Yoram Cohen - Profile on Academia.edu (original) (raw)
Papers by Yoram Cohen
Journal of Neurotrauma, 2018
Cannabis is one of the most widely used plant drugs in the world today. In spite of the large num... more Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana, there still exists much controversy surrounding its use and the potential for abuse due to the undesirable psychotropic effects. However, recent developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the psychoactivity. We have previously shown that treatment with the endocannabinoid 2-AG, which binds to both CB 1 and CB 2 receptors 1 h after traumatic brain injury in mice, attenuates neurological deficits, edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region, and neuroinflammation. Recently, we synthesized a set of camphor-resorcinol derivatives, which represent a novel series of CB 2 receptor selective ligands. Most of the novel compounds exhibited potent binding and agonistic properties at the CB 2 receptors with very low affinity for the CB 1 receptor, and some were highly anti-inflammatory. This selective binding correlated with their intrinsic activities. HU-910 and HU-914 were selected in the present study to evaluate their potential effect in the pathophysiology of traumatic brain injury (TBI). In mice and rats subjected to closed-head injury and treated with these novel compounds, we showed enhanced neurobehavioral recovery, inhibition of tumor necrosis factor a production, increased synaptogenesis, and partial recovery of the cortical spinal tract. We propose these CB 2 agonists as potential drugs for development of novel therapeutic modality to TBI.
![Research paper thumbnail of Advanced <sup>19</sup>F-NMR Studies Shed New Light on Encapsulation of Isosteric Guests in the Hexameric Capsules of Resorcin[4]arenes and Pyrogallol[4]arenes](https://attachments.academia-assets.com/117201953/thumbnails/1.jpg)
](Organic chemistry frontiers, 2024
Advanced 19 F-NMR studies shed new light on encapsulation of isosteric guests in the hexameric ca... more Advanced 19 F-NMR studies shed new light on encapsulation of isosteric guests in the hexameric capsules of resorcin[4]arenes and pyrogallol[4] arenes †
Neurotoxicology, May 1, 2015
Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo a... more Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. Methods: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1-no central antidotal treatment (n = 10); group 2-treated with midazolam (MID) at 30 min after poisoning (n = 9), group 3-treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1 H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetylaspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. Results: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID + SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3 h after exposure (1.1 AE 0.07 and 1.42 AE 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h NAA/Cr decrease (1.22 AE 0.05 and 1.32 AE 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p < 0.05). Conclusions: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with
The Journal of Organic Chemistry, 2013
Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely importa... more Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as 64 Cu, 89 Zr, 11 In, and more.
Temperature‐Dependent and pH‐Responsive Pillar[5]arene‐Based Complexes and Hydrogen‐Bond‐Based Supramolecular Pentagonal Boxes in Water
Chemistry – A European Journal, 2020
Supramolecular systems in water are of paramount importance and those based on hydrogen-bonds are... more Supramolecular systems in water are of paramount importance and those based on hydrogen-bonds are both intriguing and scarce. Here after studying the peculiar host-guest complexes formed between per-dimethylamino-pillar[5]arene 1 and the bis-sulfonates 2a-c, we describe the formation of the first hydrogen bond-based supramolecular pentagonal boxes (SPBs) which are stable in water. These pH-responsive SPBs are constructed from 1 as a body, benzene polycarboxylic acids (3a-b) as lid compounds and 2a-c as guests. We demonstrate that encapsulation of 2a-c in pillar[5]arene 1 and in the highly stable water-soluble SPBs, i. e., 1(3a)2 and 1(3b)2, is both temperature and pH dependent and, quite interestingly, depends, on the nature of the lid compounds used for capping the boxes even at high pH. We also highlight the difference in the 1H-NMR characteristics of 2b and 2c in the cavity of 1 and the SPBs.
Background and Purpose: Brain addosis from cerebral ischemia is characterized by average intracei... more Background and Purpose: Brain addosis from cerebral ischemia is characterized by average intraceiiular pH levels of approximately 5.8-6.2, which appear in turn to worsen cellular injury. We report that the brain is not injured when hypercapnia is used to reduce intraceiiular pH to about 62 during adequate oxygenation. A hyperbaric chamber is needed to achieve intraceiiular pH values so low because inspired CO 2 tensions must be increased to approximately 1 atm. Summary of Report: Using in vivo phosphorus-31 and proton nuclear magnetic resonance spectroscopy, we measured brain intraceiiular pH and lactate concentration of rats inside a nonmagnetic polycarbonate chamber at a barometric pressure of 1,500 mm Hg. Intubated rats were ventilated with a 50% O 2 /50% CO 2 gas mixture for specific times. All six rats ventilated for 15 minutes with CO 2 tensions of approximately 750 mm Hg woke up without neurological impairment, despite a decrease in intraceiiular pH to about 62. Higher CO 2 tensions and longer exposures resulted in cardiovascular collapse and sudden death, followed by the postmortem appearance of brain lactate. Conclusions: Brain intraceiiular pH values near 62 can be induced briefly in vivo in ventilated rats without injury under hyperbaric hypercapnic conditions. If attempts are made to lower brain pH in vivo even further by increasing PcOj beyond 750 mm Hg, mean arterial blood pressure and cerebral blood flow decrease to values incompatible with life.
