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Biomedical subjects

A Reggiani

Publications and source records attributed to A Reggiani.

At least 19 recordsLinked to original sources
PubMed2006

CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms.

In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)-AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)-AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5-L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced capsaicin-induced calcitonin gene-related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-AM1241 and L768242, respectively) of the dose-response curve. Experiments on capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.

Analgesics↗
PubMed2004

Preventive-comprehensive assessment (PCA): a new screening method for subclinical cognitive problems.

Physicians often need to be able to assess cognition in a simple way, particularly for screening of subclinical processes in aged people. This paper describes a new, quick test battery called preventive-comprehensive assessment (PCA). It consists of six various testing items (repetition of three words, back-spelling of the word "sport", problem searching ina complex picture, recall of the three words, three progressive colored matrices, clock drawing test), evaluating language, recent memory, executive function, judgment and thinking capacities. The total scores. compared to the normal performance of different age groups, allow us to distinguish between normal and pathological status. If abnormal results are recorded, we need to perform further and deeper neuropsychological investigations, in order to obtain the possibly exact diagnosis. The PCA battery is sensitive and reliable; it can be used in itself, or as a part of a more complex battery of an intense comprehensive evaluation (ICE), carried out in population screening aimed at promoting healthy and active aging.

Age Distribution↗
PubMed2004

Magnetic resonance spectroscopy and chromatographic methods identify altered lipid composition in human renal neoplasms.

We report on the characterization of the lipid obtained from cortical and medullary normal human kidney tissue, benign renal neoplasms (oncocytoma) and 2 different types of malignant renal neoplasms (chromophobic cell carcinoma and clear cell carcinoma). The total lipid fractions were analyzed by 13C magnetic resonance spectroscopy and thin-layer chromatography, whereas the composition of the total fatty acids and the content of total cholesterol were determined by gas chromatography. alpha-Tocopherol was detected and quantified by high-performance liquid chromatography. The spectroscopic and chromatographic analysis revealed significant differences in the renal tissues examined. It was confirmed that cholesteryl esters (mainly oleate) are typical of clear cell renal carcinomas. Their potential role as prognostic and diagnostic factors is discussed, with particular emphasis on its capability to indicate the tumor diffusion in healthy renal parenchyma. alpha-Tocopherol is prevalent in clear cell carcinoma and it is present in nearly the same low amounts in cortex, medulla and chromophobic cell renal carcinoma. Q10 coenzyme and dolichols were detected by thin-layer chromatography and they are present in significant amounts in the cortex and the benign oncocytoma. Great variations were found in the distribution of saturated and unsaturated fatty acids, especially in the docosapentaenoic, docosahexaenoic and arachidonic acids and the corresponding omega-6/omega-3 fatty acids ratio.

Chromatography↗
PubMed2003

1H-NMR and 13C-NMR lipid profiles of human renal tissues.

Lipids from human renal tissues are studied by means of (1)H- and (13)C-NMR spectroscopy. The total lipid fractions obtained from healthy kidneys, malignant renal cell carcinomas, and benign oncocytomas are characterized and analyzed to elucidate the main differences between the functional and neoplastic tissues. In all cases the lipid components are well identified. The healthy kidney is characterized by high amounts of triglycerides and the presence of cholesterol in its free form. On the contrary, renal cell carcinomas contain high amounts of cholesterol that are almost completely esterified as oleate, suggesting an intracellular localization of the cholesteryl esters synthesis. Cholesteryl esters are considered markers of renal cell carcinomas, thus supporting recent theories that these compounds play a leading role in cell proliferation. Oncocytomas are particularly rich in phosphatidylcholine and, analogous to the healthy kidney, are completely lacking in cholesteryl esters. Healthy kidneys and oncocytomas appear to have other similarities if compared with renal cell carcinomas: a very high fatty acyl/cholesterol ratio, the presence of dolichols, and a higher grade of unsaturation. The (13)C data suggest a new method for the direct evaluation of the saturated/unsaturated fatty acyl ratio.

Carcinoma, Renal Cell↗
PubMed2003

Cholesteryl esters in human malignant neoplasms.

