Papers by Franco Cantalamessa
Journal of medicinal chemistry, Jan 17, 2007
A series of novel molecular combinations (1-4), in which L-dopa (LD) is linked covalently via an ... more A series of novel molecular combinations (1-4), in which L-dopa (LD) is linked covalently via an amide bond with glutathione (GSH), were synthesized and evaluated as potential anti-Parkinson agents with antioxidant properties. These conjugates were characterized by evaluating solubility, chemical and enzymatic stabilities, and apparent partition coefficient (log P). Derivatives 2 and 4 were tested for their radical scavenging activities, by use of a test involving the Fe(II)/H2O2-induced degradation of deoxyribose. In this study, the antioxidant efficacy of codrugs 1 and 3 was also assessed through the evaluation of plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Furthermore, the central nervous effects and rat striatal concentration of LD and dopamine (DA) have been evaluated after oral administration of codrugs 1 and 3. Tested compounds prolonged the plasma LD levels and were able to induce sustained delivery of DA in rat striatum with respect ...
Journal of medicinal chemistry, Jan 23, 2006
A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with... more A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compo...
Pharmacological research communications, 1981
The antidipsogenic effect and the v@sopressin releasing effect of ELS and LENwere studied in~ WST... more The antidipsogenic effect and the v@sopressin releasing effect of ELS and LENwere studied in~ WSTR, HEBR and HOBR:rats.!Ther.esults of:theselexperiments sUggest:iforl.these substances, a~eommon:gr similar:mechanism:of:action. Conversely, theysuggest.that ~their."antidipsogenie /effect is independent from the neuro-hypophyseal 6ontrol'~ofwatereonsetvation.
Pharmacological research communications, 1982
The intracerebroventricular (i.c.v.) injection of bombesin to rats, besides inhibiting water and ... more The intracerebroventricular (i.c.v.) injection of bombesin to rats, besides inhibiting water and food intake, produced intense grooming, alteration of explorative behaviour and of spontaneous motor activity, but neither neurological nor autonomic modifications.
Toxicology, 2004
Pesticides have been considered potential chemical mutagens. In fact, some studies show that vari... more Pesticides have been considered potential chemical mutagens. In fact, some studies show that various agrochemical ingredients possess mutagenic properties inducing mutations, chromosomal alterations or DNA damage. Experimental evidence shows a marked correlation between mutagenicity and carcinogenicity and indicates that short-term mutagenicity tests are useful for predicting carcinogenicity. The present study on rat exposed to two pyrethroids, cypermethrin and permethrin, showed different lymphocyte DNA damage depending on the type of pyrethroid, the dose, and the period of treatment. Data obtained from comet assay showed that oral treatment with 150 mg/kg body weight/day of permethrin (corresponding to 1/10 of LD 50 ) for 60 days, induced a significant increase in all comet parameters. No lymphocyte DNA damage was measured after treatment with 25 mg/kg body weight/day of cypermethrin (corresponding to 1/10 of LD 50 ) for the same period. A higher dose of permethrin (300 mg/kg body weight/day), for a shorter period (22 days), did not induce lymphocyte DNA damage, while supplementation with 200 mg/kg of Vitamins E and C protected erythrocytes against plasma membrane lipids peroxidation. Moreover, treatment with Vitamins E and C maintained the activity of glutathione peroxidase, which was reduced in the presence of permethrin, and reduced the osmotic fragility, which had increased following permethrin treatment.
Toxicology, 2007
Pyrethroids are a class of insecticides involved in different neurological disorders. They cross ... more Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood-brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL 50 ) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.
Toxicology, 2002
The effects of treatment with the synthetic insecticide cypermethrin on plasma membrane fluidity,... more The effects of treatment with the synthetic insecticide cypermethrin on plasma membrane fluidity, lipid peroxidation and antioxidant status in rat erythrocytes were investigated. Rats were treated by gavage with a low dose (12.5 mg/kg body weight per day) of cypermethrin in corn oil for 60 days. DPH and TMA-DPH fluorescence anisotropy experiments show that cypermethrin treatment, compared with controls, induced a significant decrease in erythrocyte membrane fluidity measured by DPH, while no changes were observed using TMA-DPH. Cypermethrin treatment also induced a significant increase in the lipid peroxidation, measured by the formation of conjugated dienes. The increased oxidative stress resulted in a significant decrease in the acitivity of glutathione peroxidase. The results are discussed in terms of preferential localization of cypermethrin in the hydrophobic core of the membrane, where it increases lipid packing and consequently decreases membrane fluidity.
