella and five of Spirulina were analysed in order to highlight their content in terms of micro/macro nutrients. The research was oriented towards the development and validation of accurate, fast and reproducible methods for the nutritional assessment of algal biomasses, aiming to provide a guiding methodology. The lipid profiles of algal matrixes were analysed for the content of saturated, unsaturated and polyunsaturated fatty acids. The process was divided into two phases: firstly, the extraction and determination of the total lipids and pigment content; secondly, the trans-esterification of the extracted lipid-pigment portion in order to analyse fatty acid methyl esters (FAMEs) with a GC-MS method. A fingerprinting of MUFAs and PUFAs was obtained regarding microalgae species. The determination of total carotenoids and chlorophylls content in the lipid extracts was evaluated through a fast UV-Vis spectrophotometric analysis, which was validated by a new HPLC-DAD analysis. Furthermore, the total antioxidant activity of each lipid extract was determined along with the determination of the microalgae protein content. Then, with the aid of the principal component analysis (PCA) plots, the two microalgae were clustered in terms of their micro/macro nutrients, for differentiating their properties. Spirulina, resulting to have a greater antioxidant activity, supposedly due to a higher content in pigments and higher protein concentration, could be suggested for an appropriate diet for sporting people. Chlorella, instead, showed a more balanced profile of PUFAs and MUFAs and its use could be suggested for cosmetics and vegan diets. This paper puts forward an overall analytical approach, sustained by a multivariate analysis, for emphasising content differences and activity of two different microalgae strains, in order to underline specific claims for each class, addressed to defined final users.

A pathway towards a two-dimensional, bore-mounted, volume body coil concept for ultra high-field magnetic resonance imaging.

Lack of a body-sized, bore-mounted, radiofrequency (RF) body coil for ultrahigh field (UHF) magnetic resonance imaging (MRI) is one of the major drawbacks of UHF, hampering the clinical potential of the technology. Transmit field (B1 ) nonuniformity and low specific absorption rate (SAR) efficiencies in UHF MRI are two challenges to be overcome. To address these problems, and ultimately provide a pathway for the full clinical potential of the modality, we have designed and simulated two-dimensional cylindrical high-pass ladder (2D c-HPL) architectures for clinical bore-size dimensions, and demonstrated a simplified proof of concept with a head-sized prototype at 7 T. A new dispersion relation has been derived and electromagnetic simulations were used to verify coil modes. The coefficient of variation (CV) for brain, cerebellum, heart, and prostate tissues after B1 + shimming in silico is reported and compared with previous works. Three prototypes were designed in simulation: a head-sized, body-sized, and long body-sized coil. The head-sized coil showed a CV of 12.3%, a B1 + efficiency of 1.33 µT/√W, and a SAR efficiency of 2.14 µT/√(W/kg) for brain simulations. The body-sized 2D c-HPL coil was compared with same-sized transverse electromagnetic (TEM) and birdcage coils in silico with a four-port circularly polarized mode excitation. Improved B1 + uniformity (26.9%) and SAR efficiency (16% and 50% better than birdcage and TEM coils, respectively) in spherical phantoms was observed. We achieved a CV of 12.3%, 4.9%, 16.7%, and 2.8% for the brain, cerebellum, heart, and prostate, respectively. Preliminary imaging results for the head-sized coil show good agreement between simulation and experiment. Extending the 1D birdcage coil concept to 2D c-HPLs provides improved B1 + uniformity and SAR efficiency.

Fentanyl pharmacokinetics in blood of cancer patients by Gas Chromatography - Mass Spectrometry.

In order to find a correlation between Fentanyl action on pain and inter-individual variability in different cancer patients, the pharmacokinetic characterization of the drug becomes essential. Therefore, a gas chromatographic-mass spectrometric (GC-MS) in SIM mode analytical procedure has been developed and validated for the determination of Fentanyl in human blood. The sample preparation consisted of a liquid-liquid extraction (LLE) from whole blood. The analysis were carried out with Agilent 7820 A series gas chromatograph equipped with a 5977E series mass selective single quadrupole detector (MSD) with an electron impact (EI) source (70 eV), under a temperature gradient elution. The limit of detection (LoD) and the limit of quantification (LoQ) values were found to be 5.60E-02 ± 3.50E-02 ng mL-1 and 1.86E-01 ± 1.18E-01 ng mL-1 respectively. The developed method was found selective and sensitive and therefore suitable for a fast determination of Fentanyl in human blood and for its pharmacokinetic characterization. Blood samples from 31 cancer patients treated with transdermal Fentanyl (doses in the range of 12-100 µg h-1) were collected at fixed intervals during an overall exposure time of 72 h. The analysis of data and the pharmacokinetic parameters revealed dissimilar pharmacokinetic profiles in the patients examined. Patients were therefore grouped in three categories representing the different trends observed: high, medium and slow responders. These preliminary data provided significant outcomes for a correlation to clinical response.