Cholesteryl esters (CholE) were detected in human malignant neoplasms by means of in vitro nuclear magnetic resonance spectroscopy. Spectroscopic analysis of the total lipid extracts obtained from cerebral tumors revealed appreciable amount of esterified cholesterol in high grade gliomas such as glioblastomas and anaplastic oligodendrogliomas, characterized by prominent neovascularity. The finding that no CholE were detected in the healthy brain and in low grade and benign tumors supports a possible correlation between this class of lipids and histological vascular proliferation. Compared with high grade gliomas, renal cell carcinomas show higher levels of CholE, absent in the healthy renal parenchyma and in benign oncocytomas. In nefro-carcinomas, cytoplasmic lipid inclusions and prominent vascularization contribute to the increased levels of CholE present mainly as oleate. CholE are discussed as potential biochemical markers of cancer and as a target for new therapeutic strategies.

Biopsy↗
PubMed2003

Are molecular features of a chromophobic cell renal cell carcinoma correlated with clinical findings?

Lipids extracted from three human renal neoplasms have been characterized by means of 13C magnetic resonance spectroscopy. The presence of free cholesterol, high levels of unsatured fatty acids, and phosphatidylcholine, and a very high fatty acids/cholesterol ratio makes the lipid profile of a rare chromophobe cell carcinoma very similar to that of an oncocytoma. On the contrary, clear cell carcinomas are mainly characterized by the presence of almost fully esterified cholesterol and by a markedly lower level of unsatured fatty acids. Since chromophobic cell carcinomas have a more favourable prognosis than clear cell carcinomas, their analogy in the lipid composition with a benign renal neoplasm could have a clinical significance. In particular, our report suggests that cholesteryl esters and high levels of unsatured fatty acids could be a marker of a poor (clear cell carcinomas) or a good (chromophobic cell carcinomas) prognosis, respectively. More in depth studies are required of the molecular composition of the neoplastic pathologies that add new knowledge, with potential clinical implications.

Aged↗
PubMed2002

Correlation MRI/ultrastructure in cerebral ischemic lesions: application to the interpretation of cortical layered areas.

The origin and fate of cortical ischemic lesions, showing a stratified appearance at in vivo MRI-examination, was studied on rats in which a focal brain ischemia was induced by occlusion of the middle cerebral artery. One week after ischemia induction, six rats were selected in which three layers of different intensity were visible in the lesioned cortex. Two animals were sacrificed and studied by histology and electron microscopy. The external hyperintense layer was composed of pial and lesioned nervous tissue, the intermediate of degenerating nervous tissue in which an accumulation of macrophages was found, the deepest of edematous nerve tissue without a marked accumulation of macrophages. The remaining rats underwent further MRI examinations showing that, in the lesioned areas, cerebral blood volume was 14-69% lower than the contralateral healthy cortex. At histological and ultrastructural examination, a large part of the lesion was occupied by enlarged pial tissue and marginal glia. A dilatation of the ventricular cavity and cystic structures were also visible. In three animals an increase of the transverse diameter of the caudo-putamen ipsilateral to the lesion was found. The study suggests that the layered appearance is mainly due to an accumulation of macrophages in the intermediate layer and that several processes contribute to the occlusion of the space created by the removal of the necrotic tissue in stratified ischemic lesions (i.e. expansion of the pial tissue, thickening of the marginal glia; expansion of the caudo-putamen, enlargement of the ventricular cavity and development of cystic structures).

Animals↗
PubMed2002

Molecular characterization of human healthy and neoplastic cerebral and renal tissues by in vitro (1)H NMR spectroscopy (review).

The clinical impact of (1)H NMR spectroscopy in the study of human organs, brain and kidney in particular, is well demonstrated. The in vitro (1)H NMR technique is a powerful tool for monitoring changes in intracellular metabolites of human normal and neoplastic cerebral and renal tissues. Healthy and tumoral tissues of different histologic types have been fully characterized from a biochemical standpoint. Molecular characterization is performed on both the aqueous and lipid extracts of surgically removed tissue biopsies yielding a full picture of tissue biochemistry. These analyses have disclosed markers of healthy brain and kidney and of their respective neoplastic lesions. Moreover, some biochemical features can differentiate neoplasms within the same histological type. In particular, lipidic components, like cholesteryl esters (namely oleate), detected in highest grade tumors, warrant further investigation. A better understanding of the biochemistry of diseased human tissues could open the way to new diagnostic and treatment strategies.

