Carbonic anhydrase activation profile of indole-based derivatives.

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.

Effect of Detergents on Activity and Magnesium-Dependent Properties of Different Isoforms of Na+,K+-ATPase in the Crude Membrane Fraction of Rat Cerebral Cortex.

We studied the effect of various detergents (Tween-20, Triton X-100, and sodium deoxycholate) on activity and magnesium-dependent properties of Na+,K+-ATPase of the crude membrane fraction of rat cerebral cortex. All studied detergents significantly increased activity of the studied enzyme in a concentration-dependent manner. Sodium deoxycholate provided significantly higher values Na+,K+-ATPase activity (by ≈50%) than Triton X-100 and Tween-20. In the presence of Triton X-100, a changed pattern of the dependence of enzyme activity on the concentration of magnesium ions in the incubation solution was noted. Separate measurement of activities of Na+,K+-ATPase isoforms made it possible to assume that changes in magnesium-dependent properties are due to the predominant effect of Triton X-100 on ouabain-sensitive α2- and α3-isoforms.

Design, synthesis and biological activity of selective hCAs inhibitors based on 2-(benzylsulfinyl)benzoic acid scaffold.

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.

Discovery of novel 1,3-diaryltriazene sulfonamides as carbonic anhydrase I, II, VII, and IX inhibitors.

A series of new 1,3-diaryltriazene sulfonamides was synthesised by reaction of diazonium salt of metanilamide (3-aminobenzene sulfonamide) with substituted aromatic amines. The obtained new compounds were assayed as inhibitors of four physiologically and pharmacologically relevant human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1), specifically, hCA I, hCA II, and hCA VII (cytosolic isoforms), as well as the tumour-associated membrane-bound isoform hCA IX. All isoforms investigated here were inhibited by the newly synthesised 1,3-diaryltriazene sulfonamide derivatives from the micromolar to the nanomolar range. The cytosolic isoforms were inhibited with Kis in the range of 92.3-8371.1 nM (hCA I), 4.3-9194.0 nM (hCA II), and 15.6-9477.8 nM (hCA VII), respectively. For the membrane-bound tumour-associated isoform hCA IX, the KI-s ranged between 50.8 and 9268.5 nM. The structure-activity relationship (SAR) with these newly synthesised metanilamide derivatives are discussed in detail.

Carbonic anhydrase inhibition with a series of novel benzenesulfonamide-triazole conjugates.

We report the synthesis and characterisation of a novel series of triazole benzenesulfonamide derivatives, which incorporate the general pharmacophore associated with carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The synthesised compounds were tested in vitro against four human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I, hCA II, hCA IV and hCA IX. The obtained results showed that the tumour-associated hCA IX was the most sensitive to inhibition with the synthesised derivatives, with the triazolo-pyridine benzenesulfonamides 14, 16 and 17 being the most effective inhibitors. Some selected compounds were chosen for a single dose anti-proliferative activity testing against a panel of 57 human tumour cell lines and show some anti-proliferative activity ex vivo.

Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII.

4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated.

N-Nitrosulfonamides: A new chemotype for carbonic anhydrase inhibition.

A series of N(1)-substituted aromatic sulfonamides was obtained by applying a selective sulfonamide nitration synthetic strategy leading to Ar-SO2NHNO2 derivatives which were investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Two human (h) hCA isoforms, the cytosolic hCA II and the transmembrane hCA IX, in addition to the fungal enzyme from Malassezia globosa, MgCA, were included in the study. Most of the new compounds reported selectively inhibited hCA IX over hCA II and at the same time showed effective MgCA inhibitory properties, with KIs ranging between 0.22 and 8.09µM. The N-nitro sulfonamides are a new chemotype with CA inhibitory effects. As hCA IX was recently validated as antitumor/antimetastatic drug target, its selective inhibition could be exploited for interesting biomedical applications. Moreover, due to the effective MgCAs inhibitory properties of the N-nitro sulfonamides, of considerable interest in the cosmetics field as potential anti-dandruff agents, the N-nitro sulfonamides may be considered as interesting leads for the design of more efficient compounds targeting fungal enzymes.

