Colovic MB

References (7)

Title : The simultaneous action of acute paradoxical sleep deprivation and hypothyroidism modulates synaptosomal ATPases and acetylcholinesterase activities in rat brain - Todorovic_2023_Sleep.Med_105_14
Author(s) : Todorovic J , Dincic M , Krstic DZ , Colovic MB , Ostojic JN , Kovacevic S , Lopicic S , Spasic S , Brkic P , Milovanovic A
Ref : Sleep Med , 105 :14 , 2023
Abstract : BACKGROUND: Thyroid dysfunctions as well as sleep abnormalities are usually followed by neurological, psychiatric and/or behavioral disorders. On the other hand, changes in the brain adenosine triphosphatases (ATPases) and acetylcholinesterase (AChE) activities show significant importance in pathogenetic pathways in the evolution of numerous neuropsychiatric diseases. METHODS: This study aimed to evaluate the in vivo simultaneous effects of hypothyroidism and paradoxical sleep deprivation for 72 h on synaptosomalATPases and AChE activities of whole rat brains. In order to induce hypothyroidism, 6-n-propyl-2-thiouracil was administrated in drinking water during 21 days. The modified multiple platform method was used to induce paradoxical sleep deprivation. The AChE and ATPases activities were measured using spectrophotometric methods. RESULTS: Hypothyroidism significantly increased the activity of Na(+)/K(+)-ATPase compared to other groups, while at the same time significantly decreased AChE activity compared to the CT and SD groups. Paradoxical sleep deprivation significantly increased AChE activity compared to other groups. The simultaneous effect of hypothyroidism and sleep deprivation reduced the activity of all three enzymes (for Na(+)/K(+)-ATPase between HT/SD and HT group p < 0.0001, SD group p < 0.001,CT group p = 0.013; for ecto-ATPases between HT/SD and HT group p = 0.0034, SD group p = 0.0001, CT group p = 0.0007; for AChE between HT/SD and HT group p < 0.05, SD group p < 0.0001, CT group p < 0.0001). CONCLUSIONS: The effect of simultaneous existence of hypothyroidism and paradoxical sleep deprivation reduces the activity of the Na(+)/K(+)-ATPase, ecto-ATPases, and AChE, what is different from individual effect of hypothyroidism and paradoxical sleep deprivation itself. This knowledge could help in the choice of appropriate therapy in such condition.
ESTHER : Todorovic_2023_Sleep.Med_105_14
PubMedSearch : Todorovic_2023_Sleep.Med_105_14
PubMedID: 36940515

Title : A new acetylcholinesterase allosteric site responsible for binding voluminous negatively charged molecules - the role in the mechanism of AChE inhibition - Bondzic_2020_Eur.J.Pharm.Sci_151_105376
Author(s) : Bondzic AM , Lazarevic-Pasti TD , Leskovac AR , Petrovic SZ , Colovic MB , Parac-Vogt TN , Janjic GV
Ref : Eur J Pharm Sci , 151 :105376 , 2020
Abstract : Acetylcholinesterase (AChE) inhibitors are important in the treatment of neurodegenerative diseases. Two inhibitors, 12-tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA), which have polyoxometalate (POM) type structure, have been shown to inhibit AChE activity in nM concentration. Circular dichroism and tryptophan fluorescence spectroscopy demonstrated that the AChE inhibition was not accompanied by significant changes in the secondary structure of the enzyme. The molecular docking approach has revealed a new allosteric binding site, termed beta-allosteric site (beta-AS), which is considered responsible for the inhibition of AChE by POMs. To the best of our knowledge, this is the first study reporting a new allosteric site that is considered responsible for AChE inhibition by voluminous and negatively charged molecules such as POMs. The selected POMs were further subjected to genotoxicity testing using human peripheral blood cells as a model system. It was shown that WSiA and WPA induced a mild cytostatic but not genotoxic effects in human lymphocytes, which indicates their potential to be used as medicinal drugs. The identification of non-toxic compounds capable of binding to an allosteric site that so far has not been considered responsible for enzyme inhibition could be fundamental for the development of new drug design strategies and the discovery of more efficient AChE modulators.
ESTHER : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedSearch : Bondzic_2020_Eur.J.Pharm.Sci_151_105376
PubMedID: 32492460