NeuroToxicology, 2015
Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo a... more Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. Methods: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 -no central antidotal treatment (n = 10); group 2 -treated with midazolam (MID) at 30 min after poisoning (n = 9), group 3 -treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1 H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetylaspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. Results: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID + SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3 h after exposure (1.1 AE 0.07 and 1.42 AE 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h NAA/Cr decrease (1.22 AE 0.05 and 1.32 AE 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p < 0.05). Conclusions: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with
![Research paper thumbnail of Unique organization of solvent molecules within the hexameric capsules of pyrogallol[4]arene in solution](https://attachments.academia-assets.com/84622995/thumbnails/1.jpg)
](Organic letters, Jan 7, 2014
The hexameric capsules of pyrogallol[4]arene (2b) were prepared in nondeuterated solvents in the ... more The hexameric capsules of pyrogallol[4]arene (2b) were prepared in nondeuterated solvents in the absence and presence of adamantane carboxylic acid (3). The small encapsulated molecules were shown to occupy different sites within the same capsule. In the presence of 3, which are also encapsulated in the hexameric capsules, one observes yet another pair of signals for the encapsulated solvent molecules. Different NMR experiments enabled assignment of the different sites within the hexameric capsules of 2b.
Publisher’s Note: Magnetic Resonance Imaging by Synergistic Diffusion-Diffraction Patterns [Phys. Rev. Lett. 108, 058103 (2012)]
Physical Review Letters, 2012
NMR in Biomedicine, 2011
The accurate characterization of pore morphology is of great interest in a wide range of scientif... more The accurate characterization of pore morphology is of great interest in a wide range of scientific disciplines. Conventional single-pulsed field gradient (s-PFG) diffusion MR can yield compartmental size and shape only when compartments are coherently ordered using q-space approaches that necessitate strong gradients. However, double-PFG (d-PFG) methodology can provide novel microstructural information even when specimens are characterized by polydispersity in size and shape, and even when anisotropic compartments are randomly oriented. In this study, for the first time, we show that angular d-PFG experiments can be used to accurately measure cellular size and shape anisotropy of fixed yeast cells employing relatively weak gradients. The cell size, as measured by light microscopy, was found to be 5.32AE0.83mm, whereas the results from noninvasive angular d-PFG experiments yielded a cell size of 5.46AE0.45mm. Moreover, the low compartment shape anisotropy of the cells could be inferred from experiments conducted at long mixing times. Finally, similar experiments were conducted in a phantom comprising anisotropic compartments that were randomly oriented, showing that angular d-PFG MR provides novel information on compartment eccentricity that could not be accessed using conventional methods. Angular d-PFG methodology seems to be promising for the accurate estimation of compartment size and compartment shape anisotropy in heterogeneous systems in general, and biological cells and tissues in particular.
NMR in Biomedicine, 2009
Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is als... more Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is also used for efficacy studies. To date, the morphological and spectroscopic indices of this model have not been studied longitudinally by MRI; therefore the objectives of this study were aimed at following the lesion progression and changes in N-acetyl aspartate (NAA) as viewed by MRI and MRSI, respectively, in-vivo over a period of 49 days. We found that the affected areas exhibited both high and low apparent diffusion coefficients (ADC) even 49 days post QA injection in three of the six tested animals. MRI-guided histological analysis correlated areas characterized by high ADCs on day 49 with cellular loss, while areas characterized by lower ADCs were correlated with macrophage infiltration (CD68 positive stain). Our MRSI study revealed an initial reduction of NAA levels in the lesioned striatum, which significantly recovered with time, although not to control levels. Total-striatum normalized NAA levels recovered from 0.67 W 0.15 (of the contralateral row) on day 1 to 0.90 W 0.12 on day 49. Our findings suggest that NAA should be considered as a marker for neuronal dysfunction, in addition to neuronal viability. Some behavioral indices could be correlated to permanent neuronal damage while others demonstrated a spontaneous recovery parallel to the NAA recovery. Our findings may have implications in efficacy-oriented studies performed on the QA model.
