RESUMEN
The aim of this study was to compare plant-soil interactions in the native range of two congeneric European species differing in their invasive success in the world: a globally invasive Cirsium vulgare and non-invasive C. oleraceum. We assessed changes in soil nutrients and soil biota following soil conditioning by each species and compared performance of plants grown in self-conditioned and unconditioned soil, from which all, some or no biota was excluded. The invasive species depleted more nutrients than the non-invasive species and coped better with altered nutrient levels. The invasive species had higher seedling establishment which benefited from the presence of unconditioned biota transferred by soil filtrate. Biomass of both species increased in soil with self-conditioned soil filtrate and decreased in soil with self-conditioned whole-soil inoculum compared to unconditioned filtrate and inoculum. However, the increase was smaller and the decrease greater for the invasive species. The invasive species allocated less biomass to roots when associated with harmful biota, reducing negative effects of the biota on its performance. The results show that in the native range the invasive species is more limited by self-conditioned pathogens and benefits more from unconditioned mutualists and thus may benefit more from loss of effectively specialized soil biota in a secondary range. Our study highlights the utility of detailed plant-soil feedback research in species native range for understanding factors regulating species performance in their native range and pinpointing the types of biota involved in their regulation.
Asunto(s)
Micorrizas , Micorrizas/fisiología , Suelo , Microbiología del Suelo , Raíces de Plantas , Especies Introducidas , PlantasRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with ß-secretase (BACE1) activity, Aß peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Aß peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Amantadina/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Tacrina/análogos & derivados , Enfermedad de Alzheimer/metabolismo , Amantadina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Células CHO , Colinesterasas/metabolismo , Cricetulus , Dimerización , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Terapia Molecular Dirigida , Receptor Muscarínico M1/antagonistas & inhibidores , Receptor Muscarínico M1/metabolismo , Receptores Colinérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Tacrina/química , Tacrina/farmacología , XenopusRESUMEN
Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors.
Asunto(s)
Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer , Inhibidores de la Colinesterasa/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Monitoreo de Drogas/métodos , Pruebas de Enzimas , Humanos , Nootrópicos/farmacología , Transmisión Sináptica/efectos de los fármacosRESUMEN
INTRODUCTION: Alzheimer's disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD. AREAS COVERED: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options. EXPERT OPINION: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/uso terapéutico , Memantina/uso terapéutico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/fisiopatología , Animales , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/farmacología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Diseño de Fármacos , Antagonistas de Aminoácidos Excitadores/efectos adversos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Memantina/efectos adversos , Memantina/farmacología , Resultado del TratamientoRESUMEN
Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Tacrina/análogos & derivados , Tacrina/farmacología , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Butyrylcholinesterase (BChE) is an enzyme presented in quite high level in blood plasma where it participates in detoxification reactions. Due to fact that the enzyme is constituted in livers, it is a marker of liver parenchyma function. It can be used for diagnosis of poisoning for e.g., nerve agents or carbofuran and intoxication by some drugs such as rivastigmine. The present experiment is devoted for the creation of new spectrophotometric tests for assay of BChE activity in biological samples. Standard Ellman's method was compared with use of 2,6-dichloroindophenol acetate and indoxylacetate as chromogenic substrates. Maximal velocities and Michaelis constants were calculated for the substrates. Considering calibration, 2,6-dichloroindophenol acetate provided the lowest limit of detection: 1.20 × 10(-9)kat and a long linear range. All methods were verified using pooled human plasma samples and tested for potential interferents. 2,6-dichloroindophenol acetate is recommended as suitable substrate for BChE assay in clinical diagnostics.
Asunto(s)
2,6-Dicloroindofenol/química , Butirilcolinesterasa/sangre , Indoles/química , Espectrofotometría/métodos , Acetatos , Biomarcadores/sangre , Humanos , Cinética , Límite de Detección , Hígado/enzimología , Especificidad por SustratoRESUMEN
A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC50 value of 0.47 µM for hAChE and an IC50 value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Amantadina/uso terapéutico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/uso terapéutico , Dimerización , Modelos Moleculares , Tacrina/análogos & derivados , Acetilcolinesterasa/metabolismo , Amantadina/síntesis química , Amantadina/química , Amantadina/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Pruebas de Enzimas , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estándares de Referencia , Tacrina/síntesis química , Tacrina/química , Tacrina/farmacología , Tacrina/uso terapéutico , Tiourea/químicaRESUMEN
OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder. Symptomatic treatment is available by inhibitors of acetylcholinesterase (AChE) such as rivastigmine, galantamine and donepezil. As huperzine is a promising compound for AD treatment, our study was aimed at evaluating its pertinent implications in oxidative stress. METHODS: Laboratory guinea pigs were exposed to huperzine A at doses of 0, 5, 25, 125 and 625 µg/kg. The animals were observed for cognitive disorders and sacrificed one hour after exposure. Tonic-clonic seizures were noticed, but only in highly dosed animals. Ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), glutathione reductase and glutathione S-transferase were assessed in frontal, temporal and parietal lobes, the cerebellum, liver, spleen and kidney. RESULTS: Only minimal changes in enzymatic markers were recognized. Huperzine was not implicated in oxidative stress enhancement as the TBARS values remained quite stable. Surprisingly, antioxidants accumulated in the examined brain compartments as the FRAP value was significantly elevated following all doses of huperzine. CONCLUSIONS: We discuss the potency of huperzine in enhancing the antioxidant capacity of the central nervous system. Huperzine is probably implicated in more processes than cholinesterase inhibition only.