Title : Modulation of rat synaptosomal ATPases and acetylcholinesterase activities induced by chronic exposure to the static magnetic field - Dincic_2018_Int.J.Radiat.Biol__1
Author(s) : Dincic M , Krstic DZ , Colovic MB , Nesovic Ostojic J , Kovacevic S , De Luka SR , Djordjevic DM , Cirkovic S , Brkic P , Todorovic J
Ref : Int J Radiat Biol , :1 , 2018
Abstract : PURPOSE: It is considered that exposure to static magnetic fields (SMF) may have both detrimental and therapeutic effect, but the mechanism of SMF influence on the living organisms is not well understood. Since the adenosine triphosphatases (ATPases) and acetylcholinesterase (AChE) are involved in both physiological and pathological processes, the modulation of Na(+)/K(+)-ATPase, ecto-ATPases and AChE activities, as well as oxidative stress responses were followed in synaptosomes isolated from rats after chronic exposure toward differently oriented SMF. MATERIAL AND METHODS: Wistar albino rats were randomly divided into three experimental groups (six animals per group): Up and Down group - exposed to upward and downward oriented SMF, respectively, and Control group. After 50 days, the rats were sacrificed, and synaptosomes were isolated from the whole rat brain and used for testing the enzyme activities and oxidative stress parameters. RESULTS: Chronic exposure to 1 mT SMF significantly increased ATPases, AChE activities, and malondialdehyde (MDA) level in both exposed groups, compared to control values. The significant decrease in synaptosomal catalase activity (1.48 +/- 0.17 U/mg protein) induced by exposure to the downward oriented field, compared to those obtained for Control group (2.60 +/- 0.29 U/mg protein), and Up group (2.72 +/- 0.21 U/mg protein). CONCLUSIONS: It could be concluded that chronic exposure to differently oriented SMF increases ATPases and AChE activities in rat synaptosomes. Since brain ATPases and AChE have important roles in the pathogenesis of several neurological diseases, SMF influence on the activity of these enzymes may have potential therapeutic importance.
ESTHER : Dincic_2018_Int.J.Radiat.Biol__1
PubMedSearch : Dincic_2018_Int.J.Radiat.Biol__1
PubMedID: 30238840

Title : Toxicity evaluation of two polyoxotungstates with anti-acetylcholinesterase activity - Colovic_2017_Toxicol.Appl.Pharmacol_333_68
Author(s) : Colovic MB , Medic B , Cetkovic M , Kravic Stevovic T , Stojanovic M , Ayass WW , Mougharbel AS , Radenkovic M , Prostran M , Kortz U , Krstic DZ
Ref : Toxicol Appl Pharmacol , 333 :68 , 2017
Abstract : A toxicity evaluation of two Keggin-type heteropolytungstates, K7[Ti2PW10O40].6H2O and K6H[SiV3W9O40].3H2O, with different inhibitory potencies toward acetylcholinesterase activity (IC50 values of 1.04x10-6 and 4.80x10-4mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of K6H[SiV3W9O40].3H2O. Accordingly, the toxicity of these two polyoxotungstates with anti-acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study.
ESTHER : Colovic_2017_Toxicol.Appl.Pharmacol_333_68
PubMedSearch : Colovic_2017_Toxicol.Appl.Pharmacol_333_68
PubMedID: 28830837