CD44(high) /ALDH1(high) head and neck squamous cell carcinoma cells exhibit mesenchymal characteristics and GSK3ß-dependent cancer stem cell properties.

BACKGROUND: CD44 and aldehyde dehydrogenase 1 (ALDH1) have been shown to be useful markers for identification of cancer stem cells (CSCs). We previously reported that glycogen synthase kinase 3ß (GSK3ß) is involved in regulation of the self-renewal ability of head and neck squamous cell carcinoma (HNSCC) CSCs. The purpose of the present study was to clarify the role of GSK3ß in CD44(high) /ALDH1(high) HNSCC cells. METHODS: Cells with greater expression of CD44 and higher ALDH1 enzymatic activity were FACS sorted from the OM-1 HNSCC cell line. The self-renewal ability of CD44(high) /ALDH1(high) cells was then examined using a tumor sphere formation assay. mRNA expressions of the stem cell markers Sox2, Oct4, and Nanog, as well as GSK3ß were evaluated by real-time RT-PCR. RESULTS: CD44(high) /ALDH1(high) cells exhibited higher tumor sphere forming ability and increased expression of stem cell markers as compared with CD44(high) /ALDH1(low) cells. Interestingly, spindle-shaped cells positive for vimentin were found in the CD44(high) /ALDH1(high) but not the CD44(high) /ALDH1(low) cell population. In addition, the ALDH1 activity and sphere forming ability of CD44(high) /ALDH1(high) cells was significantly inhibited by GSK3ß knockdown. On the other hand, CD44(high) /ALDH1(low) cells exhibited high epidermal growth factor receptor (EGFR) expression and increased cell growth. CONCLUSIONS: Our results show that GSK3ß plays a major role in maintenance of stemness of CD44(high) /ALDH1(high) HNSCC cells. Additionally, they indicate a close relationship between CSC and mesenchymal characteristics in HNSCC.

The effect of caffeic acid phenethyl ester (CAPE) on metabolic enzymes including acetylcholinesterase, butyrylcholinesterase, glutathione S-transferase, lactoperoxidase, and carbonic anhydrase isoenzymes I, II, IX, and XII.

Caffeic acid phenethyl ester (CAPE) is an active component of honeybee propolis extracts. Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread and intensively studied metalloenzymes present in higher vertebrates including humans as many diverse isoforms. Acetylcholinesterase (AChE) is responsible for acetyl choline (ACh) hydrolysis and plays a fundamental role in nerve impulse transmission by terminating the action of the ACh neurotransmitter at cholinergic synapses and neuromuscular junctions. Butyrylcholinesterase (BChE) is another enzyme abundantly present in the liver and released into blood in a soluble form. Lactoperoxidase (LPO) is an enzyme involved in fighting pathogenic microorganisms whereas glutathione S-transferases (GSTs) are dimeric proteins present both in prokaryotic and eukaryotic organisms and involved in cellular detoxification mechanisms. In the present study, the inhibition effect of CAPE on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII, AChE, BChE, LPO, and GST was evaluated. CAPE inhibited these enzymes with Kis in the range between micromolar to picomolar. The best inhibitory effect was observed against AChE and BChE.

Quercetin regresses Dalton's lymphoma growth via suppression of PI3K/AKT signaling leading to upregulation of p53 and decrease in energy metabolism.