Magnetic Resonance in Medicine, 1993
A description is given of the design, construction, and initial use of a polycarbonate resin hype... more A description is given of the design, construction, and initial use of a polycarbonate resin hyperbaric chamber for in vivo NMR spectroscopy studies of anesthetized, ventilated rats in a horizontal bore 4.7 Tesla magnet. The chamber and its associated equipment, initially used for hyperbaric studies of rats in states of extreme hypercapnia, are also well suited for conventional hyperbaric studies, such as those related to hyperbaric oxygen therapy, oxygen toxicity, and diving. Basic technical challenges that required innovations involved: a) preservation of magnetic field homogeneity; b) avoidance of a metallic chamber body that would overload gradient and RF coils; c) physiological monitoring; and, d) remote control and stabilization of electromagnetic and physiologic factors (especially ventilatory stability) during pressure changes. A small paramagnetic bulk magnetic susceptibility shift from chamber-associated hyperbaric oxygen was observed when chamber oxygen tensions were only one atmosphere. High-quality NMR imaging and spectroscopy were demonstrated during hyperbaric conditions.
The Journal of Organic Chemistry, 1999
The ligands 6,6′-bis [(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] 2,2′-bipyridine (1... more The ligands 6,6′-bis [(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] 2,2′-bipyridine (1)and 2,9-bis[(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] -1,10-phenanthroline (2) were prepared and shown to self-assemble into double-stranded [(L) 2 Cu 3 ] 3+ -type helicates upon reaction with Cu + . Although the reaction of 1 with AgCF 3 SO 3 afforded the double-stranded helicate [(1) 2 Ag 3 ] 3+ , reaction of 2 with this salt yielded a mixture of several complexes, all of apparently double-strand nature, based on their diffusion coefficients. Addition of a large excess of AgCF 3 SO 3 afforded [(2) 2 Ag 3 ] 3+ as the sole product. In addition, it was found that the reaction of Cu + with mixtures of 1 and 6′′,6′′′-bis[(6-methyl-2,2′-bipyridin-6′-yl)methylenoxymethylenyl]-2′′,2′′′-bipyridine (4) or of 2 with 2,9-bis[(6-methyl-2,2-bipyridin-6′-yl)methylenoxymethylenyl]-1,10-phenanthroline (3) afforded mixtures of homoleptic and heteroleptic helicates. Helicate distribution seems to follow statistical expectations. Mixing of the double-stranded copper helicates of 2 and 3 in DMSO-d 6 afforded, after 2 weeks, a statistical mixture of the homoleptic and heteroleptic helicates, i.e., [(2) 2 Cu 3 ] 3+ , [(3) 2 Cu 3 ] 3+ , and [(2/3)Cu 3 ] 3+ . However, a statistical mixture was obtained within minutes from the double-stranded silver helicates of 2 and 3 in CD 3 CN. We conclude therefore that even 2 and 3, which contain three phenanthroline and three bipyridine binding sites, are not "sufficiently instructed" to avoid the formation of a heteroleptic helicate in the course of their self-assembly process.
Israel Journal of Chemistry, 2011
Inorganic Chemistry, 2004
The C 1 -symmetrical complex [Ru(bpy) 2 (ieil)][PF 6 ] 2 exhibits unique electrochemical and phot... more The C 1 -symmetrical complex [Ru(bpy) 2 (ieil)][PF 6 ] 2 exhibits unique electrochemical and photophysical properties, and forms discrete dimers in solution and in the solid state held by weak π-π stacking interactions via its isoeilatin ligand, preferentially from one of its faces and in a specific orientation.
Experimental Neurology, 2005
Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple scler... more Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple sclerosis (MS), which involves both inflammation and demyelination and is known to be species-dependent. Spinal cord abnormalities were found in more than 80% of postmortem specimens of MS patients. In the present study, T 1 , T 2 and high b-value q-space diffusion-weighted magnetic resonance imaging (MRI) were used, for the first time, to characterize the EAE model in excised swine spinal cords. The MR images were compared with histological staining and clinical scoring. Although all spinal cords were excised from swine with severe or very severe (clinical score between 3 to 5 on a scale of 5) motor impairments, T 1 -and T 2 -weighted MRI revealed white matter (WM) abnormalities in only five of the ten EAE diseased spinal cords studied, while high b-value q-space diffusion weighted MRI (q-space DWI) detected WM abnormalities in all diseased spinal cords studied. Interestingly, high b-value q-space DWI was able to detect abnormalities in the normal appearing white matter (NAWM) even in spinal cords where no plaques were identified by the T 1 -and T 2 -weighted MR images. Good anatomical correlation was observed between the high b-value q-space MR images and histology. The extent of DWI abnormalities paralleled the clinical scoring and correlated with histology. In addition, areas classified as NAWM by the T 1 -and T 2 -weighted MR images that showed abnormalities in the qspace DWI were also found to have abnormal histology. This improved detection level of the EAE model by high b-value q-space DWI over conventional T 1 -, and T 2 -weighted MRI is briefly discussed.
