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1.
J Pharmacol Exp Ther ; 367(3): 442-451, 2018 12.
Article in English | MEDLINE | ID: mdl-30291173

ABSTRACT

Safinamide (Xadago) is a novel dual-mechanism drug that has been approved in the European Union and United States as add-on treatment to levodopa in Parkinson's disease therapy. In addition to its selective and reversible monoamine oxidase B inhibition, safinamide through use-dependent sodium channel blockade reduces overactive glutamatergic transmission in basal ganglia, which is believed to contribute to motor symptoms and complications including levodopa-induced dyskinesia (LID). The present study investigated the effects of safinamide on the development of LID in 6-hydroxydopamine (6-OHDA)-lesioned rats, evaluating behavioral, molecular, and neurochemical parameters associated with LID appearance. 6-OHDA-lesioned rats were treated with saline, levodopa (6 mg/kg), or levodopa plus safinamide (15 mg/kg) for 21 days. Abnormal involuntary movements, motor performance, molecular composition of the striatal glutamatergic synapse, glutamate, and GABA release were analyzed. In the striatum, safinamide prevented the rearrangement of the subunit composition of N-methyl-d-aspartate receptors and the levodopa-induced increase of glutamate release associated with dyskinesia without affecting the levodopa-stimulated motor performance and dyskinesia. Overall, these findings suggest that the striatal glutamate-modulating component of safinamide's activity may contribute to its clinical effects, where its long-term use as levodopa add-on therapy significantly improves motor function and "on" time without troublesome dyskinesia.


Subject(s)
Alanine/analogs & derivatives , Benzylamines/pharmacology , Dyskinesia, Drug-Induced/drug therapy , Excitatory Amino Acid Agents/pharmacology , Levodopa/pharmacology , Signal Transduction/drug effects , Alanine/pharmacology , Animals , Antiparkinson Agents/pharmacology , Corpus Striatum/drug effects , Disease Models, Animal , Dopamine Agents/pharmacology , Male , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Rats , Rats, Sprague-Dawley
2.
Neuroscience ; 169(2): 584-95, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20493242

ABSTRACT

Excitatory amino acid carrier 1 (EAAC1) belongs to the family of the Na(+)-dependent glutamate carriers. Although the association between defective EAAC1 function and neurologic disease has been repeatedly studied, EAAC1 regulation is not yet fully understood. We have reported that in C6 glioma cells both the activity and membrane targeting of EAAC1 require the integrity of actin cytoskeleton. Here we show that, in the same model, EAAC1 partially co-localizes with actin filaments at the level of cell processes. Moreover, perinuclear spots in which EAAC1 co-localizes with the actin binding protein alpha-adducin are observed in some cells and, consistently, faint co-immunoprecipitation bands between EAAC1 and alpha-adducin are detected. Co-localization and partial co-immunoprecipitation of EAAC1 and adducin are still detectable after cell treatment with phorbol esters, a condition that leads to a protein kinase C (PKC)-dependent increase of EAAC1 expression on the membrane and to the phosphorylation of adducin. A co-immunoprecipitation band was also detected in protein extracts of rat hippocampus. The amount of adducin co-immunoprecipitated with EAAC1 increases after the treatment of C6 cells with retinoic acid, a differentiating agent that induces EAAC1 overexpression in this cell model. Moreover, in clones of C6 cells transfected with a hemagglutinin (HA)-tagged adducin, the bands of EAAC1 immunoprecipitated by an anti-HA antiserum were proportional to EAAC1 expression. These results suggest the existence of a pool of EAAC1 transporters associated with the actin binding protein alpha-adducin in a PKC-insensitive manner.


Subject(s)
Calmodulin-Binding Proteins/metabolism , Cytoskeletal Proteins/metabolism , Excitatory Amino Acid Transporter 3/metabolism , Actins/metabolism , Animals , Cell Line, Tumor , Hemagglutinins/metabolism , Hippocampus/metabolism , Immunoprecipitation , Phosphorylation , Protein Binding , Rats , Tissue Extracts/metabolism , Tretinoin/pharmacology
3.
J Gerontol A Biol Sci Med Sci ; 55(8): B365-72, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10952357