Toxicology, 2003
Pyrethroids are divided into two groups according to their chemical structures: type I pyrethroid... more Pyrethroids are divided into two groups according to their chemical structures: type I pyrethroids are devoid of a cyano moiety at the a-position (i.e. permethrin, PERM), while type II pyrethroids have an a-cyano moiety (i.e. cypermethrin, CY). Type I pyrethroids cause a type I poisoning syndrome or ''T syndrome '', whereas type II pyrethroids induce a type II choreoathetosis syndrome, known as ''CS syndrome ''. The aim of the present work is to compare the effect of PERM and CY on erythrocyte plasma membrane fluidity of rats, treated orally for 60 days with low and high doses of these insecticides. The different modifications induced by pyrethroids on lipid peroxidation, osmotic fragility and the antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)) were measured. The data obtained show that PERM, which proved more permeable than CY, produced an increase of fluidity and polarity in the hydrophilic Á/hydrophobic region of the erythrocyte bilayer even at low doses. Also at high doses, filtering through the membrane more easily, the PERM influenced more markedly the intracellular enzymatic activity, compared with CY, reducing GPx activity and increasing SOD activity. Because of its hydrophilic character, CY limits oxidative damage in the erythrocyte cytosol at high doses. #
Toxicology, 1999
The synthetic pyrethroid insecticide, cypermethrin (50 mg/Kg) was given during gestation to pregn... more The synthetic pyrethroid insecticide, cypermethrin (50 mg/Kg) was given during gestation to pregnant rats by gavage in corn oil. Prenatal cypermethrin-exposure induces a marked and long-lasting increase of adrenaline (A) and noradrenaline (NA) plasma concentrations. The enhancement of plasma catecholamine levels was accompanied by a marked increase of CD5 + , CD4 + , and CD8 + total T cell numbers in the peripheral blood, while in the spleen a reduction of all T cell subsets was observed. In addition, peripheral blood lymphocytes (PBL) from rats prenatally exposed to cypermethrin showed an enhanced capability to proliferate in response to different doses of Concanavalin A (ConA), or human recombinant interleukin-2 (hrIL-2), whereas an impaired proliferative response was observed in the spleen. The percent increase of NA, but not A plasma concentrations paralleles the immunomodulatory effects induced by cypermethrin neonatal exposure on T cell distribution and mitogen-induced proliferation in the peripheral blood and spleen. Collectively, our results suggest that the changes in mitogen-induced proliferative responses in the peripheral blood and spleen of prenatally cypermethrin-exposed rats may be attributable to pesticide-induced catecholamine release, which causes an increased output of CD5 + , CD4 + , and CD8 + T cells from the spleen to the peripheral blood, and a consequent lymphocytosis.
Toxicology, 1998
The synthetic pyrethroid insecticide, cypermethrin (50 mg/kg) was given during gestation to pregn... more The synthetic pyrethroid insecticide, cypermethrin (50 mg/kg) was given during gestation to pregnant rats by gavage in corn oil. Prenatal cypermethrin exposure induced a significant decrease in the absolute number of all thymocyte subsets during the first 30 days after birth, being the double negative CD4 − CD8 − , single positive CD4 and CD8 T cells preferentially affected. Later on day 60 and 90 double positive CD4 + CD8 + and single positive thymocytes gradually recovered, while the total number of CD4 − CD8 − cells was increased. Moreover, thymocytes from rats prenatally exposed to cypermethrin showed an impaired ability to proliferate in response to different doses of Concanavalin A (ConA) and human recombinant interleukin-2 (hrIL-2) and to produce and/or release IL-2. Overall, our results indicate that cypermethrin administered during prenatal period can affect multiple steps in thymocyte differentiation pathways resulting in an altered cell subset distribution and an impairment of thymocyte functions.
Toxicology, 2008
Pyrethroids are important insecticides used largely because of their high activity as an insectic... more Pyrethroids are important insecticides used largely because of their high activity as an insecticide and their low mammalian toxicity. Some studies have demonstrated that these products show neurotoxic effects on the mammalian central nervous system.