Current Opinion in Biotechnology, 2013
In recent years, enormous efforts have been made to translate nanotechnology innovations into med... more In recent years, enormous efforts have been made to translate nanotechnology innovations into medical practice. The main focuses were diagnosis and therapy with recent emphasis on multi-modal imaging. Since in many instance the sites for imaging and therapy are the same it became apparent that targeted magnetic nanoparticles (MNPs), which can be imaged, can also be used as a platform for theranostics applications. MNPs, which are characterized by high surfaceto-volume ratios, are not only excellent scaffolds for loading targeting moieties, imaging tags and drugs, but can themselves be used to induce therapeutic effects making them the platform of choice for theranostics applications. In the current assay we will outline some of the recent progress in the synthesis and functionalization of MNPs, as well as their applications in multimodal imaging. The main body of the present essay, however, focuses on recent theranostic applications of such MNPs.
Anion-Assisted Supramolecular Polymerization: From Achiral AB-Type Monomers to Chiral Assemblies
Angewandte Chemie International Edition, 2011
ABSTRACT Anionen machen den Unterschied! Gegenionen, die während der Säure-geförderten Selbstorga... more ABSTRACT Anionen machen den Unterschied! Gegenionen, die während der Säure-geförderten Selbstorganisation von Monomervorstufen des AB-Typs freigesetzt werden, docken an designierte Hilfsbindungsstellen an und erleichtern somit den Poymerisierungsprozess, während sie ihre molekularen Eigenschaften auf die gesamte supramolekulare Struktur übertragen (siehe Bild).
![Research paper thumbnail of A pulsed gradient spin echo NMR study of guest encapsulation by hydrogen-bonded tetraurea calix[4]arene dimers](https://attachments.academia-assets.com/84611273/thumbnails/1.jpg)
](Journal of the Chemical Society, Perkin Transactions 2, 1999
Diffusion coefficients, as obtained by the PGSE NMR technique, were used to probe encapsulation o... more Diffusion coefficients, as obtained by the PGSE NMR technique, were used to probe encapsulation of guests in self-assembled tetraurea calix[4]arene dimers in organic solvents and to demonstrate their destruction by DMSO.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affe... more Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sen-sory functions, and permanent disability. High b-value diffu-sion-weighted MR images (b of up to 14000 s/mm2) were ac-quired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexpo-nential, were analyzed using the q-space approach that empha-sizes the diffusion characteristics of the slow-diffusing compo-nent. From this analysis, displacement and probability maps were constructed. The computed q-space analyzed MR images that were compared with conventional T1, T2 (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q-space analyzed MR maps, provided a pronounced differentia-tion between normal tissue ...
Journal of Neurotrauma, 2018
Cannabis is one of the most widely used plant drugs in the world today. In spite of the large num... more Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana, there still exists much controversy surrounding its use and the potential for abuse due to the undesirable psychotropic effects. However, recent developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the psychoactivity. We have previously shown that treatment with the endocannabinoid 2-AG, which binds to both CB 1 and CB 2 receptors 1 h after traumatic brain injury in mice, attenuates neurological deficits, edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region, and neuroinflammation. Recently, we synthesized a set of camphor-resorcinol derivatives, which represent a novel series of CB 2 receptor selective ligands. Most of the novel compounds exhibited potent binding and agonistic properties at the CB 2 receptors with very low affinity for the CB 1 receptor, and some were highly anti-inflammatory. This selective binding correlated with their intrinsic activities. HU-910 and HU-914 were selected in the present study to evaluate their potential effect in the pathophysiology of traumatic brain injury (TBI). In mice and rats subjected to closed-head injury and treated with these novel compounds, we showed enhanced neurobehavioral recovery, inhibition of tumor necrosis factor a production, increased synaptogenesis, and partial recovery of the cortical spinal tract. We propose these CB 2 agonists as potential drugs for development of novel therapeutic modality to TBI.
