Massimo Pomponi

Present state and future development of the therapy of Alzheimer disease.

Senectutis autem nullus est certus terminus, recteque in ea vivitur quoad munus offici exsequi… vivundi est finis optumus cum integra mente certisque sensibus opus ipsa suum eadem quae coagmentavit natura dissolvit. Cicero, “De Senectute”.

Flavanones and xanthones from Maclura pomifera

Abstract (+-)Euchrestaflavanones B and C and 8-prenyltoxyloxanthone C have been isolated from the root bark of Maclura pomifera . A study of the cyclization of alvaxanthone under varying conditions is reported.

Physostigmine analogs anticholinesterases: effects of the lengthening of the N-carbamic chain of the inhibition kinetics

Data are presented about the inhibitor power of new carbamates against acetylcholinesterase. The study was carried out on two series of physostigmine analogs, N-alkyl and N-methyl,N-alkylphysostigmines. For these inhibitors, the second-order rate constants for inhibition, ki, and the first-order rate constants of reactivation, k3, have been determined. From the reported results, electronic, hydrophobic and steric effects, due to the enhancement of the alkyl chain, may have influenced all kinetics parameters discussed. In comparison to physostigmine, both the new N-methyl,N-alkylphysostigmines and the N-alkylphysostigmines showed a non-linear decrease in the values of ki and k3. This study presents the hydrophobic interactions as an important factor not only in determining carbamylation but also decarbamylation rates constants.

Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer's disease?

The assumption that disease specific risk factors are similar or the same in men and women may lead to incorrect primary prevention strategies. This study focused on the evaluation of gender-specific Alzheimers disease (AD) risk factors. In AD, female gender appears to be an important risk factor associated with the aberrant production of beta amyloid (βA) peptides. Although decreased levels in plasma DHA concentration are associated with cognitive decline in healthy elderly and Alzheimers patients, pre-treatment with DHA significantly reduced the survival of cortical neurons incubated with beta amyloid (βA). Hence, in the presence of an increasing amount of βA, paradoxically women - who have higher plasma levels of DHA - are more likely to develop AD. Aspirin (ASA) converts cyclooxygenase (COX)-2 into a form that generates new neuroprotective docosanoids from DHA; therefore, ASA might positively resolve the paradoxical effect of the concomitant presence of DHA and βA.

Is Alzheimer's Disease a Synaptic Disorder?

BACKGROUND In Alzheimers disease (AD), the common symptom is loss of memory. Learning and memory are associated with amoeboid movements of synaptic endings. Docosahexaenoic acid (DHA) is a major lipid constituent of synaptic end sites. Minor changes in the fluidity of phospholipidic membranes have a dramatic impact on the function of synapses, where membrane fluidity may influence the neurotransmitter receptor activity. METHOD Studies pertaining to the role of DHA as a neuroprotective agent was reviewed. RESULTS Here we will show a conceptual framework for the role of DHA in the prevention of AD. The DHA content has been shown to be decreased in the brain and plasma of patients affected by AD. Aspirin triggers the generation of DHA-derived mediators that are themselves neuroprotective. CONCLUSION Adequate dietary intakes of the neuroprotective DHA (and aspirin?) may slow down the progression of AD. An essential reserve of synapses from early development is needed.

Bovine hemoglobin cross-linked through the beta chains: functional and structural aspects.

2-Nor-2-formylpyridoxal (NFPLP) has been synthesized and coupled to bovine Hb according to the procedure developed by Benesch and Benesch(1). The reaction of bovine Hb with NFPLP leads to a cross-linkage between the β subunits, which greatly stabilizes the low affinity T state of the molecule and simultaneously abolishes the tendency of the tetramer to dissociate into αβ dimers. The functional properties, examined from both the equilibrium and kinetic points of view, indicate that the chemical modification affects the O affinity, abolishes cooperativity, and induces a slight decrease of the Bohr effect. From modeling studies we are confronted with two different structural alternatives; the cross-link of β chains may be formed between lysine 82 of β and the N terminus of methionine 2 of β or between the two lysine 82 residues of both β chains. Digestion of modified β globin chains and isolation of the cross-linked peptide have showed that NFPLP cross-links Met-β2 and Lys-β82. This allowed discussion in some detail of the molecular basis of the Bohr effect of the modified bovine hemoglobin. On the whole, NFPLP-modified bovine Hb could be considered as a first step toward the synthesis of a potential blood substitute.