Nutrition Research, 2006
Drug formulations Alimento Supervis (AS) and Alimento Mieleucalipto (AM), which are derived from ... more Drug formulations Alimento Supervis (AS) and Alimento Mieleucalipto (AM), which are derived from chestnut honey, have been used as vehicle and supplemented with ginseng, propolis, royal jelly and propolis, and eucalyptus, respectively. These substances are traditionally used as antiinflammatory medicine and were commercialized before conducting preclinical studies on their efficacy. The antioxidant properties of AS, AM, honey, and their respective natural components were determined by H 2 O 2 /luminol-derived and superoxide/lucigenin-derived chemiluminescence. AS and AM scavenged both superoxide anions and hydrogen peroxide more than did honey. The H 2 O 2 -scavenging activity of each natural component decreased in the following order: propolis N eucalyptus N ginseng N N royal jelly. O 2 À -scavenging activity was practically absent for all components, except for propolis, the activity that proved to be strongest. Oral pretreatment of AS, AM, and honey (2 g/kg), once daily for 7 consecutive days, prevented indomethacin-induced gastric lesions in rats by reducing the ulcer index, microvascular permeability, and myeloperoxidase activity of the stomach. D
Nutrition Research, 2003
We have studied the influence of hydropinic treatment with calcic and magnesic-sulphate-sulphurou... more We have studied the influence of hydropinic treatment with calcic and magnesic-sulphate-sulphurous spring mineral water (IDCS water) on plasma cholesterol (T-Ch), low density lipoprotein (LDL-Ch) and high density lipoprotein (HDL-Ch) levels, in experimental animals made hypercholesterolemic with a high cholesterol diet, and investigated possible mechanisms involved in lipoprotein metabolism.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1995
The antimuscarinic effects of tripitramine (1, 1, 24--tris[[5, ll-dihydro-6-oxo-6H-pyrido[2, 3b] ... more The antimuscarinic effects of tripitramine (1, 1, 24--tris[[5, ll-dihydro-6-oxo-6H-pyrido[2, 3b] [1, 4]-benzodiazepin-11-yl)carbonyl]methyl]-8, 17dimethyl-1, 8, 17, 24-tetraazatetracosane tetraoxalate), a member of a series of polymethylene tetraamines with in vitro cardioselectivity, were assessed in two in vivo preparations: anaesthetized and pithed rats. The wellknown M2 selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 ~tmol/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat; the same dose of this antagonist in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M3 receptors. In the pithed rat, this dose did not affect the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343. These in vivo data are consistent with the in vitro findings and confirm that tripitramine is a more potent and selective muscarinic M2 receptor antagonist than methoctramine.
Mechanisms of Ageing and Development, 1998
The influence of neonatal treatment with the pyrethroid insecticide cypermethrin ((R,S)hcyano-3-p... more The influence of neonatal treatment with the pyrethroid insecticide cypermethrin ((R,S)hcyano-3-phenoxybenzyl(1R,S)-cis-trans-3-(2,2-dichloro-vinyl)-2,2-dimethylcyclopropane carboxylate) on postnatal development of renal dopamine receptors was investigated by radioligand binding assay techniques. Treatment with cypermethrin was made on rats from the 10th to the 16th day after birth. Dopamine D 1 -and D 2 -like receptors were assayed in frozen sections of kidney of 21-, 30-, 60-and 90-day-old rats using as ligands of dopamine D 1 -and D 2 -like receptors [ 3 H]([R](+)-(chloro-2,3,4,5,-tetrahydro-5-phenyl-1,4,-benzazepinal hemimaleate) (SCH 23390) and [ 3 H]spiperone, respectively. Treatment with cypermethrin was without effect on the affinity (K d value) or the density (B max value) of dopamine D 1 -and D 2 -like receptors of rats of 21 days of age. In older groups, treatment with the compound reduced the affinity and increased the density of dopamine D 1 -like receptors, whereas it was without effect on the affinity of dopamine D 2 -like receptors and decreased their density. These findings indicate that neonatal treatment with the pyrethroid insecticide cypermethrin induces long-lasting impairment of renal dopamine D 1 -and D 2 -like receptors, and that
Life Sciences, 2000
The enantiomers desoxymuscarine 6 were tested in vitro on guinea pig tissues, and their muscarini... more The enantiomers desoxymuscarine 6 were tested in vitro on guinea pig tissues, and their muscarinic potency was evaluated at M 2 (heart force and rate) and M 3 (ileum and bladder) receptor subtypes together with the enantiomers of the parent compound muscarine 1. The eutomers ( ϩ )-1 and ( ϩ )-6 and distomers ( Ϫ )-1 and ( Ϫ )-6 were also assayed in vivo on pithed rat. AfÞnity, relative efÞcacy and enantioselectivity were also determined for the compounds under study at M 2 (heart force and rate) and M 3 (ileum and bladder), in order to investigate muscarinic receptor heterogeneity. The results of this study have been discussed in comparison with the data previously reported for the structurally related ßuoromuscarine ( ϩ )-4 and dißuoromuscarines ( ϩ )-5 and ( Ϫ )-5.