Various oncogenes are associated with deregulation in cell proliferation, apoptosis, and cell survival, which ultimately cause cancerous growth. Phosphatidylinositol 3-kinase (PI3K) mediated signaling plays a key role in malignant transformation. Cell proliferation and cell survival of tumor cell are induced by hyper activation of PI3K, AKT1, glycolytic enzyme LDH-A, and inactivation of tumor suppressor gene p53. Dietary flavonoids such as quercetin are considered a powerful modulator of different cellular signaling pathways. The present study is focused on the role of quercetin on regulation of PI3K/AKT pathways in Dalton's lymphoma mice. Effect of quercetin was analyzed in ascite cells in terms of cell viability, glycolytic metabolism as well as expression, and level of PI3K (regulatory and catalytic subunit), AKT1, and p53 using standard methods. Results reflect hyperactivation of PI3K signaling in ascite cells of Dalton's lymphoma mice, leading to activation of AKT1 and inactivation of p53. Quercetin modulates the pathway toward suppression of lymphoma. Glycolytic metabolism was also downregulated by quercetin. Its tumor suppressor activity was confirmed by morphological parameters and longevity of mice. The findings suggest that quercetin may contribute to lymphoma prevention by downregulating PI3K-AKT1-p53 pathway as well as by glycolytic metabolism.

Effects of the proteasome inhibitor, bortezomib, on cytodifferentiation and mineralization of periodontal ligament cells.

BACKGROUND AND OBJECTIVE: The proteasome inhibitor, bortezomib, is known to induce osteoblastic differentiation in a number of cell lines, such as mesenchymal stem cells and osteoblastic precursor cells. As periodontal ligament (PDL) cells are multipotent, we examined whether bortezomib may induce the differentiation of PDL cells into hard-tissue-forming cells. MATERIAL AND METHODS: A mouse PDL clone cell line, MPDL22 cells, was cultured in mineralization medium in the presence or absence of bortezomib. Expression of calcification-related genes and calcified-nodule formation were evaluated by real-time PCR and Alizarin Red staining, respectively. RESULTS: Bortezomib increased the expression of calcification-related mRNAs, such as tissue nonspecific alkaline phosphatase isoenzyme (ALPase), bone sialoprotein (Bsp), runt-related transcription factor 2 (Runx2) and osteopontin, and calcified-nodule formation in MPDL22 cells. These effects were induced, in part, by increasing the cytosolic accumulation and nuclear translocation of ß-catenin, leading to an increase in expression of bone morphogenetic protein (Bmp)-2, -4 and -6 mRNAs. In addition, bortezomib enhanced BMP-2-induced expression of Bsp and osteopontin mRNAs and increased calcified-nodule formation in MPDL22 cells. CONCLUSION: Bortezomib induced cytodifferentiation and mineralization of PDL cells by enhancing the accumulation of ß-catenin within the cytosol and the nucleus and increasing the expression of Bmp-2, -4 and -6 mRNAs. Moreover, bortezomib enhanced the BMP-2-induced cytodifferentiation and mineralization of PDL cells, suggesting that bortezomib may be efficacious for use in periodontal regeneration therapy.

In vitro effects of some flavones on human pyruvate kinase isoenzyme M2.

PKM2 is an important target for designing anticancer drug. Inhibitors and activators of this enzyme are suitable molecules for use in treating cancer. The aim of the present study was to investigate the effect of certain flavones on PKM2. Apigenin, wogonin, flavone, 3-hydroxyflavone, 5-hydroxyflavone, 6-hydroxyflavone, and 7-hydroxyflavone effectively inhibited PKM2, with IC50 in the range of 0.99-2.120 µM. The kinetic study indicated that these compounds acted as noncompetitive with Ki values of 3.53-5.67 µM toward phosphoenolpyruvate. Scutellarin and tangeritin demonstrated strong activation effect with AC50 values < 2 µM. Diosmetin, baicalin, baicalein, and luteolin showed an intermediate-level activator effect. These results demonstrate that flavone and their analogs could serve as leading compounds to develop new potent and selective inhibitor and activator for PKM2.

Gender-specific implications for pharmacology in childbearing age and in postmenopausal women.