Aß1-42 peptide toxicity on neuronal cells: A lipidomic study.

Currently Alzheimer's Disease (AD) pathological pathways, which lead to cell death and dementia, are not completely well-defined; in particular, the lipid changes in brain tissues that begin years before AD symptoms. Due to the central role of the amyloid aggregation process in the early phase of AD pathogenesis, we aimed at developing a lipidomic approach to evaluate the amyloid toxic effects on differentiated human neuroblastoma derived SH-SY5Y cells. First of all, this work was performed to highlight qualitative and relative quantitative lipid variations in connection with amyloid toxicity. Then, with an open outcome, the study was focused to find out some new lipid-based biomarkers that could result from the interaction of amyloid peptide with cell membrane and could justify neuroblastoma cells neurotoxicity. Hence, cells were treated with increasing concentration of Aß1-42 at different times, then the lipid extraction was carried out by protein precipitation protocol with 2-propanol-water (90:10 v/v). The LC-MS analysis of samples was performed by a RP-UHPLC system coupled with a quadrupole-time-of-flight mass spectrometer in comprehensive data - independent SWATH acquisition mode. Data processing was achieved by MS-DIAL. Each lipid class profile in SH-SY5Y cells treated with Aß1-42 was compared to the one obtained for the untreated cells to identify (and relatively quantify) some altered species in various lipid classes. This approach was found suitable to underline some peculiar lipid alterations that might be correlated to different Aß1-42 aggregation species and to explore the cellular response mechanisms to the toxic stimuli. The in vitro model presented has provided results that coincide with the ones in literature obtained by lipidomic analysis on cerebrospinal fluid and plasma of AD patients. Therefore, after being validated, this method could represent a way for the preliminary identification of potential biomarkers that could be researched in biological samples of AD patients.

Characterization of a Low-Profile, Flexible, and Acoustically Transparent Receive-Only MRI Coil Array for High Sensitivity MR-Guided Focused Ultrasound.

Magnetic resonance guided focused ultrasound (MRgFUS) is a non-invasive therapeutic modality for neurodegenerative diseases that employs real-time imaging and thermometry monitoring of targeted regions. MRI is used in guidance of ultrasound treatment; however, the MR image quality in current clinical applications is poor when using the vendor built-in body coil. We present an 8-channel, ultra-thin, flexible, and acoustically transparent receive-only head coil design (FUS-Flex) to improve the signal-to-noise ratio (SNR) and thus the quality of MR images during MRgFUS procedures. Acoustic simulations/experiments exhibit transparency of the FUS-Flex coil as high as 97% at 650 kHz. Electromagnetic simulations show a SNR increase of 13× over the body coil. In vivo results show an increase of the SNR over the body coil by a factor of 7.3 with 2× acceleration (equivalent to 11× without acceleration) in the brain of a healthy volunteer, which agrees well with simulation. These preliminary results show that the use of a FUS-Flex coil in MRgFUS surgery can increase MR image quality, which could yield improved focal precision, real-time intraprocedural anatomical imaging, and real-time 3D thermometry mapping.

Natural products as novel scaffolds for the design of glycogen synthase kinase 3ß inhibitors.