Life Sciences, 2002
A series of muscarinic agonists, straight chained, branched, cyclic alkyl and aromatic derivative... more A series of muscarinic agonists, straight chained, branched, cyclic alkyl and aromatic derivatives of the oxime 1 (demox) was designed with the aim of investigating their activity on muscarinic receptor subtypes. Effects on M 1 receptor were assessed functionally by a microphysiometer apparatus, while M 2 , M 3 , and M 4 receptor potency and affinity were studied on isolated preparations of guinea pig heart, ileum, and lung, respectively. The results suggest that the substitution of a hydrogen with a long side-chain or bulky group generally induces a decrease in potency at M 1 and M 3 subtypes, while a general increase in this parameter is obtained at M 2 subtype. Among the agonists 2 -18 , compound 4 behaves as a full agonist with a preference for M 3 subtype. Moreover, compound 12 is inactive at M 1 and M 4 receptors while it displays a full agonist activity at M 2 and M 3 subtypes. Since demox displays a variable response on cardiac M 2 receptors regulating heart force, an in-depth inquiry of the functional behaviour of this compound was carried out at M 2 receptors. In presence of 10 Ϫ 11 and 10 Ϫ 10 M demox, the binding of [ 3 H]-NMS was increased by Ϸ 30% as a consequence of an increase of the association of [ 3 H]-NMS to membranes; this effect was not observed in presence of a higher concentration of [ 3 H]-NMS. Higher concentrations of demox decreased the binding of [ 3 H]-NMS to heart atrial membranes but significantly retarded the dissociation of this radioligand. Our results suggest that demox
Journal of Medicinal Chemistry, 2006
A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with... more A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-R-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs. The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-H 2 O 2 -induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma. Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs 1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA. This evidence, together with the "in vivo" dopaminergic activity and a sustained release of the parent drug in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in treating pathologies such as Parkinson's disease, characterized by an evident decrease of DA concentration in the brain.
Journal of Medicinal Chemistry, 2009
A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect ass... more A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect associated with L-dopa (LD) therapy. Target compounds release LD and dopamine (DA) in human plasma after enzymatic hydrolysis, displaying an antioxidant effect superior to that of N-acetylcysteine (NAC). After intracerebroventricular injection of codrug 4, the levels of DA in the striatum were higher than those in LD-treated groups, indicating that this compound has a longer half-life in brain than LD.
Journal of Medicinal Chemistry, 1991
Four isomers of [(4-fluoro-5-methyl-tetrahydrofuran-2-yl)methyl]trimethylammonium iodide (4-deoxy... more Four isomers of [(4-fluoro-5-methyl-tetrahydrofuran-2-yl)methyl]trimethylammonium iodide (4-deoxy-4-fluoro-muscarines) were prepared in enantiomerically and diastereomerically pure form from (S)-(-)-methyl 4-methylphenyl sulfoxide, ethyl fluoroacetate, and allyl bromide. Their absolute configurations were assigned by 1H NMR analyses. The four optically pure compounds were tested in vitro on guinea pig and their muscarinic potency was evaluated at M3 (ileum and bladder) and M2 (heart) muscarinic receptor subtypes. Compound 1a, the most potent isomer of the series, was also tested in vivo on pithed rat and its muscarinic activity at the M1 receptor subtype was compared with that of muscarine. Moreover, affinity and relative efficacy were calculated in vitro for this compound at M2 (heart force and rate) and M3 (ileum and bladder) receptors in order to investigate muscarinic receptor heterogeneity. The 4-deoxy-4-fluoromuscarines display a similar trend of potency as the corresponding muscarines and compound 1a shows differences in the affinity constants among the studied tissues. Replacement of a hydroxyl group for a fluorine atom in the 4 position of muscarine produces 1 order of magnitude increase in affinity for cardiac M2 muscarinic receptors controlling rate, while the affinity at cardiac M2 muscarinic receptors controlling force is unchanged, opening the possibility of a further classification of cardiac muscarinic receptors.
Uploads
Papers by Franco Cantalamessa