Organic chemistry frontiers, 2024
Advanced 19 F-NMR studies shed new light on encapsulation of isosteric guests in the hexameric ca... more Advanced 19 F-NMR studies shed new light on encapsulation of isosteric guests in the hexameric capsules of resorcin[4]arenes and pyrogallol[4] arenes †
Neurotoxicology, May 1, 2015
Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo a... more Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. Methods: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1-no central antidotal treatment (n = 10); group 2-treated with midazolam (MID) at 30 min after poisoning (n = 9), group 3-treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1 H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetylaspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. Results: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID + SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3 h after exposure (1.1 AE 0.07 and 1.42 AE 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h NAA/Cr decrease (1.22 AE 0.05 and 1.32 AE 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p < 0.05). Conclusions: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with
The Journal of Organic Chemistry, 2013
Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely importa... more Magnetic resonance imaging (MRI) and positron emission tomography (PET) are two extremely important imaging modalities with unlimited tissue penetration. Molecular imaging is a field by which specific targets or biological processes are imaged. MRI, which is used for functional imaging and for the diagnosis of a broad range of pathologic conditions, suffers from limited specificity and intrinsically low sensitivity. One possibility to alleviate partially these limitations is to use contrast agents (CAs) and more importantly target-specific CAs. We have developed a modular synthesis of novel ligands and gadolinium(III)-based target-specific MRI CAs with high relaxivity and high binding affinity toward the dopamine receptors. The prepared ligands and MRI CAs are based on spiperone as targeting moiety. The prepared target-specific CAs can potentially be used for in vitro and possibly in vivo MR imaging of dopaminergic receptors. Importantly the ligands prepared using the modular approach presented in this paper may also be useful for other imaging modalities such as PET (or SPECT) by just replacing, at the last stage of the synthesis, the gadolinium cation by other metal cations having relatively long half-lives, such as 64 Cu, 89 Zr, 11 In, and more.
Temperature‐Dependent and pH‐Responsive Pillar[5]arene‐Based Complexes and Hydrogen‐Bond‐Based Supramolecular Pentagonal Boxes in Water
Chemistry – A European Journal, 2020
Supramolecular systems in water are of paramount importance and those based on hydrogen-bonds are... more Supramolecular systems in water are of paramount importance and those based on hydrogen-bonds are both intriguing and scarce. Here after studying the peculiar host-guest complexes formed between per-dimethylamino-pillar[5]arene 1 and the bis-sulfonates 2a-c, we describe the formation of the first hydrogen bond-based supramolecular pentagonal boxes (SPBs) which are stable in water. These pH-responsive SPBs are constructed from 1 as a body, benzene polycarboxylic acids (3a-b) as lid compounds and 2a-c as guests. We demonstrate that encapsulation of 2a-c in pillar[5]arene 1 and in the highly stable water-soluble SPBs, i. e., 1(3a)2 and 1(3b)2, is both temperature and pH dependent and, quite interestingly, depends, on the nature of the lid compounds used for capping the boxes even at high pH. We also highlight the difference in the 1H-NMR characteristics of 2b and 2c in the cavity of 1 and the SPBs.
Background and Purpose: Brain addosis from cerebral ischemia is characterized by average intracei... more Background and Purpose: Brain addosis from cerebral ischemia is characterized by average intraceiiular pH levels of approximately 5.8-6.2, which appear in turn to worsen cellular injury. We report that the brain is not injured when hypercapnia is used to reduce intraceiiular pH to about 62 during adequate oxygenation. A hyperbaric chamber is needed to achieve intraceiiular pH values so low because inspired CO 2 tensions must be increased to approximately 1 atm. Summary of Report: Using in vivo phosphorus-31 and proton nuclear magnetic resonance spectroscopy, we measured brain intraceiiular pH and lactate concentration of rats inside a nonmagnetic polycarbonate chamber at a barometric pressure of 1,500 mm Hg. Intubated rats were ventilated with a 50% O 2 /50% CO 2 gas mixture for specific times. All six rats ventilated for 15 minutes with CO 2 tensions of approximately 750 mm Hg woke up without neurological impairment, despite a decrease in intraceiiular pH to about 62. Higher CO 2 tensions and longer exposures resulted in cardiovascular collapse and sudden death, followed by the postmortem appearance of brain lactate. Conclusions: Brain intraceiiular pH values near 62 can be induced briefly in vivo in ventilated rats without injury under hyperbaric hypercapnic conditions. If attempts are made to lower brain pH in vivo even further by increasing PcOj beyond 750 mm Hg, mean arterial blood pressure and cerebral blood flow decrease to values incompatible with life.