Women have three very important physiological functions that are not observed in men--menstruation, pregnancy and lactation. Each of these mechanisms influences pharmacokinetics and pharmacodynamics of many drugs. Individualization of pharmacotherapy is a major challenge of modern medicine. The differences in response to drug are responsible for the effectiveness of pharmacological treatment and the occurrence and severity of toxic effects and side effects. Therapeutic decision should be based not only on account of the dose-effect, but the consideration of gender, genetic and environmental differences affecting the final therapeutic effect. Many important differences between men and women like sex-based differences in normal physiology, or in the predisposition to a specific disease, can be due to genetic differences, the actions of the sex steroid hormones or an interaction between these factors. Women generally have a lower body mass, a reduced hepatic clearance, differences in activity of cytochrome P450 (CYP) enzymes (increase in CYP3A4, decrease in CYP2D6, CYP2C19 and CYP1A2) and different from men's rate of drug metabolism. Other important factors contributing to gender differences in the pharmacokinetics of drugs are conjugation, absorption, protein binding and urinary excretion. It still remains unexplained how gender differences affect the increased risk of side effects. This review is an attempt to assess the biological, physiological and hormonal basis of women differences in the pharmacokinetics and pharmacodynamics of many drugs.

PKCθ-regulated signalling in health and disease.

Protein kinase Cθ (PKCθ) is a key enzyme in T-lymphocytes where it plays an important role in signal transduction downstream of the activated T-cell receptor (TCR) and the CD28 co-stimulatory receptor. Antigenic stimulation of T-cells triggers PKCθ translocation to the centre of the immunological synapse (IS) at the contact site between antigen-specific T-cells and antigen-presenting cells (APCs). The IS-residing PKCθ phosphorylates and activates effector molecules that transduce signals into distinct subcellular compartments and activate the transcription factors, nuclear factor κB (NF-κB), nuclear factor of activated T-cells (NFAT) and activating protein 1 (AP-1), which are essential for the induction of T-cell-mediated responses. Besides its major biological role in T-cells, PKCθ is expressed in several additional cell types and is involved in a variety of distinct physiological and pathological phenomena. For example, PKCθ is expressed at high levels in platelets where it regulates signal transduction from distinct surface receptors, and is required for optimal platelet activation and aggregation, as well as haemostasis. In addition, PKCθ is involved in physiological processes regulating insulin resistance and susceptibility to obesity, and is expressed at high levels in gastrointestinal stromal tumours (GISTs), although the functional importance of PKCθ in these processes and cell types is not fully clear. The present article briefly reviews selected topics relevant to the biological roles of PKCθ in health and disease.

Investigating multifaceted action of ibuprofen derivatives towards cox isozymes and interleukin-6 (IL-6) site correlating with various target sites.

The multifaceted action of new ibuprofen analogs has been investigated against inflammation, neurological and pro-inflammation factors. On the basis of ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, molecular docking as well as molecular dynamics simulation, compound 3 was thought to have good anti-inflammatory activity. As the presence of structural interactions such as conventional hydrogen bonds and electrostatic interactions through the nitrogen atoms of the linker in compound 3 gave strong evidence of its potency. The major finding of the current work is that the presence of appropriate number of hetero atoms (NH, OH) in a compound makes it more efficient than the number of labile groups (i.e., hydroxyl groups). Additionally, the position of hetero atoms in a compound and orientation also play a vital role in its efficacy. It was also screened for in vitro anti-inflammatory activity by membrane stability method, where it has shown 90.8% protection of RBC hemolysis. Thus, compound 3 with effective structural features may have good anti-inflammatory activity.Communicated by Ramaswamy H. Sarma.

Cell-specific mRNA alterations in Na+, K+-ATPase α and ß isoforms and FXYD in mice treated chronically with carbamazepine, an anti-bipolar drug.