Brain Neoplasms↗
PubMed2001

Can voltammetry measure nitrogen monoxide (NO) and/or nitrites?

Recently, voltammetry with carbon fibre electrodes (CFE) has been implemented for real time measurement of nitrogen monoxide (NO) indicating that it is oxidised at the potential value of nitrites, approximately +700 mV. In contrast, here we show that modified CFE can monitor NO at oxidation potentials different than that of nitrites, i.e. +550 mV. Indeed, at +550 mV a significant increase of amperometric current levels was obtained when NO but not nitrites, were added to a phosphate buffer saline solution (PBS). Differential pulse voltammetry (DPV) supports these findings as two oxidation peaks were obtained when examining air preserved NO; peak 1 at +550 mV and peak 2 at +700 mV, respectively. In contrast, only peak 2 was monitored when nitrites or a solution of NO oxidised in air was added to PBS. Biological support to these in vitro data comes from the observation that the relaxation of an adrenaline-contracted aortic ring produced via addition of NO is concomitant with peak 1 at +550 mV. The relaxation is almost completed before the appearance of peak 2 at +700 mV. Furthermore, in vivo experiments performed in the striatum of rats show that the amperometric signal monitored at +550 mV is responsive to glutamatergic stimulation or inhibition of NO synthase.

2-Amino-5-phosphonovalerate↗
PubMed2001

The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging.

The neuroprotective activity of GV150526 (3-[2-(Phenylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt), a selective glycine receptor antagonist of the NMDA receptor, has been evaluated by magnetic resonance imaging (MRI) in a rat model of middle cerebral artery occlusion. The aim of the work was to evaluate, using an in vivo method, whether GV150526 was able to reduce the extent of ischemic brain damage when administered both before and after (6 h) middle cerebral artery occlusion. GV150526 was administered at a dose of 3 mg/kg i.v. T2-weighted (T2W) and diffusion weighted (DW) images were acquired at 6, 24 and 144 h after the establishment of the cerebral ischemia. Substantial neuroprotection was demonstrated at all investigated time points when GV150526 was administered before the ischemic insult. The ischemic volume was reduced by 84% and 72%, compared to control values, when measured from T2W and DW images, acquired 24 h after middle cerebral artery occlusion. Administration of the same dose of GV150526, 6 h post-ischemia, also resulted in a significant (p < 0.05) neuroprotection. The ischemic volume was reduced by 48% from control values when measured from T2W images and by 45% when measured from DW images. No significant difference was found between volumes of brain ischemia obtained by either MRI or triphenyltetrazolium chloride staining. These data confirm the potential neuroprotective activity of the glycine receptor antagonist GV150526 when administered either before or up to 6 h after ischemia.

Animals↗
PubMed2001

In silico research in drug discovery.

Target and lead discovery constitute the main components of today's early pharmaceutical research. The aim of target discovery is the identification and validation of suitable drug targets for therapeutic intervention, whereas lead discovery identifies novel chemical molecules that act on those targets. With the near completion of the human genome sequencing, bioinformatics has established itself as an essential tool in target discovery and the in silico analysis of gene expression and gene function are now an integral part of it, facilitating the selection of the most relevant targets for a disease under study. In lead discovery, advances in chemoinformatics have led to the design of compound libraries in silico that can be screened virtually. Moreover, computational methods are being developed to predict the drug-likeness of compounds. Thus, drug discovery is already on the road towards electronic R&D.

Computational Biology↗
PubMed2000

Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.

Animals↗
PubMed2000

Regional cerebral blood volume mapping after ischemic lesions.