Title : In vitro evaluation of neurotoxicity potential and oxidative stress responses of diazinon and its degradation products in rat brain synaptosomes - Colovic_2015_Toxicol.Lett_233_29
Author(s) : Colovic MB , Vasic VM , Avramovic NS , Gajic MM , Djuric DM , Krstic DZ
Ref : Toxicol Lett , 233 :29 , 2015
Abstract : Although primary toxic action of organophosphorous insecticides is associated with acetylcholinesterase inhibition, later studies suggest that oxidative stress may be responsible for induced organophosphates toxicity. These studies mostly include thio forms, while the effects of their metabolites/degradation products have been less investigated. Therefore, this paper studies the toxic effects of diazinon degradation products, diazoxon and 2-isopropyl-6-methyl-4-pyrimidinol, and compares them with the toxic potential of the parent compound. The toxicity induced by various concentrations of the investigated compounds was in vitro evaluated by the activities of acetylcholinesterase, ATPases, antioxidant defense enzymes and lactate dehydrogenase, and malondialdehyde level in rat brain synaptosomes. Diazinon inhibited acetylcholinesterase and Na(+)/K(+)-ATPase in dose-dependent manner, while the inhibition of ecto-ATPase activity was less than 15% at all investigated concentrations. It did not demonstrate noteworthy prooxidative properties causing increase (up to 10%) in antioxidant enzymes activity and malondialdehyde level, as a marker of lipid peroxidation. Diazinon oxidation product, diazoxon was found as the most toxic investigated compound. Beside the expected strong inhibitory effect on acetylcholinesterase, it induced dose-dependent and almost complete inhibition of Na(+)/K(+)-ATPase and ecto-ATPase at the highest investigated concentration (0.1mM). Increasing diazoxon concentrations activated catalase (up to 30%), superoxide dismutase (up to 50%), glutathione peroxidase (up to 30%), and significantly increased malondialdehyde level (up to 50%). The investigated hydrolysis product of diazinon, 2-isopropyl-6-methyl-4-pyrimidinol did not remarkably alter the activities of acetylcholinesterase, Na(+)/K(+)-ATPase, catalase, glutathione peroxidase and lipid peroxidation level (up to about 10%). Although this diazinon metabolite has been known as non toxic, it induced superoxide dismutase stimulation up to 30%. Finally, even high concentrations of both diazinon and its metabolites did noticeably affect lactate dehydrogenase activity as a marker of synaptosomal integrity. The changes in investigated biochemical parameters in rat brain synaptosomes could serve as indicators of toxicity due to the exposure to thio organophosphates and/or their break-down products.
ESTHER : Colovic_2015_Toxicol.Lett_233_29
PubMedSearch : Colovic_2015_Toxicol.Lett_233_29
PubMedID: 25562544

Title : Acetylcholinesterase inhibitors: pharmacology and toxicology - Colovic_2013_Curr.Neuropharmacol_11_315
Author(s) : Colovic MB , Krstic DZ , Lazarevic-Pasti TD , Bondzic AM , Vasic VM
Ref : Curr Neuropharmacol , 11 :315 , 2013
Abstract : Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer's disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.
ESTHER : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedSearch : Colovic_2013_Curr.Neuropharmacol_11_315
PubMedID: 24179466

Title : Single and simultaneous exposure of acetylcholinesterase to diazinon, chlorpyrifos and their photodegradation products - Colovic_2011_Pestic.Biochem.Physiol_100_16
Author(s) : Colovic MB , Krstic DZ , Uscumlic GS , Vasic VM
Ref : Pesticide Biochemistry and Physiology , 100 :16 , 2011
Abstract : In vitro inhibition of electric eel acetylcholinesterase (AChE) by single and simultaneous exposure to organophosphorus insecticides diazinon and chlorpyrifos, and their transformation products, formed due to photoinduced degradation, was investigated. Increasing concentrations of diazinon, chlorpyrifos and their oxidation products, diazoxon and chlorpyrifos-oxon, inhibited AChE in a concentration-dependent manner. IC50 (20 min) values, obtained from the inhibition curves, were (in mol/l): (5.1 +/- 0.3) 10-8, (4.3 +/- 0.2) 10-6 and (3.0 +/- 0.1) 10-8 for diazoxon, chlorpyrifos and chlorpyrifos-oxon, respectively, while maximal diazinon concentration was lower than its IC50 (20 min). Calculated KI values, in mol/l, of 7.9 10-7, 9.6 10-6 and 4.3 10-7 were obtained for diazoxon, chlorpyrifos and chlorpyrifos-oxon, respectively. However, 2-isopropyl-4-methyl-6-pyrimidinol (IMP) and 3,5,6-trichloro-2-pyridinol, diazinon and chlorpyrifos hydrolysis products, did not noticeably affect the enzyme activity at all investigated concentrations. Additive inhibition effect was achieved for lower concentrations of the inhibitors (diazinon/diazoxon -1 10-4/1 10-8 mol/l i.e., chlorpyrifos/chlorpyrifos-oxon -2 10-6/3 10-8 mol/l), while an antagonistic effect was obtained for all higher concentrations of the organophosphates. Inhibitory power of 1 10-4 mol/l diazinon irradiated samples can be attributed mostly to the formation of diazoxon, while the presence of non-inhibiting photodegradation product IMP did not affect diazinon and diazoxon inhibitory efficiencies.
ESTHER : Colovic_2011_Pestic.Biochem.Physiol_100_16
PubMedSearch : Colovic_2011_Pestic.Biochem.Physiol_100_16