Evidence accumulating during almost 50 years suggests Na(+), K(+)-ATPase dysfunction in bipolar disorder, a disease treatable with chronic administration of lithium salts, carbamazepine or valproic acid. Three Na(+), K(+)-ATPase α subunits (α1-3) and two ß subunits (ß1 and ß2) are expressed in brain together with the auxiliary protein FXYD7. FXYD7 decreases K(+) affinity, and thus contributes to stimulation of the enzyme at elevated extracellular K(+) concentrations. Na(+), K(+)-ATPase subtype and FXYD7 genes were determined by RT-PCR in mice co-expressing one fluorescent signal with an astrocytic marker or a different fluorescent signal with a neuronal marker and treated for 14 days with carbamazepine. Following fluorescence-activated cell sorting of neurons and astrocytes it was shown that α2 Expression was upregulated in astrocytes and neurons and α1 selectively in neurons, but α3 was unchanged. ß1 was upregulated in astrocytes, but not in neurons. ß2 was unaffected in astrocytes and absent in neurons. FXYD7 was downregulated specifically in neurons. According to cited literature data these changes should facilitate K(+) uptake in neurons, without compromising preferential uptake in astrocytes at increased extracellular K(+) concentrations. This process seems to be important for K(+) homeostasis of the cellular level of the brain (Xu et al. Neurochem Res E-pub Dec. 12, 2012).

Differential regulation of vascular tone and remodeling via stimulation of type 2 and type 6 adenylyl cyclases in the ductus arteriosus.

RATIONALE: Prostaglandin (PG)E(2), which increases intracellular cAMP via activation of adenylyl cyclases (ACs), induces vasodilation and hyaluronan-mediated intimal thickening (IT) in the ductus arteriosus (DA) during late gestation. After birth, however, differential regulation of vasodilation and IT is preferable for treatment of patients with patent DA and DA-dependent congenital cardiac malformations. OBJECTIVE: Our objectives were to examine whether AC isoforms play differential roles in DA vasodilation and IT. METHODS AND RESULTS: AC2 and AC6 were more highly expressed in rat DA than in the aorta during the perinatal period. AC6-targeted siRNA counteracted PGE(1)-induced hyaluronan production in rat DA smooth muscle cells. Overexpression of AC6 enhanced PGE(1)-induced hyaluronan production and induced IT in DA explants. Furthermore, IT of the DA was less marked in mice lacking AC6 than in wild-type and AC5-deficient mice. Stimulation of AC2 attenuated AC6-induced hyaluronan production via inhibition of the p38 mitogen-activated protein kinase pathway and AC6-induced IT of the DA. An AC2/6 activator, 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] forskolin (FD1), did not induce hyaluronan-mediated IT in DA explants, although an AC5/6 activator, 6-[3-(dimethylamino)propionyl]-14,15-dihydroforskolin (FD6) did. Moreover, FD1 induced longer vasodilation of the DA than did PGE(1) without significant adverse effects in vivo. CONCLUSIONS: AC6 is responsible for hyaluronan-mediated IT of the DA and AC2 inhibited AC6-induced hyaluronan production. Stimulation of both AC2 and AC6 by FD1 induced longer vasodilation without hyaluronan-mediated IT in the DA in vivo. FD1 may be a novel alternative therapy to currently available PGE therapy for patients with DA-dependent congenital heart disease.

Diverse action of acrylamide on cytochrome P450 and glutathione S-transferase isozyme activities, mRNA levels and protein levels in human hepatocarcinoma cells.