NeuroToxicology, 2015
Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo a... more Introduction: Magnetic resonance (MR) imaging is a sensitive modality for demonstrating in vivo alterations in brain structure and function after acute organophosphate (OP) poisoning. The goals of this study were to explore early imaging findings in organophosphate-poisoned animals, to assess the efficacy of centrally acting antidotes and to find whether early MR findings can predict post-poisoning cognitive dysfunction. Methods: Sprague-Dawley rats were poisoned with the agricultural OP paraoxon and were treated with immediate atropine and obidoxime (ATOX) to reduce acute mortality caused by peripheral inhibition of acetylcholinesterase. Animals were randomly divided into three groups based on the protocol of centrally acting antidotal treatment: group 1 -no central antidotal treatment (n = 10); group 2 -treated with midazolam (MID) at 30 min after poisoning (n = 9), group 3 -treated with a combination of MID and scopolamine (SCOP) at 30 min after poisoning (n = 9) and controls (n = 6). Each animal had a brain MR examination 3 and 24 h after poisoning. Each MR examination included the acquisition of a T2 map and a single-voxel 1 H MR spectroscopy (localized on the thalami, to measure total creatine [Cr], N-acetylaspartate [NAA] and cholines [Cho] levels). Eleven days after poisoning each animal underwent a Morris water maze to assess hippocampal learning. Eighteen days after poisoning, animals were euthanized, and their brains were dissected, fixed and processed for histology. Results: All paraoxon poisoned animals developed generalized convulsions, starting within a few minutes following paraoxon injection. Brain edema was maximal on MR imaging 3 h after poisoning. Both MID and MID + SCOP prevented most of the cortical edema, with equivalent efficacy. Brain metabolic dysfunction, manifested as decreased NAA/Cr, appeared in all poisoned animals as early as 3 h after exposure (1.1 AE 0.07 and 1.42 AE 0.05 in ATOX and control groups, respectively) and remained lower compared to non-poisoned animals even 24 h after poisoning. MID and MID + SCOP prevented much of the 3 h NAA/Cr decrease (1.22 AE 0.05 and 1.32 AE 0.1, respectively). Significant correlations were found between imaging findings (brain edema and spectroscopic changes) and clinical outcomes (poor learning, weight loss and pathological score) with correlation coefficients of 0.4-0.75 (p < 0.05). Conclusions: MR imaging is a sensitive modality to explore organophosphate-induced brain damage. Delayed treatment with midazolam with or without scopolamine provides only transient neuroprotection with some advantage in adding scopolamine. Early imaging findings were found to correlate with
Organic letters, Jan 7, 2014
The hexameric capsules of pyrogallol[4]arene (2b) were prepared in nondeuterated solvents in the ... more The hexameric capsules of pyrogallol[4]arene (2b) were prepared in nondeuterated solvents in the absence and presence of adamantane carboxylic acid (3). The small encapsulated molecules were shown to occupy different sites within the same capsule. In the presence of 3, which are also encapsulated in the hexameric capsules, one observes yet another pair of signals for the encapsulated solvent molecules. Different NMR experiments enabled assignment of the different sites within the hexameric capsules of 2b.
Publisher’s Note: Magnetic Resonance Imaging by Synergistic Diffusion-Diffraction Patterns [Phys. Rev. Lett. 108, 058103 (2012)]
Physical Review Letters, 2012
NMR in Biomedicine, 2011
The accurate characterization of pore morphology is of great interest in a wide range of scientif... more The accurate characterization of pore morphology is of great interest in a wide range of scientific disciplines. Conventional single-pulsed field gradient (s-PFG) diffusion MR can yield compartmental size and shape only when compartments are coherently ordered using q-space approaches that necessitate strong gradients. However, double-PFG (d-PFG) methodology can provide novel microstructural information even when specimens are characterized by polydispersity in size and shape, and even when anisotropic compartments are randomly oriented. In this study, for the first time, we show that angular d-PFG experiments can be used to accurately measure cellular size and shape anisotropy of fixed yeast cells employing relatively weak gradients. The cell size, as measured by light microscopy, was found to be 5.32AE0.83mm, whereas the results from noninvasive angular d-PFG experiments yielded a cell size of 5.46AE0.45mm. Moreover, the low compartment shape anisotropy of the cells could be inferred from experiments conducted at long mixing times. Finally, similar experiments were conducted in a phantom comprising anisotropic compartments that were randomly oriented, showing that angular d-PFG MR provides novel information on compartment eccentricity that could not be accessed using conventional methods. Angular d-PFG methodology seems to be promising for the accurate estimation of compartment size and compartment shape anisotropy in heterogeneous systems in general, and biological cells and tissues in particular.
