Rosanna Matucci

Effect of taurine on calcium levels and contractility in guinea-pig ventricular strips

Taurine increases the calcium levels in guinea-pig ventricular strips at external calcium concentrations of 0.45, 0.9 and 1.8 mM. At 2.7 mM calcium, however, a decrease is observed. Analogous changes occur in contractile force. It is also seen that the superfusion of ventricular strips with taurine-free medium produces a decrease in taurine content at the end of 120 min superfusion. Taurine levels can be restored by superfusion with 10 mM taurine; a linear relationship exists between external taurine and internal taurine levels.

The protective effects of taurine on hypoxia (performed in the absence of glucose) and on reoxygenation (in the presence of glucose) in guinea-pig heart

In isolated guinea-pig heart submitted to hypoxia in the absence of substrate and subsequent reoxygenation 1-20 mM taurine decreases LDH release and ventricular arrhythmias, and the recovery of normal electrical and mechanical activity is increased. The taurine effect is dose-dependent, and is not mimicked by beta-alanine. Moreover, taurine reduces the increase in calcium gain of reoxygenated heart.

Synthesis and Biological Evaluation of 2-Mercapto-1,3-benzothiazole Derivatives with Potential Antimicrobial Activity

The enhancement of bacterial resistance of pathogens to currently available antibiotics constitutes a serious public health threat. So, intensive efforts are underway worldwide to develop new antimicrobial agents. To identify compounds with a potent antimicrobial profile, we designed and synthesized low molecular weight 2‐mercaptobenzothiazole derivatives 2a–2l and 3a–3l. Both series were screened for in‐vitro antibacterial activity against the representative panel of Gram‐positive and Gram‐negative bacteria strains. The biological screening identified compounds 2e and 2l as the most active ones showing an interesting antibacterial activity with MIC values of 3.12 μg/mL against Staphylococcus aureus and 25 μg/mL against Escherichia coli, respectively. The replacement of the S‐H by the S‐Bn moiety resulted in considerable loss of the antibacterial action of the 3a–3l series. The antibiotic action of compounds 2e and 2l was also investigated by testing their activity against some clinical isolates with different antimicrobial resistance profile. Moreover, the involvement of the NorA efflux pump in the antibacterial activity of our molecules was evaluated. Finally, in this paper, we also describe the cytotoxic activity of the most interesting compounds by MTS assay against HeLa and MRC‐5 cell lines.

Pharmacological effects of 3‐iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold

3‐Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg−1, i.p.), an inhibitor of amine oxidative metabolism.

EFFECTS OF A NEW POTENT ANALOG OF TOCAINIDE ON hNav1.7 SODIUM CHANNELS AND IN VIVO NEUROPATHIC PAIN MODELS

The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin.

Antisense 'knockdowns' of M1 receptors induces transient anterograde amnesia in mice

The effect on memory processes of inactivation of the M1 gene by an antisense oligodeoxyribonucleotide (aODN) was investigated in the mouse passive avoidance test. Mice received a single intracerebroventricular (i.c.v.) injection of M1 aODN (0.3, 1.0 or 2.0 nmol per injection), degenerated ODN (dODN) or vehicle on days 1, 4 and 7. An amnesic effect, comparable to that produced by antimuscarinic drugs, was observed 12, 24, 48 and 72 h after the last i.c.v. aODN injection, whereas dODN and vehicle, used as controls, did not produce any effect. Reduction in the entrance latency to the dark compartment induced by aODN disappeared 7 days after the end of aODN treatment, which indicates the absence of any irreversible damage or toxicity caused by aODN. Quantitative reverse transcription-polymerase chain reaction analysis demonstrated that a decrease in M1 mRNA levels occurred only in the aODN-treated group, being absent in all control groups. Furthermore, a reduction in M1 receptors was observed in the hippocampus of aODN-treated mice. Neither aODN, dODN nor vehicle produced any behavioral impairment of mice. These results indicate that the integrity and functionality of M1 receptors are fundamental in the modulation of memory processes.

Inotropic effect of taurine in guinea-pig ventricular strips

At 0.9 mM CaCl2 taurine prevented the negative inotropic effect due to low calcium concentration in guinea-pig ventricular strips but not in rat strips. This taurine effect was dose-dependent. The presence (in the perfusion medium) of beta-alanine, an inhibitor of taurine transport, antagonized the effect of taurine suggesting that the action of taurine was correlated to its transport. Neither propranolol, cimetidine nor indomethacin affected the response to taurine in guinea-pig ventricular strips.

[3H]-nitrendipine binding in membranes obtained from hypoxic and reoxygenated heart

We compared the binding properties of [3H]-nitrendipine in heart membranes from normal guinea-pig heart and from hypoxic or hypoxic and reoxygenated heart. The [3H]-nitrendipine binds a single class of high capacity (Bmax 667.2 +/- 105.2) with high affinity (KD 0.14 +/- 0.02) binding sites. By contrast, in membranes of hypoxic and reoxygenated heart the Bmax decreases significantly while it remains unaffected during hypoxia. Xanthinoxidase activity is increased in hypoxic-reoxygenated hearts.

Presynaptic auto- and hetero-receptors in the cholinergic regulation of pain

Abstract By modulating central acetylcholine release, presynaptic autoreceptor (M 2 ) and heteroreceptors (D 2 and A 1 ) can regulate the pain threshold through postsynaptic M 1 muscarinic receptors which were thus seen to be ultimately responsible for cholinergic antinociception. As regards antinociception, muscarinic autoreceptors belong to the M 2 receptor subtype. Antinociception is obtained by either antagonizing M 2 , D 2 and A 1 receptors or activating M 1 receptors. The two types of receptors were found to have opposite stereochemical requirements, since autoreceptors were blocked by (R)-(+)-hyoscyamine only, while postsynaptic receptors were preferentially inhibited by the (S)-(-) enantiomer. This observation was confirmed with other antimuscarinic compounds, since only the enantiomers having the same absolute configuration as (R)-(+)-hyoscyamine were active.

Synthesis and cholinergic affinity of diastereomeric and enantiomeric isomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)- pyrrolidine, 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and of Their iodomethylates.

Four out of the eight possible stereoisomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine, 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and the corresponding iodomethylates have been synthesised. They were formally derived from hybridisation of potent though unselective agonists studied before, such as 1,3-dioxolane 1 and 1,3-oxathiolane 2, with the structure of nicotine. It was expected that, by exalting the molecular complexity of the parent compounds, in particular through stereochemical complication in the proximity of the critical cationic head of the molecule, the chance to find agonists able to discriminate among cholinergic receptors subtypes would increase. The relative and absolute configuration of the compounds obtained has been established by means of NMR spectroscopy and X-ray crystallography. In preliminary studies, their binding affinity has been evaluated on rat brain nicotinic and muscarinic receptors. While none of the compounds showed any nicotinic affinity up to the dose of 10 microM, most of the iodomethylates were endowed with promising affinity for the muscarinic receptors.