Humans are exposed to acrylamide in their diet and cigarette smoke. Acrylamide is metabolized into glycidamide by CYP2E1. However, very few studies regarding the effects of acrylamide on cytochrome P450 and Glutathione S-Transferase (GST) isozymes have been pursued. The aim of this study is to elucidate the effects of acrylamide on cytochrome P450 and GST isozymes in HepG2 cell line. Treatment with 1.25 and 2.5 mM acrylamide caused 9.5- and 3.7-fold increases and 4.0- and 3.3-fold increases in CYP1A-associated ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities, respectively. These increases were consistent with increases in mRNA and protein levels of these isozymes. Similarly, CYP2E1-associated aniline 4-hydroxylase (ANH) activity, protein levels, and mRNA levels increased 2.1- and 2.6-fold, 2.4- and 3.2-fold, and 1.4- and 1.9-fold following 1.25 and 2.5 mM acrylamide treatments, respectively. In addition, GST-mu activity was increased 2.4- and 5.1-fold by acrylamide. Moreover, GST-mu mRNA and protein levels increased twofold as a result of acrylamide treatment. In contrast, GST-pi protein and mRNA levels decreased significantly. In conclusion, human cell exposure to acrylamide causes an increase in the levels of carcinogenicity and toxicity and a disturbance in drug metabolism, possibly due to complex effects on P450 and GST isozymes.

A dual function of the furanocoumarin chalepensin in inhibiting Cyp2a and inducing Cyp2b in mice: the protein stabilization and receptor-mediated activation.

Chalepensin, a furanocoumarin, is present in several medicinal Rutaceae plants and causes a mechanism-based inhibition of human and mouse cytochrome P450 (P450, CYP) 2A in vitro. To address the in vivo effect, we investigated the effects of chalepensin on multiple hepatic P450 enzymes in C57BL/6JNarl mice. Oral administration of 10 mg/kg chalepensin to mice for 7 days significantly decreased hepatic coumarin 7-hydroxylation (Cyp2a) and increased 7-pentoxyresorufin O-dealkylation (Cyp2b) activities, whereas activities of Cyp1a, Cyp2c, Cyp2e1, and Cyp3a were not affected. Without affecting its mRNA level, the decreased Cyp2a activity was accompanied by an increase in the immunodetected Cyp2a5 protein level. In chalepensin-treated mice, microsomal Cyp2a5 was less susceptible to ATP-fortified cytosolic degradation than that in control mice, resulting in the elevated protein level. The in vitro inactivation through NADPH-fortified pre-incubation with chalepensin also protected microsomal Cyp2a5 against protein degradation. Using cell-based reporter systems, chalepensin at a concentration near unbound plasma concentration activated mouse constitutive androstane receptor (CAR), in agreement with the observed induction of Cyp2b. These findings revealed that suicidal inhibition of Cyp2a5 and the CAR-mediated Cyp2b9/10 induction concurrently occurred in chalepensin-treated mice.

Inhibition of acetylcholinesterase activity in brain and behavioral analysis in adult rats after chronic administration of fenproporex.

Fenproporex is an amphetamine-based anorectic and it is rapidly converted in vivo into amphetamine. It elevates the levels of extracellular dopamine in the brain. Acetylcholinesterase is a regulatory enzyme which is involved in cholinergic synapses and may indirectly modulate the release of dopamine. Thus, we investigated whether the effects of chronic administration of fenproporex in adult rats alters acquisition and retention of avoidance memory and acetylcholinesterase activity. Adult male Wistar rats received repeated (14 days) intraperitoneal injection of vehicle or fenproporex (6.25, 12.5 or 25 mg/kg i.p.). For behavioral assessment, animals were submitted to inhibitory avoidance (IA) tasks and continuous multiple trials step-down inhibitory avoidance (CMIA). Acetylcholinesterase activity was measured in the prefrontal cortex, hippocampus, hypothalamus and striatum. The administration of fenproporex (6.25, 12.5 and 25 mg/kg) did not induce impairment in short and long-term IA or CMIA retention memory in rats. In addition, longer periods of exposure to fenproporex administration decreased acetylcholinesterase activity in prefrontal cortex and striatum of rats, but no alteration was verified in the hippocampus and hypothalamus. In conclusion, the present study showed that chronic fenproporex administration decreased acetylcholinesterase activity in the rat brain. However, longer periods of exposure to fenproporex did not produce impairment in short and long-term IA or CMIA retention memory in rats.