Plasma levels of n-3 fatty acids in bipolar patients: Deficit restricted to DHA

Epidemiological studies suggest that n-3 polyunsaturated fatty acid (n-3 FA) deficiency is a risk factor for bipolar disorders (BDs). The aim of this study was to determine whether such a deficit does exist in patients with BD and to characterize the overall plasma fatty acid (FA) profile in these patients. Using gas chromatography/mass spectrometry, we measured fasting plasma levels of 15 FAs in 42 patients diagnosed with BD according to DSM-IV criteria and in 57 age- and gender-matched healthy controls. Plasma docosahexaenoic acid (DHA) levels were significantly decreased in bipolar patients (p < 0.001 versus healthy controls). Compared with controls, patients had higher plasma levels of all other FAs, including arachidonic acid (AA, p < 0.001), alpha-linolenic acid (ALA, p < 0.001), and eicosapentaenoic acid (EPA) (p < 0.001). Although in the present study we observed significant DHA deficits in the plasma of bipolar patients our findings do not support the therapeutic use of ALA and/or EPA supplementation. DHA may provide a basis for possible pharmacological intervention in psychiatric disorders at the level of second messengers linked to the phosphatidylinositol cycle. Finally, measurement of FA levels in plasma seems to be more reliable and reproducible than assays of erythrocyte FA content.

Studies on a new series of THA analogues: Effects of the aromatic residues that line the gorge of AChE

A series of N‐monoalkylsubstituted 1,2,3,4‐tetrahydro‐9‐aminoacridines have been prepared after modelling simulation of the AChE–inhibitor complex. Molecular modelling has predicted a number of hydrophobic residues to be involved in the catalytic mechanism of this interaction between the binding sites of AChE and this series of aminoacridines. In these compounds the acridine moiety becomes sandwiched between the rings of PHE330 and TRP84. In particular, the alkyl chain shows the important role of aromatic groups as binding sites. Their in vitro inhibitory properties (enzyme from Electrophorus electricus) confirm the aromatic groups as a general and significant characteristic of the mechanism of AChE inhibition.

New triterpene quinone-methides from hippocrateaceae

In addition to pristimerin and tingenone, the new pigments 21-hydroxypristimerin and hydroxypristimerinene have been isolated from an unidentified Salacia sp., while pristimerinene, also new, was found in Prionostemma aspera.

2,3-DPG-Hb complex: a hypothesis for an asymmetric binding.

This study was undertaken to test the symmetry of 2,3-diphosphoglycerate (2,3-DPG) binding site in hemoglobin (Hb). From Arnones study [A. Arnone, Nature (London) 237 (1972) 146] the 2,3-DPG binding site is located at the top of the cavity, that runs through the center of the deoxy-Hb molecule. However, it is possible that this symmetry reported by Arnone, for crystals of 2,3-DPG-Hb complex, might not be conserved in solution. In this paper, we report the 31P nuclear magnetic resonances of the 2,3-DPG interaction with Hb. The 2,3-DPG chemical shifts of the P2 and P3 resonance are both pH- and hemoglobin-dependent [protein from man, polar bear (Ursus maritimus), Arctic fox (Alopex lagopus) and bovine]. 2,3-DPG binds tightly to deoxyhemoglobin and weakly, nevertheless significantly, to oxyhemoglobin. In particular, our results suggest similar spatial position of the binding site of 2,3-DPG in both forms of Hb in solutions. However, the most unexpected result was the apparent loss of symmetry in the binding site, which might correlate with the ability of the hemoglobin to modulate its functional behavior. The different interactions of the phosphate groups indicate small differences in the quaternary structure of the different deoxy forms of hemoglobin. Given the above structural perturbation an asymmetric binding in the complex could justify, at least in part, different physiological properties of Hb. Regardless, functionally relevant effects of 2,3-DPG seem to be measured and best elucidated through solution studies.