INTRODUCTION: The different and relevant roles of GSK-3 are of critical importance since they deal with development, metabolic homeostasis, cell polarity and fate, neuronal growth and differentiation as well as modulation of apoptotic potential. Given their involvement with different diseases, many investigations have been undertaken with the aim of discovering new and promising inhibitors for this target. In this context, atural products represent an invaluable source of active molecules. AREAS COVERED: In order to overcome issues such as poor pharmacokinetic properties or efficacy, frequently associated with natural compounds, different GSK-3ß inhibitors belonging to alkaloid or flavonoid classes have been subjected to structural modifications in order to obtain more potent and safer compounds. Herein, the authors report the results obtained from studies where natural compounds have been used as hits with the aim of providing new kinase inhibitors endowed with a better inhibitory profile. EXPERT OPINION: Structurally modification of natural scaffolds is a proven approach taking advantage of their pharmacological characteristics. Indeed, whatever the strategy adopted is and, despite the limitations associated with the structural complexity of natural products, the authors recommend the use of natural scaffolds as a promising strategy for the discovery of novel and potent GSK-3ß inhibitors.

Multi-target neuroprotective effects of herbal medicines for Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease is the most common form of dementia, but its treatment options remain few and ineffective. To find new therapeutic strategies, natural products have gained interest due to their neuroprotective potential, being able to target different pathological hallmarks associated with this disorder. Several plant species are traditionally used due to their empirical neuroprotective effects and it is worth to explore their mechanism of action. AIM OF THE STUDY: This study intended to explore the neuroprotective potential of seven traditional medicinal plants, namely Scutellaria baicalensis, Ginkgo biloba, Hypericum perforatum, Curcuma longa, Lavandula angustifolia, Trigonella foenum-graecum and Rosmarinus officinalis. The safety assessment with reference to pesticides residues was also aimed. MATERIALS AND METHODS: Decoctions prepared from these species were chemically characterized by HPLC-DAD and screened for their ability to scavenge four different free radicals (DPPH•, ABTS•+, O2•‒ and •NO) and to inhibit enzymes related to neurodegeneration (cholinesterases and glycogen synthase kinase-3ß). Cell viability through MTT assay was also evaluated in two different brain cell lines, namely non-tumorigenic D3 human brain endothelial cells (hCMEC/D3) and NSC-34 motor neurons. Furthermore, and using GC, 21 pesticides residues were screened. RESULTS: Regarding chemical composition, chromatographic analysis revealed the presence of several flavonoids, phenolic acids, curcuminoids, phenolic diterpenoids, one alkaloid and one naphthodianthrone in the seven decoctions. All extracts were able to scavenge free radicals and were moderate glycogen synthase kinase-3ß inhibitors; however, they displayed weak to moderate acetylcholinesterase and butyrylcholinesterase inhibition. G. biloba and L. angustifolia decoctions were the less cytotoxic to hCMEC/D3 and NSC-34 cell lines. No pesticides residues were detected. CONCLUSIONS: The results extend the knowledge on the potential use of plant extracts to combat multifactorial disorders, giving new insights into therapeutic avenues for Alzheimer's disease.

MRSaiFE: An AI-based Approach Towards the Real-Time Prediction of Specific Absorption Rate.

The purpose of this study is to investigate feasibility of estimating the specific absorption rate (SAR) in MRI in real time. To this goal, SAR maps are predicted from 3T- and 7T-simulated magnetic resonance (MR) images in 10 realistic human body models via a convolutional neural network. Two-dimensional (2-D) U-Net architectures with varying contraction layers and different convolutional filters were designed to estimate the SAR distribution in realistic body models. Sim4Life (ZMT, Switzerland) was used to create simulated anatomical images and SAR maps at 3T and 7T imaging frequencies for Duke, Ella, Charlie, and Pregnant Women (at 3, 7, and 9 month gestational stages) body models. Mean squared error (MSE) was used as the cost function and the structural similarity index (SSIM) was reported. A 2-D U-Net with 4 contracting (and 4 expanding) layers and 64 convolutional filters at the initial stage showed the best compromise to estimate SAR distributions. Adam optimizer outperformed stochastic gradient descent (SGD) for all cases with an average SSIM of 90.5∓3.6 % and an average MSE of 0.7∓0.6% for head images at 7T, and an SSIM of >85.1∓6.2 % and an MSE of 0.4∓0.4% for 3T body imaging. Algorithms estimated the SAR maps for 224×224 slices under 30 ms. The proposed methodology shows promise to predict real-time SAR in clinical imaging settings without using extra mapping techniques or patient-specific calibrations.

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects.

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aß42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.

(±)-BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3ß Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.