Francesco Occhiuto

A drug used in traditional medicine: Harpagophytum procumbens DC. II: Cardiovascular activity

In conscious normotensive rats the dried crude methanolic extract of Harpagophytum procumbens secondary roots caused a significant dose-dependent reduction of arterial blood pressure. The decrease was significant only at higher doses given by gavage (dried extract = 400 mg/kg). At the same time a decrease of heart rate was observed. In the same experimental conditions, harpagoside presented an activity lower than doses of Harpagophytum procumbens extract containing corresponding quantities of harpagoside. In spontaneously beating Langendorff preparations of rabbit heart, the Harpagophytum procumbens methanolic extract caused a mild decrease in the heart rate with a concomitant mild positive inotropic effect at lower doses but a marked negative inotropic effect at higher doses. The coronary flow decreased at higher doses only. The negative chronotropic and positive inotropic effects of harpagoside were comparatively higher with respect to that of the extract, whereas harpagide had only a slight negative chronotropic effect and a considerable negative inotropic one. Both in experiments on intact rats and on isolated rabbit heart, the Harpagophytum procumbens extract also demonstrated a protective action with regard to arrhythmias induced by aconitine, and particularly to those provoked by calcium chloride and epinephrine--chloroform.

The isoflavones mixture from Trifolium pratense L. protects HCN 1-A neurons from oxidative stress.

Oxidative stress‐induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases such as Alzheimers disease and Parkinsons. Using the Alzheimers disease‐associated hydrogen peroxide (H2O2), we investigated the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Trifolium pratense L. (Red clover) against oxidative stress‐induced cell death in human cortical cell line HCN 1‐A maintained in culture. Neuronal viability was determined by MTT or trypan blue test and neuronal integrity by morphological analysis.

Computational Studies to Discover a New NR2B/NMDA Receptor Antagonist and Evaluation of Pharmacological Profile

The ionotropic glutamate NMDA/NR2B receptor and its interaction with ifenprodil‐like noncompetitive ligands were investigated by a combined ligand‐based and target‐based approach. First, we generated 3D pharmacophore hypotheses and identified common chemical features that are shared by a training set of well‐known NR2B antagonists. The binding mode of the most representative ligand was also studied by molecular docking. Because the docking results and the suggested 3D pharmacophore model were in good agreement, we obtained new information about the NR2B ifenprodil site. The best pharmacophoric hypothesis was used as a query for in silico screening; this allowed the identification of new “hit”. We synthesized “hit‐compound” analogues, and some of the molecules showed significant activity both in binding and functional assay as well as in vivo anticonvulsant efficacy in DBA/2 mice. The most active derivatives also exhibited neuroprotective effects against glutamate‐induced toxicity in HCN‐1A cells.

Effects of Calotropis procera on oestrous cycle and on oestrogenic functionality in rats

Effects of ethanolic and aqueous extracts of Calotropis procera (Ait.) R.Br. roots, have been studied on oestrous cycle and on some parameters of oestrogenic functionality in rats. Both extracts have been shown to interrupt the normal oestrous cycle in 60 and 80%, respectively, of rats treated. The rats exhibited prolonged dioestrous stage of the oestrous cycle with consequent temporary inhibition of ovulation. The contemporary administration of commercial oestro-progestinic preparation exhibited the same effects in 100% of rats treated. However, the extracts have not demonstrated to possess oestrogenic activity when tested in immature female bilaterally ovariectomized rats.

The phytoestrogenic isoflavones from Trifolium pratense L. (Red clover) protects human cortical neurons from glutamate toxicity

The endogenous steroid estrogen has been shown to affect neuronal growth, differentiation and survival. Genistein, daidzein and other isoflavones have been shown to mimic the pharmacological actions of the gonadal steroid estrogen with which they have structural similarities. Several studies have looked at the effect of isoflavones in the brain. In the present study, human cortical cell line HCN 1-A maintained in culture was used to test the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Red clover against glutamate toxicity. Neuronal viability was determined by MTT or trypan blue test and neuronal membrane damage was quantitatively measured by lactate dehydrogenase (LDH). The results obtained indicate that exposure of HCN 1-A cell cultures to glutamate resulted in concentration-dependent decreases in neuron viability. Concentration of glutamate ranging from 0.01 to 5 mM was toxic to these cultures. A 24-h pretreatment with 0.5, 1 and 2 microg/ml isoflavones enriched fraction (IEF) significantly increased cell survival and significantly decreased cellular lactate dehydrogenase release from differentiated cortical neurons, indicating that neurons treated with isoflavones were protected from the cell death induced by glutamate exposure. Moreover, the pretreatment with IEF prevented the morphological disruption caused by glutamate as shown by microscopical inspection. These findings indicate that IEF has a neuroprotective effect in human cortical neurons and that this effect might be resulted from his antioxidant and estrogenic actions.