NMR in Biomedicine, 2009
Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is als... more Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is also used for efficacy studies. To date, the morphological and spectroscopic indices of this model have not been studied longitudinally by MRI; therefore the objectives of this study were aimed at following the lesion progression and changes in N-acetyl aspartate (NAA) as viewed by MRI and MRSI, respectively, in-vivo over a period of 49 days. We found that the affected areas exhibited both high and low apparent diffusion coefficients (ADC) even 49 days post QA injection in three of the six tested animals. MRI-guided histological analysis correlated areas characterized by high ADCs on day 49 with cellular loss, while areas characterized by lower ADCs were correlated with macrophage infiltration (CD68 positive stain). Our MRSI study revealed an initial reduction of NAA levels in the lesioned striatum, which significantly recovered with time, although not to control levels. Total-striatum normalized NAA levels recovered from 0.67 W 0.15 (of the contralateral row) on day 1 to 0.90 W 0.12 on day 49. Our findings suggest that NAA should be considered as a marker for neuronal dysfunction, in addition to neuronal viability. Some behavioral indices could be correlated to permanent neuronal damage while others demonstrated a spontaneous recovery parallel to the NAA recovery. Our findings may have implications in efficacy-oriented studies performed on the QA model.
Magnetic Resonance in Medicine, 1993
A description is given of the design, construction, and initial use of a polycarbonate resin hype... more A description is given of the design, construction, and initial use of a polycarbonate resin hyperbaric chamber for in vivo NMR spectroscopy studies of anesthetized, ventilated rats in a horizontal bore 4.7 Tesla magnet. The chamber and its associated equipment, initially used for hyperbaric studies of rats in states of extreme hypercapnia, are also well suited for conventional hyperbaric studies, such as those related to hyperbaric oxygen therapy, oxygen toxicity, and diving. Basic technical challenges that required innovations involved: a) preservation of magnetic field homogeneity; b) avoidance of a metallic chamber body that would overload gradient and RF coils; c) physiological monitoring; and, d) remote control and stabilization of electromagnetic and physiologic factors (especially ventilatory stability) during pressure changes. A small paramagnetic bulk magnetic susceptibility shift from chamber-associated hyperbaric oxygen was observed when chamber oxygen tensions were only one atmosphere. High-quality NMR imaging and spectroscopy were demonstrated during hyperbaric conditions.
The Journal of Organic Chemistry, 1999
The ligands 6,6′-bis [(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] 2,2′-bipyridine (1... more The ligands 6,6′-bis [(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] 2,2′-bipyridine (1)and 2,9-bis[(2-methyl-1,10-phenanthrolin-9-yl)methylenoxymethylenyl] -1,10-phenanthroline (2) were prepared and shown to self-assemble into double-stranded [(L) 2 Cu 3 ] 3+ -type helicates upon reaction with Cu + . Although the reaction of 1 with AgCF 3 SO 3 afforded the double-stranded helicate [(1) 2 Ag 3 ] 3+ , reaction of 2 with this salt yielded a mixture of several complexes, all of apparently double-strand nature, based on their diffusion coefficients. Addition of a large excess of AgCF 3 SO 3 afforded [(2) 2 Ag 3 ] 3+ as the sole product. In addition, it was found that the reaction of Cu + with mixtures of 1 and 6′′,6′′′-bis[(6-methyl-2,2′-bipyridin-6′-yl)methylenoxymethylenyl]-2′′,2′′′-bipyridine (4) or of 2 with 2,9-bis[(6-methyl-2,2-bipyridin-6′-yl)methylenoxymethylenyl]-1,10-phenanthroline (3) afforded mixtures of homoleptic and heteroleptic helicates. Helicate distribution seems to follow statistical expectations. Mixing of the double-stranded copper helicates of 2 and 3 in DMSO-d 6 afforded, after 2 weeks, a statistical mixture of the homoleptic and heteroleptic helicates, i.e., [(2) 2 Cu 3 ] 3+ , [(3) 2 Cu 3 ] 3+ , and [(2/3)Cu 3 ] 3+ . However, a statistical mixture was obtained within minutes from the double-stranded silver helicates of 2 and 3 in CD 3 CN. We conclude therefore that even 2 and 3, which contain three phenanthroline and three bipyridine binding sites, are not "sufficiently instructed" to avoid the formation of a heteroleptic helicate in the course of their self-assembly process.