ABSTRACT

Because progressive fibrosis is a histological hallmark of the aging kidney, we sought to characterize the course of some fibrosis-related genes [pro-alpha2(I)collagen (COL-I), pro-alpha1(III)collagen (COL-III), and transforming growth factors beta1 and beta3 (TGF-beta1 and TGF-beta3)] of interstitial collagen accumulation [COL-I and COL-III proteins, hydroxyproline (PRO-OH), histology] and its degradation (matrix metalloproteinase MMP-1 and -2) during maturation and early aging in rats. During the lifespan considered we observed no changes in the mRNA, except that COL-I mRNA tended to be up-regulated from 2 to 19 months of age. However, progressive fibrosis was histologically detectable, with COL-I accumulation (p < .05 and p < .01 in 12-month- and 19-month-old rats vs the youngest), and confirmed by the PRO-OH tissue levels (p = .0001); COL-III seemed to be less involved. The MMP-1 protein level decreased significantly in the cortex of 12-month- and 19-month-old rats (p < .05), whereas MMP-2 protein level and activity remained essentially unchanged. These results show that, during aging of the kidney, (i) renal cortex fibrosis is explained by COL-I accumulation as a consequence of an altered balance between its synthesis and degradation, and (ii) the expression of the pleiotropic factor TGF-beta in the renal cortex is not modified.


Subject(s)
Collagen/biosynthesis , Collagen/genetics , Kidney Cortex/metabolism , Kidney Cortex/pathology , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/genetics , Age Factors , Animals , Fibrosis , Gene Expression , Hydroxyproline/metabolism , Kidney Cortex/enzymology , Male , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 2/metabolism , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley
4.
J Pharmacol Exp Ther ; 288(3): 1074-83, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10027844

ABSTRACT

A genetic alteration in the adducin genes is associated with hypertension and up-regulation of the expression of renal Na, K-ATPase in Milan-hypertensive (MHS) rats, in which increased ouabain-like factor (OLF) levels are also observed. PST 2238, a new antihypertensive compound that antagonizes the pressor effect of ouabain in vivo and normalizes ouabain-dependent up-regulation of the renal Na-K pump, was evaluated for its ability to lower blood pressure and regulate renal Na,K-ATPase activity in MHS genetic hypertension. In this study, we show that PST 2238, given orally at very low doses (1 and 10 microg/kg for 5-6 weeks), reduced the development of hypertension in MHS rats and normalized the increased renal Na,K-ATPase activity and mRNA levels, whereas it did not affect either blood pressure or Na,K-ATPase in Milan-normotensive (MNS) rats. In addition, a similar antihypertensive effect was observed in adult MHS rats after a short-term treatment. In cultured rat renal cells with increased Na-K pump activity at Vmax due to overexpression of the hypertensive variant of adducin, 5 days of incubation with PST 2238 (10(-10-)-10(-9) M) lowered the pump rate to the level of normal wild-type cells, which in turn were not affected by the drug. In conclusion, PST 2238 is a very potent compound that in MHS rats reduces blood pressure and normalizes Na-K pump alterations caused by a genetic alteration of the cytoskeletal adducin. Because adducin gene mutations have been associated with human essential hypertension, it is suggested that PST 2238 may display greater antihypertensive activity in those patients carrying such a genetic alteration.


Subject(s)
Androstanols/therapeutic use , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Kidney Medulla/drug effects , Sodium-Potassium-Exchanging ATPase/biosynthesis , Animals , Blood Pressure/drug effects , Calmodulin-Binding Proteins/biosynthesis , Calmodulin-Binding Proteins/genetics , Cells, Cultured , Down-Regulation , Enzyme Inhibitors/pharmacology , Heart Rate/drug effects , Hypertension/enzymology , Hypertension/genetics , Kidney Medulla/enzymology , Male , Mutation , Ouabain/pharmacology , RNA, Messenger/analysis , Rats , Rats, Inbred SHR , Rats, Inbred Strains , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Transfection
5.
Bioorg Med Chem ; 6(10): 1889-94, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9839018

ABSTRACT

The four stereoisomers of the 2-hydroxy derivatives of digitoxigenin and 3-epidigitoxigenin have been synthesized, their structures established by NMR, and their binding affinity for the digitalis receptor on Na+, K(+)-ATPase evaluated. These derivatives showed lower affinities than the parent compounds. The hydrophilic hydroxy groups in the alpha position are more detrimental to the affinity than hydroxy groups in the beta position.