A drug used in traditional medicine: harpagophytum procumbens dc. iii. effects on hyperkinetic ventricular arrhythmias by reperfusion

In Langendorff preparations of rat heart, hyperkinetic ventricular arrhythmias (HVA) have been induced by an ischaemic perfusion (coronary flux 0.5 ml/min; pressure 8 mmHg) and following reperfusion at basal conditions (coronary flux 8 ml/min; pressure 50 mmHg). Crude methanolic extracts of Harpagophytum procumbens secondary roots and harpagoside showed a significant, dose-dependent, protective action toward HVA induced by reperfusion.

Effects of Some Malian Medicinal Plants on the Respiratory Tract of Guinea-pigs

Crossopteryx febrifuga, Pteleopsis suberosa and Entada africana are used in Mali traditional medicine for fever and various respiratory diseases. We have investigated the effects of these three drugs in the form of a decoction on the respiratory tract using different experimental models.

Rhodiola rosea Extract Protects Human Cortical Neurons against Glutamate and Hydrogen Peroxide‐induced Cell Death Through Reduction in the Accumulation of Intracellular Calcium

The aim of this study was to investigate the neuroprotective effects of a titolated extract from Rhodiola rosea L. (RrE) and of salidroside (Sa), one of the major biologically active compounds extracted from this medicinal plant, against oxidative stressor hydrogen peroxide (H2O2) and glutamate (GLU)‐induced cell apoptosis in a human cortical cell line (HCN 1‐A) maintained in culture. The results obtained indicate that exposure of differentiated HCN 1‐A neurons to GLU or H2O2 resulted in concentration‐dependent cell death. A 24 h pre‐treatment with RrE significantly increased cell survival and significantly prevented the plasma membrane damage and the morphological disruption caused by GLU or H2O2, indicating that neurons treated with RrE were protected from the neurotoxicity induced by the oxidative stressor used. In addition, RrE significantly reduced H2O2 or GLU‐induced elevation of intracellular free Ca2+ concentration. The results obtained have also shown that Sa caused similar effects in all experimental models used; however, the potency of the action was lower than that of the extract containing corresponding quantities of Sa. These findings indicate that RrE has a neuroprotective effect in cortical neurons and suggest that the antioxidant activity of the RrE, due to the structural features of the synergic active principles they contain, may be responsible for its ability to stabilize cellular Ca2+ homeostasis. Copyright

3,3′-Di [1,3-thiazolidine-4-one] system. II. Anti-inflammatory and anti-histaminic properties in new substituted derivatives

Abstract In pursuing our search on anti-inflammatory dl and meso 3,3′-di[1,3-thiazolidine-4-one] compounds, two series of derivatives have been prepared by modifying the substitution pattern at positions 1 and 2 of the heterocyclic rings and by introducing an ethylene chain between nitrogen atoms. The anti-inflammatory activity of these compounds has been preliminarily assayed against carrageenin-induced rat paw edema: those proven to be active were also tested for analgesic, anti-pyretic and anti-histamine properties. As a whole, the obtained results suggest that some of the new derivatives possess significant anti-histamine activity. The meso forms generally are more active than dl ones in agreement with the previously emphasized SAR of the chiral systems under study.

3,3′-Di(1,3-thiazolidine-4-one) system. V. Synthesis and pharmacological properties of 3,3′(1,2-ethanediyl)bis-(2-heteroaryl-1,3-thiazolidine-4-one) derivatives

A class of anti-inflammatory, analgesic and histamine H1- and H2-receptor antagonists the 2,2′-diheteroarylbisthiazolidinones and their 1,1′-disulfones, obtained as [RR, SS] and [RS, SR] isomers, is described. The heteroaryl substitution at 2 and 2′ carbons generally improves the pharmacological activities with respect to those of the previously studied 2,2′-diaryl analogues. In particular the 2,2′-dithienyl derivatives exhibit analgesic properties and, as [RS, SR] isomers 6b, 11b, 12b H2-histamine receptor antagonism as well. The most effective acute anti-inflammatory agents appear to be the 2,2′-di(3-pyridyl) compounds 8a, 8b, 14a, 14b which also display analgesic activity. Moreover, an H1-histamine receptor antagonism is almost selectively exerted by the 2,2′-di(2-pyridyl) derivatives 7a, 7b, 13a, 13b. The relationships between the assessed activities and the chirality and/or the sulfur oxidation state of the molecules are discussed. The anti-cancer potential was also evaluated against P 388 murine lymphocytic leukemia; however, the results were not significant.