The possible persistence of a microvascular deficit at long time intervals after cerebral ischemia induction is not well established. In rats, we have generated in vivo maps of the regional cerebral blood volume (rCBV) at different time intervals after middle cerebral artery occlusion (MCAo) with the aim to evaluate the persistence of a rCBV deficit in the damaged area or in the surrounding regions. The rats were examined by magnetic resonance imaging (MRI) at different time intervals, starting from the first day until three months after ischemia and postmortem histological and ultrastructural correlation was obtained. All MRI experiments were carried out using an imager-spectrometer equipped with a 4.7 Tesla magnet. To produce the susceptibility-weighted rCBV images, a suspension of superparamagnetic iron oxide nanoparticles (AMI-25) was injected to the rat. In a control group (nonoperated or sham-operated rats), a symmetrical distribution of rCBV values was found between the two hemispheres (differences between left and right cortex below 8%). In the rats with MCAo an evident vascular asymmetry was found 24 h after ischemia (differences between left and right ranging from 22 and 77%) and reduced rCBV values were evident in the ischemic areas. In a time range following the 15th day most of the rats showed a complete recovery of the lesion while only four animals still had a small residual lesion, as probed by T2-weighted (T2W) images. In three of these four cases, the reduction of rCBV in the ipsilateral cortex with respect to the contralateral was greater than 20%. Correlation was found (Y > 0.8) between late rCBV measurement and the initial volume of the lesion (hyperintense region in T2W images). The postmortem measurements correlate much better with the rCBV data than with the T2W ones. In conclusion, the present work demonstrates that cortical lesions may result in a deficit of rCBV for long periods and that a mismatch between T2w and rCBV data can be present during the repair process.

Animals↗
PubMed2000

Involvement of cholecystokinin within craving for cocaine: role of cholecystokinin receptor ligands.

In the brain, cholecystokinin (CCK) has been described to act as a central neurotransmitter or neuromodulator involved in functions such as food consumption, stress and anxiety. Recently, the CCK system has been involved in drug dependence phenomena and proposed to be correlated to a putative state of 'drug preferring' phenotype within free choice tests. CCK exerts its action in the CNS through at least two different G-protein coupled high affinity receptors, CCK1 and CCK2. Various selective CCK receptor agonists and antagonists have been synthesised. In particular, L-364,718 has been demonstrated to be a potent and selective CCK1 receptor antagonist, whereas L-365,260 is a potent and selective CCK2 receptor antagonist. More recently, GV150013 has been reported to be a highly selective CCK2 receptor antagonist. This paper reviews the putative role of the CCK system within drug dependence phenomena. In particular, it analyses the relationship between central CCK activity and the exhibition of spontaneous preference for drugs of abuse, such as cocaine or alcohol. The potential therapeutic role for CCK receptor antagonists is also discussed.

Animals↗
PubMed2000

The glio-pial system in cortical ischemic lesions.

The ultrastructural features of the glio-pial system have been analyzed in an animal model of brain focal ischemic lesion. Aim of the work was to describe the relationship between glial and pial cells in a condition of ischemic neurodegeneration and the eventual involvement of these cells in removal of debris and reconstruction of the glial-limiting lamina. The study was performed in rats in which the right middle cerebral artery was occluded. The development of a lesion and its extension was controlled in vivo 24 h after the middle cerebral artery occlusion by magnetic resonance imaging. The rats were sacrificed 10 or 15 days after the occlusion and their brain was processed for transmission and scanning electron microscopy. The ultrastructural examination of the lesion revealed that the nervous parenchyma was replaced by cicatricial tissue composed by glial and pial areas. The pial areas were composed mainly by leaf-like cells forming a network. Their main cytoplasmic feature was the presence of large lysosomes in which ferritine-like particles were often enclosed. The glial areas were composed by strictly packed cells which displayed at scanning electron microscopy a spider-like shape with a central body and elongated cell processes. These results suggest a role for the glio-pial system in acute ischemia. In particular, the pial cells seem to be directly involved in removal of cell debris while glial cells seem mainly devoted to the reconstruction of the glial limiting lamina.

Animals↗
PubMed1999

Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia.

A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.

Animals↗
PubMed1999

The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats.

The neuroprotective activity of the novel glycine receptor antagonist (E)-3[(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-c arboxylic acid sodium salt) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D-aspartate) receptor antagonists. First, it was found that neuronal vacuolization in the posterior cingulate/retrosplenial area of the cortex was not induced by GV150526 (200 mg/kg, i.v.), but was evident after injection of the NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant path-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) injected 30 min or 150 min prior to tetanization did not block potentiation of the e.p.s.p. slope and population spike amplitude. In contrast, in animals treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and population spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o.) did not show any impairment in learning when compared to control. MK801 (0.08 mg/kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 is devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This, drug has therapeutic potential with a much greater margin of safety than NMDA channel blockers or competitive NMDA receptor antagonists.

Action Potentials↗