Subject(s)
Digitoxigenin/analogs & derivatives , Digitoxigenin/chemistry , Digitoxigenin/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Digitoxigenin/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Structure-Activity Relationship
6.
J Pharmacol Exp Ther ; 285(1): 83-94, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9535997

ABSTRACT

The inhibition of the long-term pressor effect of ouabain may be useful for the therapy of essential hypertension. Here, for the first time, a selective inhibitor of the ouabain pressor effect is described. In vitro, 17beta-(3-furyl)-5beta-androstane-3beta, 14beta, 17alpha-triol (PST 2238) displaced ouabain from its binding sites on purified sodium, potassium ATPase enzyme (Na-K ATPase) (IC50 1.7 x 10(-6) M) without interacting with other receptors involved in blood pressure regulation or hormonal control. In cultured renal cells, incubation with ouabain (10(-10) to 10(-8) M) for 5 days stimulated the Na-K pump at Vmax, whereas PST 2238 showed the same effect at micromolar concentration. The ouabain-dependent increase in the Na-K pump rate was abolished by PST 2238 at concentrations from 10(-14) to 10(-9) M. In rats made hypertensive by chronic infusion of 50 microg/kg/day of ouabain, PST 2238 given p.o at very low doses (0.1-1 microg/kg/day for 4 weeks) abolished the increase in blood pressure and renal Na-K ATPase activity caused by ouabain. PST 2238 did not affect either blood pressure or renal Na-K ATPase activity in normotensive rats. In conclusion, PST 2238 is a very potent compound that normalizes both blood pressure and alterations in the Na-K pump caused by ouabain. Thus it represents the prototype of a new class of antihypertensive drugs that could be effective in forms of hypertension sustained by the concomitant increase of endogenous ouabain levels and alterations in the Na-K pump.


Subject(s)
Androstanols/pharmacology , Antihypertensive Agents/pharmacology , Cardiotonic Agents/antagonists & inhibitors , Ouabain/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/drug effects , Androstanols/metabolism , Animals , Antihypertensive Agents/metabolism , Cardiotonic Agents/metabolism , Cells, Cultured/drug effects , Male , Ouabain/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sodium-Potassium-Exchanging ATPase/metabolism
7.
J Med Chem ; 40(21): 3484-8, 1997 Oct 10.
Article in English | MEDLINE | ID: mdl-9341924

ABSTRACT

A series of digitalis-like compounds, with the lactone ring shifted from the original position through a spacer or replaced by a series of guanylhydrazone substituent-bearing chains, was synthesized and evaluated for inhibition of Na+,K(+)-ATPase and for inotropic activity. The highest Na+,K(+)-ATPase inhibition (IC50) and inotropic activity (EC50) were reached with the vinylogous guanylhydrazone 5 where a cardenolide-like polarized alpha,beta-unsaturated system and a basic guanidino group were both present at the 17 beta-position; for this compound IC50 and EC50 values were comparable to or higher than those of Thomas' parent guanylhydrazone 1, digitoxigenin, and digoxin. A substantial improvement of the desired positive inotropic activity versus the toxic arrhythmogenic concentration was not reached within this series; only a slightly better therapeutic index can be envisaged for compounds 5 and 4, even though, for the latter, to the detriment of potency, presumably because of a weaker interaction with the receptor, due to the lack of a cardenolide-like polarized system.


Subject(s)
Androstanes/chemical synthesis , Androstanes/pharmacology , Cardiotonic Agents/chemical synthesis , Cardiotonic Agents/pharmacology , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Androstanes/chemistry , Androstanes/toxicity , Animals , Arrhythmias, Cardiac/chemically induced , Cardiotonic Agents/chemistry , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guinea Pigs , Hydrazones/chemistry , Hydrazones/toxicity , Kidney/enzymology , Molecular Structure , Myocardial Contraction/drug effects , Structure-Activity Relationship
8.
Steroids ; 61(10): 572-82, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8910970

ABSTRACT

The synthesis of seco-D and D-homo digitalis derivatives, from the carda-14,20(22)-dienolide 1, is described. Selective ozonolysis gave the seco-D 14-ketoaldehyde 2a. Modification of the two carbonyl groups and of the alpha, beta-unsaturated lactone ring of the seco-D 14-ketoaldehyde 2a allowed preparation of derivatives with a broad range of binding affinity to the Na+, K(+)-ATPase receptor. Some of the seco-D derivatives (10, 11b, and 13b) showed a binding affinity similar to that of digitoxigenin, demonstrating that the D-ring is not essential for recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 times lower than that of digitoxigenin, was that of the C/D cis compound 29b; the C/D trans analog 28b showed a 7-fold decrease in binding affinity, indicating that the C/D configuration plays an important role in D-homo derivatives as in the classical digitalis compounds.


Subject(s)
Digitalis Glycosides/chemical synthesis , Digitalis Glycosides/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Digitalis Glycosides/chemistry , Digitoxigenin/analogs & derivatives , Digitoxigenin/chemistry , Ouabain/metabolism , Structure-Activity Relationship
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