Israel Journal of Chemistry, 2011
Inorganic Chemistry, 2004
The C 1 -symmetrical complex [Ru(bpy) 2 (ieil)][PF 6 ] 2 exhibits unique electrochemical and phot... more The C 1 -symmetrical complex [Ru(bpy) 2 (ieil)][PF 6 ] 2 exhibits unique electrochemical and photophysical properties, and forms discrete dimers in solution and in the solid state held by weak π-π stacking interactions via its isoeilatin ligand, preferentially from one of its faces and in a specific orientation.
Experimental Neurology, 2005
Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple scler... more Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple sclerosis (MS), which involves both inflammation and demyelination and is known to be species-dependent. Spinal cord abnormalities were found in more than 80% of postmortem specimens of MS patients. In the present study, T 1 , T 2 and high b-value q-space diffusion-weighted magnetic resonance imaging (MRI) were used, for the first time, to characterize the EAE model in excised swine spinal cords. The MR images were compared with histological staining and clinical scoring. Although all spinal cords were excised from swine with severe or very severe (clinical score between 3 to 5 on a scale of 5) motor impairments, T 1 -and T 2 -weighted MRI revealed white matter (WM) abnormalities in only five of the ten EAE diseased spinal cords studied, while high b-value q-space diffusion weighted MRI (q-space DWI) detected WM abnormalities in all diseased spinal cords studied. Interestingly, high b-value q-space DWI was able to detect abnormalities in the normal appearing white matter (NAWM) even in spinal cords where no plaques were identified by the T 1 -and T 2 -weighted MR images. Good anatomical correlation was observed between the high b-value q-space MR images and histology. The extent of DWI abnormalities paralleled the clinical scoring and correlated with histology. In addition, areas classified as NAWM by the T 1 -and T 2 -weighted MR images that showed abnormalities in the qspace DWI were also found to have abnormal histology. This improved detection level of the EAE model by high b-value q-space DWI over conventional T 1 -, and T 2 -weighted MRI is briefly discussed.
Current Opinion in Biotechnology, 2013
In recent years, enormous efforts have been made to translate nanotechnology innovations into med... more In recent years, enormous efforts have been made to translate nanotechnology innovations into medical practice. The main focuses were diagnosis and therapy with recent emphasis on multi-modal imaging. Since in many instance the sites for imaging and therapy are the same it became apparent that targeted magnetic nanoparticles (MNPs), which can be imaged, can also be used as a platform for theranostics applications. MNPs, which are characterized by high surfaceto-volume ratios, are not only excellent scaffolds for loading targeting moieties, imaging tags and drugs, but can themselves be used to induce therapeutic effects making them the platform of choice for theranostics applications. In the current assay we will outline some of the recent progress in the synthesis and functionalization of MNPs, as well as their applications in multimodal imaging. The main body of the present essay, however, focuses on recent theranostic applications of such MNPs.
Anion-Assisted Supramolecular Polymerization: From Achiral AB-Type Monomers to Chiral Assemblies
Angewandte Chemie International Edition, 2011
ABSTRACT Anionen machen den Unterschied! Gegenionen, die während der Säure-geförderten Selbstorga... more ABSTRACT Anionen machen den Unterschied! Gegenionen, die während der Säure-geförderten Selbstorganisation von Monomervorstufen des AB-Typs freigesetzt werden, docken an designierte Hilfsbindungsstellen an und erleichtern somit den Poymerisierungsprozess, während sie ihre molekularen Eigenschaften auf die gesamte supramolekulare Struktur übertragen (siehe Bild).
Journal of the Chemical Society, Perkin Transactions 2, 1999
Diffusion coefficients, as obtained by the PGSE NMR technique, were used to probe encapsulation o... more Diffusion coefficients, as obtained by the PGSE NMR technique, were used to probe encapsulation of guests in self-assembled tetraurea calix[4]arene dimers in organic solvents and to demonstrate their destruction by DMSO.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affe... more Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sen-sory functions, and permanent disability. High b-value diffu-sion-weighted MR images (b of up to 14000 s/mm2) were ac-quired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexpo-nential, were analyzed using the q-space approach that empha-sizes the diffusion characteristics of the slow-diffusing compo-nent. From this analysis, displacement and probability maps were constructed. The computed q-space analyzed MR images that were compared with conventional T1, T2 (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q-space analyzed MR maps, provided a pronounced differentia-tion between normal tissue ...